oSIST prEN ISO 10993-4:2026

• Abstract:

  ISO 10993-4:2017 specifies general requirements for evaluating the interactions of medical devices with blood.; It describes; a) a classification of medical devices that are intended for use in contact with blood, based on the intended use and duration of contact as defined in ISO 10993‑1,; b) the fundamental principles governing the evaluation of the interaction of devices with blood,; c) the rationale for structured selection of tests according to specific categories, together with the principles and scientific basis of these tests.; Detailed requirements for testing cannot be specified because of limitations in the knowledge and precision of tests for evaluating interactions of devices with blood. This document describes biological evaluation in general terms and may not necessarily provide sufficient guidance for test methods for a specific device.; The changes in this document do not indicate that testing conducted according to prior versions of this document is invalid. For marketed devices with a history of safe clinical use, additional testing according to this revision is not recommended.

• Status: Not Published
• Public Enquiry End Date: 22-Sep-2026
• ICS: 11.100.20 - Biological evaluation of medical devices
• Technical Committee: VAZ - Healthcare
• Current Stage: 4020 - Public enquire (PE) (Adopted Project)
• Start Date: 09-Jul-2026
• Due Date: 26-Nov-2026
• Directive: Harmonized Standard2017/745 - Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC
• Mandate: M/575 - Medical devices in support of Regulation (EU) 2017/745 and in vitro diagnostic medical devices in support of Regulation (EU) 2017/746
• Mandate: M/575 AMD 2 - Medical devices in support of Regulation (EU) 2017/745 and in vitro diagnostic medicial devices in support of Regulation (EU) 2017746
• Ref Project: prEN ISO 10993-4 - Biological evaluation of medical devices - Part 4: Selection of tests for interactions with blood (ISO/DIS 10993-4:2026)

• Revises: SIST EN ISO 10993-4:2017 - Biological evaluation of medical devices - Part 4: Selection of tests for interactions with blood (ISO 10993-4:2017)
• Effective Date: 05-Nov-2024
• Revises: SIST EN ISO 10993-4:2017/A1:2025 - Biological evaluation of medical devices - Part 4: Selection of tests for interactions with blood - Amendment 1 (ISO 10993-4:2017/Amd 1:2025)
• Effective Date: 05-Nov-2024

Overview

oSIST prEN ISO 10993-4:2026 - Biological evaluation of medical devices - Part 4: Selection of tests for interactions with blood - establishes the general requirements for assessing how medical devices interact with blood. Developed by SIST, this draft international standard provides a structured approach for classifying blood-contacting medical devices and selecting relevant biological tests, supporting regulatory compliance, patient safety, and device efficacy.

This standard is part of the ISO 10993 series, which is recognized worldwide for biocompatibility evaluation of medical devices. The focus of Part 4 is specifically the safe, science-based evaluation of devices intended for direct or indirect blood contact, addressing the unique risks associated with blood-device interactions.

Key Topics

• Device Classification: Outlines a system for categorizing medical devices based on type and duration of blood contact, referencing ISO 10993-1. Devices are classified as non-blood-contacting, indirectly blood-contacting (external communicating), or directly blood-contacting (including implanted devices).

• Evaluation Principles: Describes fundamental principles to systematically evaluate blood interactions, with emphasis on simulating clinical conditions such as flow, temperature, and anticoagulation.

• Test Selection Rationale: Provides guidance for the structured selection of test types (in vitro, ex vivo, and in vivo), supported by current scientific knowledge and regulatory expectations.

• Limitations of Testing: Acknowledges that no single set of test methods can address all potential blood interactions for every device. The standard provides general direction, stressing the importance of risk analysis and clinical context.

• Test Categories: Highlights essential categories for evaluation, such as thrombosis, haemolysis, platelet activation, coagulation, complement activation, and haematology. Appropriate controls and rationales are required for every test setup.

• Regulatory Alignment: Emphasizes consistency with General Safety and Performance Requirements (as per EU Medical Device Regulation 2017/745) and the integration of clinical history for already-marketed devices.

Applications

Organizations and manufacturers use ISO 10993-4:2026 for:

• Regulatory Submissions: Meeting requirements for CE marking in Europe or approvals in other jurisdictions by demonstrating the safety of blood-contacting device components.

• Risk Management: Conducting effective risk assessments and implementing mitigation strategies for device-induced adverse blood reactions such as thrombosis or haemolysis.

• Design and Development: Informing design specifications and material selection for devices such as catheters, stents, valves, blood tubing, extracorporeal circuits, and implantable devices.

• Routine Evaluation: Applying a scientific, repeatable framework for ongoing biological evaluation of devices throughout their lifecycle.

• Predicate Device Comparisons: Using established devices with documented clinical safety (legally-marketed comparator devices) as reference controls in testing new, similar devices.

Related Standards

For a comprehensive biological evaluation of medical devices, ISO 10993-4:2026 refers to and works in conjunction with several other key standards, including:

• ISO 10993-1: General principles for biological evaluation within a risk management process
• ISO 10993-12: Sample preparation and reference materials for biological testing
• ISO/TS 10993-20: Guidance on the scientific basis for test selection and methodology
• ISO 10993 Series: Full scope of biocompatibility, including cytotoxicity, sensitization, and systemic effects

Additionally, device-specific "vertical standards" (e.g., for cardiovascular implants or dialysis equipment) may provide further, more detailed requirements that take precedence over the general directions in ISO 10993-4:2026.

Summary

Implementing oSIST prEN ISO 10993-4:2026 supports effective, compliant biological evaluation of medical devices that interact with blood, from rapid assessment of established device types to the safe development of novel technologies. This standard is critical for medical device manufacturers, regulatory professionals, and clinical teams seeking to promote device safety and regulatory compliance in international markets.

SLOVENSKI STANDARD
01-september-2026
Biološko ovrednotenje medicinskih pripomočkov - 4. del: Izbira preskusov za
ugotavljanje interakcij s krvjo (ISO/DIS 10993-4:2026)
Biological evaluation of medical devices - Part 4: Selection of tests for interactions with
blood (ISO/DIS 10993-4:2026)
Biologische Beurteilung von Medizinprodukten - Teil 4: Auswahl von Prüfungen zur
Wechselwirkung mit Blut (ISO/DIS 10993-4:2026)
Évaluation biologique des dispositifs médicaux - Partie 4: Choix des essais pour les
interactions avec le sang (ISO/DIS 10993-4:2026)
Ta slovenski standard je istoveten z: prEN ISO 10993-4
ICS:
11.100.20 Biološko ovrednotenje Biological evaluation of
medicinskih pripomočkov medical devices
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

DRAFT
International
Standard
ISO/DIS 10993-4
ISO/TC 194
Biological evaluation of medical
Secretariat: DIN
devices —
Voting begins on:
Part 4: 2026-07-01
Selection of tests for interactions
Voting terminates on:
2026-09-23
with blood
Évaluation biologique des dispositifs médicaux —
Partie 4: Choix des essais pour les interactions avec le sang
ICS: 11.100.20; 11.100
THIS DOCUMENT IS A DRAFT CIRCULATED
FOR COMMENTS AND APPROVAL. IT
IS THEREFORE SUBJECT TO CHANGE
AND MAY NOT BE REFERRED TO AS AN
INTERNATIONAL STANDARD UNTIL
PUBLISHED AS SUCH.
This document is circulated as received from the committee secretariat.
IN ADDITION TO THEIR EVALUATION AS
BEING ACCEPTABLE FOR INDUSTRIAL,
TECHNOLOGICAL, COMMERCIAL AND
USER PURPOSES, DRAFT INTERNATIONAL
STANDARDS MAY ON OCCASION HAVE TO
ISO/CEN PARALLEL PROCESSING
BE CONSIDERED IN THE LIGHT OF THEIR
POTENTIAL TO BECOME STANDARDS TO
WHICH REFERENCE MAY BE MADE IN
NATIONAL REGULATIONS.
RECIPIENTS OF THIS DRAFT ARE INVITED
TO SUBMIT, WITH THEIR COMMENTS,
NOTIFICATION OF ANY RELEVANT PATENT
RIGHTS OF WHICH THEY ARE AWARE AND TO
PROVIDE SUPPORTING DOCUMENTATION.
Reference number
ISO/DIS 10993-4:2026(en)
DRAFT
ISO/DIS 10993-4:2026(en)
International
Standard
ISO/DIS 10993-4
ISO/TC 194
Biological evaluation of medical
Secretariat: DIN
devices —
Voting begins on:
Part 4:
Selection of tests for interactions
Voting terminates on:
with blood
Évaluation biologique des dispositifs médicaux —
Partie 4: Choix des essais pour les interactions avec le sang
ICS: 11.100.20; 11.100
THIS DOCUMENT IS A DRAFT CIRCULATED
FOR COMMENTS AND APPROVAL. IT
IS THEREFORE SUBJECT TO CHANGE
AND MAY NOT BE REFERRED TO AS AN
INTERNATIONAL STANDARD UNTIL
PUBLISHED AS SUCH.
This document is circulated as received from the committee secretariat.
IN ADDITION TO THEIR EVALUATION AS
BEING ACCEPTABLE FOR INDUSTRIAL,
© ISO 2026
TECHNOLOGICAL, COMMERCIAL AND
USER PURPOSES, DRAFT INTERNATIONAL
All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may
STANDARDS MAY ON OCCASION HAVE TO
ISO/CEN PARALLEL PROCESSING
be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting on
BE CONSIDERED IN THE LIGHT OF THEIR
the internet or an intranet, without prior written permission. Permission can be requested from either ISO at the address below
POTENTIAL TO BECOME STANDARDS TO
WHICH REFERENCE MAY BE MADE IN
or ISO’s member body in the country of the requester.
NATIONAL REGULATIONS.
ISO copyright office
RECIPIENTS OF THIS DRAFT ARE INVITED
CP 401 • Ch. de Blandonnet 8
TO SUBMIT, WITH THEIR COMMENTS,
CH-1214 Vernier, Geneva
NOTIFICATION OF ANY RELEVANT PATENT
Phone: [phone]
RIGHTS OF WHICH THEY ARE AWARE AND TO
PROVIDE SUPPORTING DOCUMENTATION.
Email: [e-mail]
Website: www.iso.org
Published in Switzerland Reference number
ISO/DIS 10993-4:2026(en)
ii
ISO/DIS 10993-4:2026(en)
Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 Abbreviated terms . 4
5 Types of devices in contact with blood (as categorized in ISO 10993-1) . 5
5.1 Non-blood-contact devices .5
5.2 External communicating devices . .5
5.2.1 General .5
5.2.2 External communicating devices that indirectly contacting blood .5
5.2.3 External communicating devices directly contacting circulating blood .5
5.3 Implant devices .6
6 Characterization of blood interactions . 6
6.1 General requirements .6
6.2 Categories of tests and blood interactions .16
6.2.1 Recommended tests for interactions of devices with blood .16
6.2.2 Pass-Fail Criteria .17
6.2.3 Non-contact devices .17
6.2.4 External communicating devices and implant devices.17
6.2.5 Limitations .17
6.3 Types of tests .17
6.3.1 In vitro tests .17
6.3.2 Ex vivo tests .18
6.3.3 In vivo tests .18
Annex A (informative) Preclinical evaluation of cardiovascular devices and prostheses .20
Annex B (informative) Recommended laboratory tests — Principles, scientific basis and
interpretation .25
Annex C (informative) Thrombosis — Methods for in vivo testing .37
Annex D (informative) Haematology/haemolysis — Methods for testing — Evaluation of
haemolytic properties of medical devices and medical device materials .43
Annex E (informative) Complement — Methods for testing .51
Annex F (informative) Less common laboratory tests .54
Annex G (informative) Tests which are not recommended .58
Annex ZA (informative) Relationship between this European Standard the General Safety and
Performance Requirements of Regulation (EU) 2017/745 aimed to be covered .60
Bibliography .62

iii
ISO/DIS 10993-4:2026(en)
Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards
bodies (ISO member bodies). The work of preparing International Standards is normally carried out through
ISO 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. ISO collaborates closely
with the International Electrotechnical Commission (IEC) on all matters of electrotechnical standardization.
The procedures used to develop this document and those intended for its further maintenance are described
in the ISO/IEC Directives, Part 1. In particular the different approval criteria needed for the different types
of ISO documents should be noted. This document was drafted in accordance with the editorial rules of the
ISO/IEC Directives, Part 2 (see www.iso.org/directives).
Attention is drawn to the possibility that some of the elements of this document may be the subject of patent
rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of any patent
rights identified during the development of the document will be in the Introduction and/or on the ISO list of
patent declarations received (see www.iso.org/patents).
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation on the voluntary nature of standards, the meaning of ISO specific terms and
expressions related to conformity assessment, as well as information about ISO's adherence to the World
Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT) see the following URL:
www.iso.org/iso/foreword.html.
This document was prepared by Technical Committee ISO/TC 194, Biological and clinical evaluation of medical
devices, in collaboration with the European Committee for Standardization (CEN) Technical Committee
CEN/TC 206, Biocompatibility of medical and dental materials and devices, in accordance with the Agreement
on technical cooperation between ISO and CEN (Vienna Agreement).
This fourth edition cancels and replaces the third edition (ISO 10993-4:2017), which has been technically
revised.
The following changes were made:
— Reference to ISO/TR 10993-20 was replaced by ISO/TS 10993-20;
— Definitions to “indirect blood contact” and “legally-marketed comparator device” were updated;
— Table 1 in 6.1.6 was updated;
— Figure 2 was updated;
— Bibliography was updated;
— Annex ZA was added to reflect the relationship between this European Standard the General Safety and
Performance Requirements of Regulation (EU) 2017/745 aimed to be covered
The changes in this document do not indicate that testing conducted according to prior versions of this
document is invalid. For marketed devices with a history of safe clinical use, additional testing according to
this revision is not recommended.

iv
ISO/DIS 10993-4:2026(en)
Introduction
The selection and design of test methods for the interactions of medical devices with blood should take
into consideration device design, materials, clinical utility, usage environment and risk benefit. This level of
specificity can only be covered in vertical standards.
The initial source for developing this document was the publication, Guidelines for blood/material
[17]
interactions, Report of the National Heart, Lung, and Blood Institute chapters 9 and 10. This publication
[18]
was subsequently revised .
v
DRAFT International Standard ISO/DIS 10993-4:2026(en)
Biological evaluation of medical devices —
Part 4:
Selection of tests for interactions with blood
1 Scope
This document specifies general requirements for evaluating the interactions of medical devices with blood.
It describes
a) a classification of medical devices that are intended for use in contact with blood, based on the intended
use and duration of contact as defined in ISO 10993-1,
b) the fundamental principles governing the evaluation of the interaction of devices with blood,
c) the rationale for structured selection of tests according to specific categories, together with the
principles and scientific basis of these tests.
Detailed requirements for testing cannot be specified because of limitations in the knowledge and precision
of tests for evaluating interactions of devices with blood. This document describes biological evaluation in
general terms and may not necessarily provide sufficient guidance for test methods for a specific device.
2 Normative references
The following documents are referred to in the text in such a way that some or all of their content constitutes
requirements of this document. For dated references, only the edition cited applies. For undated references,
the latest edition of the referenced document (including any amendments) applies.
ISO 10993-1, Biological evaluation of medical devices — Part 1: Requirements and general principles for the
evaluation of biological safety within a risk management process
ISO 10993-12, Biological evaluation of medical devices — Part 12: Sample preparation and reference materials
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 10993-1, ISO 10993-12 and the
following apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
— IEC Electropedia: available at https:// www .electropedia .org/
— ISO Online browsing platform: available at https:// www .iso .org/ obp
3.1
anticoagulant
agent which prevents or delays blood coagulation
EXAMPLE Heparin, ethylenediaminetetraacetic acid (EDTA), sodium citrate.
3.2
blood/device interaction
interaction between blood or a blood component and a device

ISO/DIS 10993-4:2026(en)
3.3
coagulation
phenomenon that results from activation of the clotting (coagulation) factor cascade
Note 1 to entry: Factors of the coagulation cascade and fibrinolytic systems can be measured following exposure to
devices either in vitro or in vivo.
3.4
complement system
part of the innate immune system consisting of over 30 distinct plasma proteins, including enzymes,
cofactors, and cellular receptors which may be involved in the promotion of thrombosis
Note 1 to entry: Effector molecules produced from complement components are possible components in the phenomena
of inflammation, phagocytosis and cell lysis. Complement activation related to immunotoxicity, hypersensitivity and
generation of anaphylatoxins is not covered in this document. (See ISO/TS 10993-20.)
Note 2 to entry: The focus in this document is complement activation as it can promote and accelerate haemolysis,
platelet and leukocyte activation and thrombosis on device material surfaces. (See also Annex E on complement
activation.)
3.5
direct blood contact
term used when the device or device material comes into physical contact with blood or blood constituents
3.6
embolization
process whereby a blood thrombus, or foreign object, is carried in the bloodstream and which may become
lodged and cause obstructed blood flow downstream
3.7
ex vivo test system
term applied to a test system that shunts blood directly from a human subject or test animal into a test
chamber located outside the body
Note 1 to entry: If using an animal model, the blood may be shunted directly back into the animal (recirculating) or
collected in test tubes for evaluation (single pass). In either case, the test chamber is located outside the body.
3.8
haematology
study of blood that includes quantification of cellular and plasma components of the blood
3.9
haematocrit
ratio of the volume of erythrocytes to that of whole blood in a given sample
3.10
haemolysis
liberation of haemoglobin from erythrocytes, either by destruction or through a partially damaged but
intact cell membrane
3.11
haemocompatible
able to come into contact with blood without any appreciable clinically-
significant adverse reactions such as thrombosis, haemolysis (3.10), platelet, leukocyte, and complement
activation, and/or other blood-associated adverse event occurring
3.12
indirect blood contact
nature of devices that contact the patient’s blood path at one point and serve as a conduit for entry into
the vascular system or devices that contact cerebrospinal fluid (CSF) as CSF is reabsorbed into the venous
system
EXAMPLE Drug and parenteral nutrition solution delivery devices.

ISO/DIS 10993-4:2026(en)
3.13
legally-marketed comparator device
LMCD
approved, or cleared currently marketed medical device that is recognized to be safe based on the history
of safe clinical use, used as a reference control in an in vitro or in vivo safety evaluation of a test device of
similar design, material(s), and clinical use
Note 1 to entry: It may be necessary that the LMCD be legally marketed in the same region as the regulatory submission
for the test device.
3.14
non-blood-contact
nature of the device or material contact with the patient’s body where the device or potentially extracted
material does not have direct or indirect contact with blood
3.15
colloidal osmotic pressure
total influence of the proteins or other large molecular mass substances on the osmotic activity of plasma
3.16
platelets
anuclear, cellular bodies that are present in blood and contribute to the process of thrombosis by adhering
to surfaces, releasing factors, and/or aggregating to form a haemostatic plug
3.17
platelet adherent
having the tendency to allow or promote platelets (3.16) to attach to its surface
Note 1 to entry: This is often characterized relative to a negative control, positive control, and/or LMCD upon blood
contact due to its surface properties.
Note 2 to entry: Platelet adherent does not necessarily mean platelet activating, i.e. platelets on a surface may or may
not be activated.
3.18
thrombin generating
due to its surface properties, having the tendency to promote or show increased
thrombin formation
Note 1 to entry: This is often characterized relative to a negative control, positive control, and/or LMCD upon blood
contact.
3.19
thrombogenic
due to its surface properties, having the tendency to form or promote thrombus
formation
Note 1 to entry: This is often characterized relative to a negative control, positive control, and/or LMCD upon blood
contact.
3.20
thromboembolization
process where a dislodged thrombus (3.21) is carried downstream, where it may cause subsequent vascular
blockage or occlusion
3.21
thrombus
coagulated mixture of red blood cells, aggregated platelets (3.16), fibrin and other cellular elements

ISO/DIS 10993-4:2026(en)
3.22
thrombosis
formation of a thrombus (3.21) under in vivo, ex vivo, or in vitro simulated conditions, caused by activation of
the coagulation system and platelets (3.16) in flowing whole blood
Note 1 to entry: Thrombosis can also occur in regions of a blood vessel or device where there is stasis.
3.23
whole blood
unfractionated blood drawn from a human donor or test animal
Note 1 to entry: The blood may be non-anticoagulated or anticoagulated, e.g. contain sodium citrate or heparin as an
anticoagulant.
4 Abbreviated terms
Bb enzymatically active fragment of Factor B produced by cleavage (by Factor D) in the
activation of the alternative pathway
β-TG beta-thromboglobulin
C4d degradation product of C4 by classical pathway complement activation
C3a, C5a complement split products from C3 and C5
CH-50 amount of complement required to lyse 50 % of an RBC suspension
D-Dimer specific fibrin degradation products (F XIII cross-linked fibrin) consisting of
D-fragment dimer
ELISA enzyme-linked immunosorbent assay
FDP fibrin/fibrinogen degradation products
FPA fibrinopeptide A
F1.2 the non-catalytic fragment split off from prothrombin in its conversion to thrombin (also re-
ferred to as F1+2)
iC3b inactive form of C3b, a sub-fragment of C3
IFU instruction for use
IVC inferior vena cava
LMCD legally marketed comparator device
MSC mechanical circulatory support
MRI magnetic resonance imaging
PET positron emission tomography
PF-4 platelet factor 4
PFH plasma free hemoglobin
PRP platelet-rich plasma
PT prothrombin time
ISO/DIS 10993-4:2026(en)
PTT partial thromboplastin time
SC5b-9 product of terminal pathway complement activation
SEM scanning electron microscopy
TAT thrombin-antithrombin complexe
TCC terminal complement complex; also called membrane attack complex (MAC); estimated by
measuring SC5b-9
TT thrombin time
TxB2 thromboxane B2
5 Types of devices in contact with blood (as categorized in ISO 10993-1)
5.1 Non-blood-contact devices
Non-blood-contact devices are devices that do not have direct or indirect contact with either blood or blood
constituents that reside in the body or that are returned to the body. An in vitro diagnostic device and a
blood-collection tube are examples of non-blood-contact devices. Some devices, such as introducer systems
for implants, may contain both blood-contacting and non-blood-contacting components.
5.2 External communicating devices
5.2.1 General
These are devices that contact the circulating blood and serve as a conduit into the vascular system. Some
devices may have components or portions with different types of contact (direct and indirect). Examples
include but are not limited to the following.
5.2.2 External communicating devices that indirectly contacting blood
— blood monitors with indirect blood contact.
— devices for the storage and administration of saline and/or therapeutics (e.g. tubing and bags);
— extension sets;
5.2.3 External communicating devices directly contacting circulating blood
— atherectomy devices;
— blood collection devices;
— blood monitoring devices with direct blood contact;
— cannulae;
— cardiopulmonary bypass circuitry;
— cell savers;
— devices for adsorption of specific substances from blood;
— devices for the storage and administration of blood and blood products (e.g. tubing and bags);
— donor and therapeutic apheresis equipment;

ISO/DIS 10993-4:2026(en)
— extracorporeal membrane oxygenators;
— haemodialysis/haemofiltration devices;
— interventional cardiology and vascular devices;
— intravascular catheters (balloon, imaging, laser, ultrasound);
— leukocyte removal filters;
— percutaneous circulatory support devices;
— retrograde coronary perfusion catheters;
— vascular guide wires.
5.3 Implant devices
Implant devices are placed largely or entirely within the vascular system. Examples include but are not
limited to the following:
— annuloplasty rings;
— arteriovenous shunts;
— blood monitors (implantable);
— circulatory support devices (ventricular-assist devices, artificial hearts, intra-aortic balloon pumps);
— embolization devices;
— endovascular synthetic vascular grafts;
— implantable defibrillator and cardioverter leads;
— inferior vena cava filters;
— internal drug delivery catheters;
— intravascular oxygenators (artificial lungs);
— mechanical or tissue heart valves;
— pacemaker leads;
— surgical synthetic or tissue vascular grafts;
— vascular stents.
6 Characterization of blood interactions
6.1 General requirements
IMPORTANT — Since this is a horizontal International Standard, sound rationales can be supplied
to justify the choice of test category(ies) based on the device being characterized. For example, for
devices with prolonged and long-term blood contact, in vivo testing for evidence of thrombosis is
typically needed for device characterization in the thrombosis category. For many devices with
limited blood contact, in vitro thrombogenicity testing under clinically relevant or well-defined
blood flow conditions can generally be used, if the test is appropriately designed. In some cases, with
written rationales, a panel of material-mediated tests (e,g., test tube models with defined gentle
agitation) from the categories of coagulation, platelets, haematology and complement can be used
for thrombogenicity evaluation.

ISO/DIS 10993-4:2026(en)
Note on written rationales: In general, the predictive nature of an in vitro test is significantly related to the
test’s use of blood exposure conditions that mimic intended clinical use. Thus, use of in vitro tests using
acute benchtop exposure conditions is generally most applicable to acute blood contact conditions rather
than permanent exposure applications. Consequently, written rationales should highlight and contrast
important factors of the in vitro vs. clinical use conditions. Such factors include but are not limited to blood
exposure duration, type of blood flow, and use of antithrombotic drugs, blood freshness, etc.
6.1.1 Figure 1 illustrates a decision tree that can be used to determine whether testing for interaction
with blood is necessary. Blood interactions can be divided into several categories based on the primary
process or system being measured. Table 1 lists examples of devices which contact circulating blood and
the categories of testing appropriate to each device. The list is not all inclusive and sound judgement shall be
applied to devices not listed in the tables.
For medical devices where a specific International Standard (vertical standard) exists, the biological
evaluation requirements and test methods set forth in that vertical standard shall take precedence over the
general requirements suggested in this document.
6.1.2 Where possible, tests shall use an appropriate model or system which simulates the geometry and
conditions of contact of the device with blood during clinical applications. The simulation should include
an appropriate duration of contact, temperature, sterile condition, anticoagulant (and level; see 6.1.12)
and flow conditions. As stated in ISO 10993-12, clause 7: "Testing shall be performed on the final product,
representative samples from the final product, materials processed in the same manner as the final product
(see ISO 10993-1), or on appropriate extracts of any of these. The choice of test sample shall be justified."
Only direct or indirect blood-contacting parts should be tested. For direct contact haemocompatibility
testing (e.g., direct haemolysis, complement activation, coagulation, platelet activation, haematology, in
vitro/ex vivo thrombosis), testing should be conducted using only the direct blood contacting components of
the device to minimize interference of non-direct blood contacting components on the results. For extract-
based haemocompatibility testing (e.g., indirect haemolysis), testing should be conducted using only the
direct and indirect blood-contacting components of the device. The test article shall be described, and a
justification shall be provided if the test article includes device components that include different tissue
contact than described above. The selected test methods and parameters should be in accordance with the
current state of the art.
Appropriate type and level of anticoagulant may be case specific depending on both the device use indication
and the type of test conducted. Include information on the specific type and level of anticoagulation used
and provide a discussion on the ability to discern positive and negative responses. For further information,
see 6.1.6 and C.2 for animal studies, 6.1.12 for in vivo and ex vivo tests, 6.3.1 for in vitro tests and A.3 for
catheters and guide wires.
As many tests for haemocompatibility are recognized to be generally surface-contact dependent (e.g., direct
contact haemolysis, complement activation, coagulation, platelet activation, haematology, and in vitro/ex
vivo thrombosis) such tests will not apply to indirect contact applications. For externally communicating
medical devices or components that have indirect blood contact, generally only an indirect contact
haemolysis test is recommended.
6.1.3 Controls (positive and negative) shall be used unless their omission can be justified. Where possible,
testing should include a relevant predicate device already in clinical use (i.e. a LMCD) or a well-characterized
material (see ISO 10993-1 for more information) .
Controls should include negative and positive reference materials. All materials and LMCDs tested shall
meet all quality control and quality assurance specifications of the manufacturer and test laboratory. All
materials and devices tested shall be identified as to source, manufacturer, grade and type.
6.1.4 Testing of materials which are candidates for components of a device may be conducted for
screening purposes. However, such preliminary tests do not serve as a substitute for the requirement that
the complete sterilized device or device component should be tested under conditions which simulate or
exaggerate clinical application.

ISO/DIS 10993-4:2026(en)
NOTE 1 Changes in manufacturing process e.g., change in manufacturer, use of different manufacturing aids that
can affect the surface properties, or chemistry of the complete sterilized device, can also impact haemocompatibility.
NOTE 2 Where aging could impact the final device properties, use of aged samples can also be necessary. (For
example, the properties of biologically active coatings such as heparin could change over time.)
6.1.5 Tests which do not simulate the conditions of a device during use may not predict accurately the
nature of the blood/device interactions which can occur during clinical applications. In addition, the capacity
of short-term in vitro or ex vivo tests to predict performance in actual clinical applications is thought to
be higher when the clinical application involves limited exposure rather than prolonged or permanent
exposure.
NOTE Simplified testing of candidate device materials (e.g. surface geometric and functional chemical
modifications) can serve as a crucial step in device material identification, optimization and selection.
6.1.6 If an animal study is to be conducted, devices whose intended use is ex vivo (external communication)
should be tested ex vivo and devices whose intended use is in vivo (implants) should be tested in vivo in an
animal model simulating as closely as possible conditions of clinical use. Protocols in such investigations
should specifically call out each test category (see 6.2.1) being evaluated and describe the specific method(s)
of assessment. See Figures 1 and 2.

ISO/DIS 10993-4:2026(en)
a
For direct and indirect contact devices, the necessity for haemocompatibility testing should be considered
based upon appropriate risk analysis, including prior haemocompatibility testing, clinical data, extractable/
leachable data, and/or information on surface characteristics. For example, for devices with direct contact,

ISO/DIS 10993-4:2026(en)
extractable/leachable testing may not be sufficient if the surface morphology is changed, even if the
extractable/leachable chemistry is the same (see ISO 10993-1).
Figure 1 — Decision tree to help determine whether testing for interaction with blood is necessary

ISO/DIS 10993-4:2026(en)
Table 1 — Circulating blood-contacting devices or device components and the categories of appropriate testing for consideration —
External communicating devices and implant devices
Test category
c
Thrombosis
Haemolysis
Device examples
In vitro
In vivo/
Platelet activa- a
d Ex vivo
Material-induced Mechanically-induced Coagulation Complement Haematology
tion
e
External communicating devices indirectly contacting blood
Blood monitors with indirect blood contact X
Devices for storage and administration of saline and/or therapeu-
X
tics (e.g. tubing and bags), extension sets
b
External communicating devices directly contacting circulating blood
Blood collection devices X X X X
f
Blood administration sets and extension sets X X X X X
Catheters (e.g. atherectomy devices, intravascular ultrasound
catheters, antegrade/retrograde coronary perfusion catheters, X X X X X
guide wires); cannulae
Cell savers X X X X
Devices for adsorption of specific substances from blood X X X X X
Donor and therapeutic aphaeresis equipment and cell separation
X X X X X
systems
Cardiopulmonary bypass system and components X X X X X X X
Haemodialysis/haemofiltration equipment X X X X X X X
Leukocyte removal filter X X X X X X
Percutaneous circulatory support devices X X X X X X X
Implant devices
Annuloplasty rings, mechanical heart valves X X  X
a
Thrombosis is an in vivo or ex vivo phenomenon but can be simulated with in vitro conditions. In vivo or ex vivo testing might not be necessary if appropriate and validated in vitro thrombosis testing is performed.
b
Some examples here may contain other components with indirect blood contact. For device components that only have indirect blood contact, direct contact material-induced haemolysis, mechanical haemolysis, thrombosis,
and complement activation may not be necessary. For direct blood contacting devices, both direct and indirect contact haemolysis testing is recommended. For components with indirect blood contact, generally only an indirect
contact haemolysis test is recommended.
c
It is recognized that coagulation, platelet, and leucocyte responses are primarily involved in the process of thrombosis. Therefore, in vitro thrombogenicity methods can be acceptable in place of in vivo testing if scientifically
justified. The manufacturer should justify which specific testing in the coagulation, platelet and haematology test categories is appropriate for their devices. NOTE: Many of these markers are obtained by conducting commercially-
available and validated clinical tests on human plasma generated from an appropriate human blood in vitro model and study design. For example, see [27] and [210].
d
Complement activation testing is also requested by certain regulatory authorities to address other end points such as anaphylaxis for all devices with direct blood contact.
e
Except for devices composed of novel materials, each test in the category of thrombosis is generally not necessary for indirect blood contact devices.
f
For blood administration sets without using mechanical pumps, mechanically induced haemolysis testing is generally not necessary.
g
For devices that are designed to promote blood clotting (e.g., embolization devices or hemostatic devices) testing to characterize pro-thrombogenic properties may be needed. In addition, the risk of thromboembolism in
non-targeted blood vessels associated with the use of prothrombotic devices should be adequately evaluated using appropriate in vivo test models.

ISO/DIS 10993-4:2026(en)
Table 1 (continued)
Test category
c
Thrombosis
Haemolysis
Device examples
In vitro
In vivo/
a
Platelet activa-
Ex vivo
d
Material-induced Mechanically-induced Coagulation Complement Haematology
tion
g
Embolization devices X   X
Endovascular grafts X   X
Implantable defibrillator and cardioverter leads X   X
Intra-aortic balloon pumps X X  X
Pacemaker leads X   X
Prosthetic (synthetic) vascular grafts and patches, including
X   X
arteriovenous shunts
Stents (vascular) X   X
Tissue heart valves, vascular grafts and patches and AV shunts X   X
Total artificial hearts X X  X
Vena cava filters X   X
Ventricular-assist devices X X  X
a
Thrombosis is an in vivo or ex vivo phenomenon but can be simulated with in vitro conditions. In vivo or ex vivo testing might not be necessary if appropriate and validated in vitro thrombosis testing is performed.
b
Some examples here may contain other components with indirect blood contact. For device components that only have indirect blood contact, direct contact material-induced haemolysis, mechanical haemolysis, thrombosis,
and complement activation may not be necessary. For direct blood contacting devices, both direct and indirect contact haemolysis testing is recommended. For components with indirect blood contact, generally only an indirect
contact haemolysis test is recommended.
c
It is recognized that coagulation, platelet, and leucocyte responses are primarily involved in the process of thrombosis. Therefore, in vitro thrombogenicity methods can be acceptable in place of in vivo testing if scientifically
justified. The manufacturer should justify which specific testing in the coagulation, platelet and haematology test categories is appropriate for their devices. NOTE: Many of these markers are obtained by conducting commercially-
available and validated clinical tests on human plasma generated from an appropriate human blood in vitro model and study design. For example, see [27] and [210].
d
Complement activation testing is also requested by certain regulatory authorities to address other end points such as anaphylaxis for all devices with direct blood contact.
e
Except for devices composed of novel materials, each test in the category of thrombosis is generally not necessary for indirect blood contact devices.
f
For blood administration sets without using mechanical pumps, mechanically induced haemolysis testing is generally not necessary.
g
For devices that are designed to promote blood clotting (e.g., embolization devices or hemostatic devices) testing to characterize pro-thrombogenic properties may be needed. In addition, the risk of thromboembolism in
non-targeted blood vessels associated with the use of prothrombotic devices should be adequately evaluated using appropriate in vivo test models.

ISO/DIS 10993-4:2026(en)
6.1.7 In vitro tests are regarded as useful in screening external communicating devices or implants and
potential early interactions between devices/materials with blood, but may not be accurate predictors of
blood/device interactions occurring upon prolonged or repeated exposure or permanent contact (see 6.3.1).
NOTE 1 Example in vitro models: 1.Test Tube (references X, Y, Z), 2. Closed Loop (references A, B, C), Odd Geometry
(references D, E, F; e.g., SpinVessel), Device Specific Models (references G, H, I).
NOTE2 For new devices or devices where there is a change in geometry, testing under physiologic flow can be
needed. For long-term catheters or permanent implants, in vitro test systems might not be sufficient due to blood
stability issues.
6.1.8 Devices or device components which come into very brief/transient contact with circulating blood
(e.g. lancets, hypodermic needles, capillary tubes that are used for less than 1 min) generally do not require
blood/device interaction testing.
NOTE 1 For products made with materials such as coatings that could be left in contact with blood after the device
is removed, blood/device interaction testing might be necessary.
NOTE 2 If some device components (e.g. syringe bodies) are in contact with fluids that will ultimately be injected
into the patient, and the storage time is unspecified or greater than 1 min, haemolysis testing of the fluid-contacting
component would be needed, even though the device itself would be in contact with circulating blood for less than
1 min.
6.1.9 Disposable laboratory equipment used for the collection of blood and performance of in vitro tests on
blood shall be evaluated to ascertain that there is no significant interference with the test being performed.
6.1.10 If tests are selected in the manner described and testing is conducted under conditions which
simulate clinical applications, the results of such testing have the greatest probability of predicting clinical
performance of devices. For devices that operate over a range of conditions, the extreme and the average
conditions should be considered. However, species differences and other factors may limit the predictability
of any test.
6.1.11 Because of species differences in blood reactivity, human blood should be used where possible (with
the exception of established test methods with animal blood, such as some haemolysis tests).
...