ISO/TS 24560-1:2022
(Main)Tissue-engineered medical products — MRI evaluation of cartilage — Part 1: Clinical evaluation of regenerative knee articular cartilage using delayed gadolimium-enhanced MRI of cartilage (dGEMRIC) and T2 mapping
Tissue-engineered medical products — MRI evaluation of cartilage — Part 1: Clinical evaluation of regenerative knee articular cartilage using delayed gadolimium-enhanced MRI of cartilage (dGEMRIC) and T2 mapping
This document provides a principle to determine the parameter settings and operating methods for the evaluation of the composition and structure of articular cartilage by dGEMRIC and T2-mapping MRI in humans with a typical example of the methods; each are distinct MRI technologies that allow for noninvasive observation of soft tissue characteristics. The methods provided in this document are intended for application in the evaluation of the clinical effects of tissue-engineered cartilage or other cartilage regeneration products used in the knee joint, and are also applicable for the evaluation of regenerative cartilage in other joints, although some modification of parameters is needed. This document describes a longitudinal evaluation of the water content, the glycosaminoglycan (GAG) concentration, and the concentration and orientation of collagen fibres in regenerative cartilage when using dGEMRIC and T2-mapping techniques in 1,5 T or 3,0 T magnetic resonance imaging equipment.
Produits médicaux issus de l'ingénierie tissulaire — Évaluation du cartilage par IRM — Partie 1: Évaluation clinique de la régénération du cartilage articulaire du genou par séquences IRM tardives après injection de gadolinium (dGEMRIC) et cartographie T2
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TECHNICAL ISO/TS
SPECIFICATION 24560-1
First edition
2022-07
Tissue-engineered medical
products — MRI evaluation of
cartilage —
Part 1:
Clinical evaluation of regenerative
knee articular cartilage using delayed
gadolimium-enhanced MRI of
cartilage (dGEMRIC) and T2 mapping
Produits médicaux issus de l'ingénierie tissulaire — Évaluation du
cartilage par IRM —
Partie 1: Évaluation clinique de la régénération du cartilage
articulaire du genou par séquences IRM tardives après injection de
gadolinium (dGEMRIC) et cartographie T2
Reference number
ISO/TS 24560-1:2022(E)
© ISO 2022
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ISO/TS 24560-1:2022(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2022
All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may
be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting on
the internet or an intranet, without prior written permission. Permission can be requested from either ISO at the address below
or ISO’s member body in the country of the requester.ISO copyright office
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Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
© ISO 2022 – All rights reserved
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ISO/TS 24560-1:2022(E)
Contents Page
Foreword ........................................................................................................................................................................................................................................iv
Introduction .................................................................................................................................................................................................................................v
1 Scope ................................................................................................................................................................................................................................. 1
2 Normative references ..................................................................................................................................................................................... 1
3 Terms and definitions .................................................................................................................................................................................... 1
4 Principles ..................................................................................................................................................................................................................... 3
5 T2 mapping evaluation in human knee articular cartilage ................................................................................... 4
5.1 Characterization parameters and methods ................................................................................................................. 4
5.2 T2 value measurement process ............................................................................................................................................... 6
5.2.1 Post-processing of imaging ....................................................................................................................................... 6
5.2.2 Measurement method .................................................................................................................................................... 6
5.2.3 ROIs of regenerative cartilage ................................................................................................................................ 7
5.2.4 ROIs of normal control cartilage .......................................................................................................................... 8
5.3 T2 value evaluation ............................................................................................................................................................................ 8
5.3.1 Purpose of evaluation .................................................................................................................................................... 8
5.3.2 In vivo evaluation of regenerative cartilage with T2 value ......................................................... 8
6 dGEMRIC evaluation in human knee articular cartilage .......................................................................................... 9
6.1 Characterization parameters and methods ................................................................................................................. 9
6.2 T1 value measurement process ............................................................................................................................................ 11
6.2.1 Post-processing of imaging .................................................................................................................................... 11
6.2.2 Measurement method ................................................................................................................................................. 11
6.2.3 ROIs of regenerative cartilage .............................................................................................................................12
6.2.4 ROIs of normal control cartilage .......................................................................................................................12
6.3 ΔR1 value calculation .................................................................................................................................................................... 12
6.4 ΔR1 value evaluation .....................................................................................................................................................................12
6.4.1 Purpose of evaluation .................................................................................................................................................12
6.4.2 In vivo evaluation of regenerative cartilage with ΔR1 values ................................................13
7 Acceptable standard for MR evaluation ...................................................................................................................................14
7.1 Requirements for MR equipment ........................................................................................................................................ 14
7.2 Requirements for MR parameters...................................................................................................................................... 14
7.3 Requirements for the MR longitudinally evaluation ......................................................................................... 14
7.4 Exclusion criteria .............................................................................................................................................................................. 14
8 Limitation .................................................................................................................................................................................................................15
Annex A (informative) Example of measurement results ..........................................................................................................16
Annex B (informative) Introduction of T1ρ MR Imaging technology ............................................................................26
Bibliography .............................................................................................................................................................................................................................28
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ISO/TS 24560-1:2022(E)
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 of 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
www.iso.org/iso/foreword.html.This document was prepared by Technical Committee ISO/TC 150, Implants for surgery, Subcommittee
SC 7, Tissue-engineered medical products.Any feedback or questions on this document should be directed to the user’s national standards body. A
complete listing of these bodies can be found at www.iso.org/members.html.© ISO 2022 – All rights reserved
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ISO/TS 24560-1:2022(E)
Introduction
Tissue-engineered cartilage has shown desirable results for the repair of cartilage defects, and histologic
findings indicate that the repaired tissue has a hyaline-like cartilage structure. Kang H.J. et al., Zheng
M.H. et al. and Behrens P. et al. reported that the histologic change after matrix-associated autologous
[1-3]chondrocyte implantation/transplantation (MACI/MACT) was a hyaline-like cartilage. The knee
articular cartilage can also be repaired or regenerated via other tissue engineering approaches using
other seed cells such as mesenchymal stem cells or even by tissue regeneration free of external seed
[4-6]cells . MACI and other approaches lead to a maturation of the cartilage matrix over time with the
development of an organized collagen architecture. For long-term follow-up of regenerative cartilage,
clinical scores and morphological evaluations are commonly used. Furthermore, histological evaluation
from arthroscopic biopsies provides a gold standard for morphological and biochemical assessments
of regenerative cartilage tissue. However, this process is invasive and unacceptable for patients after
cartilage repair surgery. Magnetic resonance (MR) is a noninvasive technique that can be used for the
evaluation of a cartilage microstructure. Xu X and other researchers reported that MR-based biochemical
imaging techniques, such as delayed gadolinium-enhanced MRI of the cartilage (dGEMRIC) and T2
[7-12]mapping, show the capability of evaluating the biochemical character of articular cartilage . The
T2 relaxation time is sensitive to the content of effective hydrogen atoms, and thus to the concentration
[13]of collagen, the main component of cartilage extracellular matrix . Besides, the orientation changes
in the collagen network of articular cartilage produce the depthwise T2 anisotropy through the magic
[14]angle effect . The dGEMRIC technique enables an indirect estimation of the fixed charge density (FCD)
[15]of cartilage, which mainly arises from the aggregated proteoglycan biomacromolecules . Since both
collagen and proteoglycan components are important for determining the functional characteristics
of cartilage, a combination of T2 mapping and dGEMRIC techniques provides a better evaluation of
articular regenerative cartilage. Therefore, standardization of T2 mapping and dGEMRIC techniques is
needed for the evaluation of regenerative articular cartilage.This document is intended to guide the clinical biochemical evaluation of regenerative articular
cartilage with MR. dGEMRIC and T2 mapping are recommended for the clinical evaluation of
regenerative cartilage. These techniques have been used for patients who received tissue-engineered
cartilage implantation or transplantation (MACI/MACT). The validation data from different hospitals
are provided Annex A.This document provides general principles for imaging and the measurement method of T2 mapping
and dGEMRIC of knee cartilage using 1,5 T or 3,0 T MRI equipment. These techniques are also applicable
for other articular cartilage, such as the ankle joint, hip joint, and shoulder joint, but the imaging
parameters should be adjusted and modified for better image quality.© ISO 2022 – All rights reserved
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TECHNICAL SPECIFICATION ISO/TS 24560-1:2022(E)
Tissue-engineered medical products — MRI evaluation of
cartilage —
Part 1:
Clinical evaluation of regenerative knee articular cartilage
using delayed gadolimium-enhanced MRI of cartilage
(dGEMRIC) and T2 mapping
1 Scope
This document provides a principle to determine the parameter settings and operating methods for the
evaluation of the composition and structure of articular cartilage by dGEMRIC and T2-mapping MRI
in humans with a typical example of the methods; each are distinct MRI technologies that allow for
noninvasive observation of soft tissue characteristics.The methods provided in this document are intended for application in the evaluation of the clinical
effects of tissue-engineered cartilage or other cartilage regeneration products used in the knee joint,
and are also applicable for the evaluation of regenerative cartilage in other joints, although some
modification of parameters is needed.This document describes a longitudinal evaluation of the water content, the glycosaminoglycan (GAG)
concentration, and the concentration and orientation of collagen fibres in regenerative cartilage when
using dGEMRIC and T2-mapping techniques in 1,5 T or 3,0 T magnetic resonance imaging equipment.
2 Normative referencesThere are no normative references in this document.
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
ISO and IEC maintain terminology databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at https:// www .iso .org/ obp— IEC Electropedia: available at https:// www .electropedia .org/
3.1
pulse sequences
train of programmed radio frequency pulses and gradient pulses
Note 1 to entry: In MRI, it is a time protocol for encoding images to obtain k-space data.
3.2number of averages
number of repeated acquired identical MR signals from the same programmed pulse sequence
3.3voxel
three-dimensional cuboid representing the minimum unit comprising a three-dimensional image
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ISO/TS 24560-1:2022(E)
3.4
pixel
two-dimensional cuboid representing the minimum unit comprising an image
3.5
field of view
FOV
width and height of an imaged region
Note 1 to entry: It is expressed in cm by cm or mm by mm.
3.6
matrix
array of scalars arranged in frequency encoding direction and phase encoding direction in a two-
dimensional MR imageNote 1 to entry: It is typically expressed in number of pixels in frequency encoding direction by number of pixels
in phase encoding direction.Note 2 to entry: In MRI, the scalars in the array are called pixel of the matrix.
3.7slice thickness
thickness of the imaging plane
Note 1 to entry: It is expressed in cm or mm.
3.8
signal-to-noise ratio
SNR
single number obtained by dividing the image signal by the image noise
3.9
region of interest
ROI
user-defined area on an image in which parameter of interested is calculated
3.10
echo time
time from the centre of the 90-degree excitation RF-pulse to the centre of the echo
Note 1 to entry: It is expressed in ms.3.11
repetition time
time interval for repetition of the basic unit of magnetic resonance pulse sequences
Note 1 to entry: It is expressed in ms.3.12
proton density-weighted image
PDWI
magnetic resonance image reflecting the concentration of protons in tissue
3.13
matrix-associated autologous chondrocyte implantation/transplantation
MACI/MACT
procedure involving expansion of autologous chondrocytes and seeding the cells onto a three-
dimensional biomaterial scaffold© ISO 2022 – All rights reserved
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ISO/TS 24560-1:2022(E)
3.14
scaffold
support or structural component or delivery vehicle, or matrix, consisting of synthetic and/or naturally-
derived material(s), for modulating the biological properties or transport of administered and/or
endogenous cells and/or binding/transport of bioactive agentsNote 1 to entry: Biological properties include (but are not limited to) adhesion, migration, proliferation, and
differentiation.[SOURCE: ASTM F2312 -11: 2020, Clause 4]
3.15
gradient recalled echo
GRE
MR sequence that generates gradient echoes as a consequence of echo refocusing
3.16
delayedgadolinium enhanced MRI of the cartilage
dGEMRIC
pre-contrast and post-contrast T1 mapping of cartilage
3.17
longitudinal relaxation time
time taking for the longitudinal magnetization to recover approximately 63 % of its initial value after
being flipped into the magnetic transverse plane by a 90° radiofrequency pulseNote 1 to entry: It is expressed in ms.
3.18
transverse relaxation time
time taking for the magnetic resonance signal to irreversibly decay to 37 % of its initial value after
being flipped into the magnetic transverse plane by a 90° radiofrequency pulseNote 1 to entry: It is expressed in ms.
3.19
T1 mapping
two-dimensional spatial distributions of T1 value of tissue
3.20
T2 mapping
two-dimensional spatial distributions of T2 value of tissue
3.21
longitudinal relaxation rate calculated as 1/T1
4 Principles
Articular cartilage is a type of hyaline cartilage that is characterized by an extracellular matrix that
[16]contains a fine network of collagen and proteoglycan . In regenerative articular cartilage, it is
important to evaluate whether the implanted tissues regenerate to hyaline or hyaline-like cartilage
with time. MRI is a noninvasive technique that can provide an indirect method for assessing the
composition and microstructure of articular regenerative cartilage, including content and organization
[12],[17]of the collagen network and the proteoglycan, as the main component in the extracellular matrix .
Delayed gadolinium enhanced MRI of the cartilage (dGEMRIC) is a technique pertinent to the T1
relaxation-time measurement that uses the negative ionic charge of gadopentetate dimeglumine (Gd-
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ISO/TS 24560-1:2022(E)
2- 2-
DTPA ) to map the fixed charge density of the cartilage GAG. Gd-DTPA is repelled by negatively
charged GAGs and is therefore negatively related to the local proteoglycan concentration. Consequently,
Gd-DTPA accumulates in areas of low GAG content, and a cartilage will have a shorter T1 relaxation
time in these regions. The ability to measure spatial variations in the cartilage GAG concentration in
vitro with dGEMRIC has been validated biochemically and histologically using both bovine and human
cartilage. The feasibility of using dGEMRIC in vivo has also been demonstrated, and the interpretation
[18-21]of MR images as representing a GAG distribution is supported by literature evidence . The GAG is a
component of normal hyaline cartilage that is critical to its mechanical strength. Thus, as a noninvasive
method of indirectly monitoring the GAG concentration in cartilage, dGEMRIC is a potentially useful
method for assessing regenerative cartilage.[22]
T2 mapping usually involves imaging at several echo times along the T2 decay curve and T2
relaxation time of different tissues can be calculated after data processing. In cartilage, changes in the
T2-relaxation times are dependent upon the quantity of water and the integrity of the proteoglycan–
collagen matrix. T2 relaxation time mapping provides an indirect assessment of the collagen structure
and orientation as it relates to the free water content. The presence of unbound water molecules slows
the loss of transverse magnetization following an RF pulse, such that regions of cartilage with more free
water have higher T2 relaxation times. In healthy cartilage, the collagen matrix traps and immobilizes
water molecules. When this structured matrix breaks down, the extra space is filled with free, unbound
water, and leads to elevated T2 relaxation times. The correlation between T2 relaxation time mapping
[23],[24]and the collagen content has been validated, both in vitro and in vivo . The T2 value of cartilage is
a dipolar interaction due to the slow anisotropic motion of water molecules in the collagen matrix and
[14],[25]varies as a function of the collagen arrangement in the static magnetic field , the strength of this
interaction is orientation-dependent and reaches its minimum at an angle of 54,7 (between the static
field and the axis of interacting protons, the so-called “magic angle”. Consequently, T2 changes along
cartilage thickness are reported to follow the orientational changes in the collagen fibril network.
Using appropriate arrangement of the articular surface with respect to the B0 field the resulting
laminated appearance in T2 maps approximately corresponds to the histological collagenous zones: the
superficial zone (orientation of collagen fibrils parallel to the articular surface), the transitional zone
(random fibril orientation) and the deep or radial zone (fibrils perpendicular to the articular surface
and perpendicular to the bone), which reveals the spatial collagen architecture in articular cartilage.
This spatial variation is a marker for hyaline-like matrix organization after cartilage repair.
MACI/MACT uses biomaterial scaffolds (natural or synthetic materials) as a carrier and seeds cells of
autologous chondrocytes. The repaired tissue can develop an organized collagen network, which is the
[1-3],[26],[27]basis for histological characterization of normal hyaline articular cartilage over time . It is
possible to longitudinally evaluate the water content, the GAG concentration, and the concentration and
orientation of collagen fibres in regenerative cartilage after MACI/MACT by using the dGEMRIC and T2
mapping techniques.In this document, T2 mapping and dGEMRIC data obtained from subjects who received MACI using
different MRI equipment are included Annex A.5 T2 mapping evaluation in human knee articular cartilage
5.1 Characterization parameters and methods
The 1,5 T or 3,0 T magnetic resonance imaging equipment and multichannel phased-array knee coil
are recommended for T2 mapping examination of knee cartilage. It is recommended to use the same
field strength equipment for longitudinal evaluation to avoid the influence of static magnetic field B0
on the relaxation time of the tissue. Before MRI examinations, the subject should rest for more than
30 min to avoid mechanical loading by exercise, which can influence the T2 value of knee cartilage. B0
and B1 shimming is highly recommended before scanning the T2-mapping sequence for every patient.
Sagittal proton density-weighted images with fat saturation (FS-PDWI) and three-dimensional gradient
recalled echo (3D-GRE) pulse sequences are recommended for morphological evaluation of cartilage.
3D-GRE pulse sequences with spoiled gradient (such as SPGR, FLASH, and VIBE) or steady-state free
precession (such as DESS) can be chosen in different MR manufactures. The pixel size in plane of the
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ISO/TS 24560-1:2022(E)
3D-GRE pulse sequence should be consistent with pixel size in plane of the T2 mapping sequence, which
can ensure the accuracy of the image fusion registration.A regularly repeated phantom test is recommended to ensure the status and stability of the MR system.
Phantom-based quality control is required after any change in the MR system hardware and software.
The protocol of T2 mapping consists of a sagittal, multi-echo spin echo pulse sequence for T2
measurement. Table 1 lists the recommended imaging parameters of T2 mapping in 1,5 T and 3,0 T MR
equipment, as a reference.Table 1 — Recommended Magnetic resonance parameters of T2 mapping evaluation
T2 mapping
Parameters
1,5 T 3,0 T
FOV (mm x mm) 160 × 160 160 × 160
TR (ms) range 1 200 to 2 000 range 1 200 to 2 000
multiple TE (no less than 4 echo times), more multiple TE (no less than 4 echo times), more
echo times corresponds to more accurate echo times corresponds to more accurateTE (ms)
T2 calculation, and the maximum echo time T2 calculation, and the maximum echo time
should be shorter than 80 ms should be shorter than 80 msParallel the acceleration factor should be no larger the acceleration factor should be no larger
acquisition than 2 than 2Matrix no less than 256 × 256 no less than 320 × 320
Pixel size in plane
no larger than 0,6 × 0,6 no larger than 0,5 × 0,5
(mm )
Number of
1 or 2 1 or 2
averages (NA)
Slice thickness
3 is recommended (ranging 3,0 to 4,0) 3 is recommended (ranging 3,0 to 4,0)
(mm)
Image plane sagittal plane sagittal plane
Number of slices no more than 30 slices no more than 30 slices
NOTE The parameters were suggested to be adjusted with different MR equipment and different signal-receiving coil.
MR examination of PDWI and T1-weighted 3D-GRE pulse sequences should achieve the following
standards:a) the field of view (FOV) should be no larger than 160 mm × 160 mm and no smaller than 140 mm ×
140 mm;b) the pixel size in plane of the PDWI pulse sequence should not be larger than 0,5 mm × 0,5 mm in 3,0
Tesla MRI equipment and should not be larger than 0,6 mm x 0,6 mm in 1,5 Tesla MRI equipment;
c) a 3,0-4,0 mm slice thickness is suggested in the PDWI pulse sequence;d) for image matching, some parameters, such as FOV, the scanning centre and slice thickness, are
suggested to be kept the same for both PDWI and T2 mapping;e) the voxel size of the 3D-GRE pulse sequence should be isotropic and not larger than 0,5 mm ×
0,5 mm × 0,5 mm in 3,0 Tesla MRI equipment and should not be larger than 0,6 mm × 0,6 mm ×
0,6 mm in 1,5 Tesla MRI equipment;f) the fat-saturation technique is suggested in PDWI and 3D-GRE pulse sequences, such as water-
excitation or fat water separation methods;g) imaging with high resolution can require multiple signal averages in 1,5 Tesla MR equipment for a
higher signal-to-noise ratio (SNR);© ISO 2022 – All rights reserved
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ISO/TS 24560-1:2022(E)
h) if images are acquired with fat suppression, lowering the imaging bandwidth improves the overall
SNR.5.2 T2 value measurement process
5.2.1 Post-processing of imaging
Post-processing of the multiple images generated by the T2 mapping sequences can be performed
online on the scanner or offline using algorithms written in separate programs, such as MATLAB (the
MathworksInc, Natick, MA). Automated processing on the scanner typically generates a pixel-by-pixel
map of T2 relaxation times, and the T2 maps can be overlain on anatomical images through image
registration. Generally, sagittal PDW images and 3D-GRE images are recommended for morphological
evaluation of regenerative cartilage and native cartilage. PDW images are sensitive to the signal
abnormality of regenerative tissue, and 3D-GRE pulse sequence is used to obtain anatomical images for
its high resolution. T2 map images can be registered to 3D GRE images for verification of regenerative
cartilage and native cartilage (see Figure 1).5.2.2 Measurement method
T2 relaxation time is obtained by pixel-wise mono-exponential fitting of signal decay at different echo
times, and discarding the first echo for curve fitting is recommended in post-processing to minimize
[28]the error in T2 . If the regenerative cartilage showed longer T2 component not covered by the entire
ETL, bi-exponential curves including the offset as an additional parameter should be applied and the
corresponding model can be manually selected in the MATLAB software for imaging processing.
The SE pulse sequence signal intensity (S) shall be calculated by Formula (1).SM=×()11−−expT()RT//×−expT()ET2 (1)
where
S is the SE pulse sequence signal intensity;
M is equilibrium longitudinal magnetization;
TR is the repetition time;
T1 is the longitudinal relaxation time;
TE is the echo time;
T2 is the transverse relaxation time.
When TR>>T1, (1-exp(-TR/T1)) approaches 1. When TR is not much longer than T1(mostly in multi
echo spin echo T2 mapping sequence), TR is fixed, and the T1 value of the tissue is also relatively fixed
...© ISO 2022 – All rights reserved
ISO/TS 24560-1 (E)
ISO TC 150/SC 7
Date: 2022-06-07
Secretariat: JISC
Tissue Engineered Medical Products –-engineered medical products — MRI
Evaluationevaluation of Cartilage–cartilage — Part 1: Clinical
Evaluationevaluation of Regenerative Knee Articular Cartilage Using
Delayed Gadolinium-Enhancedregenerative knee articular cartilage using delayed
gadolimium-enhanced MRI of the Cartilagecartilage (dGEMRIC) and T2
Mappingmapping
TS stage
Warning for WDs and CDs
This document is not an ISO International Standard. It is distributed for review and comment. It is subject to
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https://www.iso.org/iso/how-to-write-standards.pdfA model manuscript of a draft International Standard (known as “The Rice Model”) is available at
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© ISO 2021
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ISO/TS 24560-1:2022(E)
© ISO 2022
All rights reserved. Unless otherwise specified, or required in the context of its implementation, no
part of this publication may be reproduced or utilized otherwise in any form or by any means,
electronic or mechanical, including photocopying, or posting on the internet or an intranet, without
prior written permission. Permission can be requested from either ISO at the address below or ISO’s
member body in the country of the requester.ISO copyright office
CP 401 • Ch. de Blandonnet 8
CH-1214 Vernier, Geneva
Phone: +41 22 749 01 11
Email: copyright@iso.org
Website: www.iso.orgwww.iso.org
Published in Switzerland
4 © ISO 2022 – All rights reserved
iv © ISO 2022 – All rights reserved
---------------------- Page: 3 ----------------------
ISO/TS 24560-1:2022(E)
Contents
Foreword ..................................................................................................................................................................... i7
Introduction ................................................................................................................................................................ 8
1 Scope ................................................................................................................................................................ 1
2 Normative references ................................................................................................................................ 1
3 Terms and definitions ................................................................................................................................ 1
4 Principles ....................................................................................................................................................... 4
5 T2 mapping evaluation in human knee articular cartilage ........................................................... 6
5.1 Characterization parameters and methods ........................................................................................ 6
5.2 T2 value measurement process .............................................................................................................. 7
5.3 T2 value evaluation .................................................................................................................................. 10
6 dGEMRIC evaluation in human knee articular cartilage ............................................................... 12
6.1 Characterization parameters and methods ...................................................................................... 12
6.2 T1 value measurement process ............................................................................................................ 14
6.3 ΔR1 value calculation ............................................................................................................................... 15
6.4 ΔR1 value evaluation ................................................................................................................................ 16
7 Acceptable standard for MR evaluation ............................................................................................. 19
7.1 Requirements for MR equipment ......................................................................................................... 19
7.2 Requirements for MR parameters ....................................................................................................... 19
7.3 Requirements for the MR longitudinally evaluation ..................................................................... 19
7.4 Exclusion criteria ....................................................................................................................................... 19
8 Limitation..................................................................................................................................................... 15
Annex A (informative) Example of measurement results ......................................................................... 21
Annex B (informative) A introduction of T1ρ MR Imaging technology ................................................. 34
Bibliography ............................................................................................................................................................. 36
Foreword ..................................................................................................................................................................... iv
Introduction ................................................................................................................................................................. v
1 Scope ................................................................................................................................................................ 1
2 Normative references ................................................................................................................................ 1
3 Terms and definitions ................................................................................................................................ 1
4 Principles ....................................................................................................................................................... 4
5 T2 mapping evaluation in human knee articular cartilage ........................................................... 5
5.1 Characterization parameters and methods ........................................................................................ 5
5.2 T2 value measurement process .............................................................................................................. 6
5.3 T2 value evaluation .................................................................................................................................... 8
© ISO 2022 – All rights reserved 5© ISO 2022 – All rights reserved v
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ISO/TS 24560-1:2022(E)
6 dGEMRIC evaluation in human knee articular cartilage ................................................................. 9
6.1 Characterization parameters and methods ........................................................................................ 9
6.2 T1 value measurement process ............................................................................................................ 11
6.3 ΔR1 value calculation ............................................................................................................................... 12
6.4 ΔR1 value evaluation ................................................................................................................................ 13
7 Acceptable standard for MR evaluation ............................................................................................. 14
7.1 Requirements for MR equipment ......................................................................................................... 14
7.2 Requirements for MR parameters ....................................................................................................... 14
7.3 Requirements for the MR longitudinally evaluation ...................................................................... 14
7.4 Exclusion criteria ....................................................................................................................................... 14
8 Limitation ..................................................................................................................................................... 15
Annex A (informative) Example of measurement results .......................................................................... 16
Annex B (informative) A introduction of T1ρ MR Imaging technology .................................................. 24
Bibliography .............................................................................................................................................................. 26
6 © ISO 2022 – All rights reservedvi © ISO 2022 – All rights reserved
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ISO/TS 24560-1:2022(E)
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/directiveswww.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/patentswww.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 of 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
www.iso.org/iso/foreword.htmlwww.iso.org/iso/foreword.html.This document was prepared by Technical Committee ISO/TC 150, Implants for surgery, Subcommittee
SC 7, Tissue-engineered medical products.Any feedback or questions on this document should be directed to the user’s national standards body. A
complete listing of these bodies can be found atwww.iso.org/members.htmlwww.iso.org/members.html.
© ISO 2022 – All rights reserved 7
© ISO 2022 – All rights reserved vii
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ISO/TS 24560-1:2022(E)
Introduction
Tissue-engineered cartilage has shown desirable results for the repair of cartilage defects, and
histologic findings indicate that the repaired tissue has a hyaline-like cartilage structure. Kang H.J. et al.,
Zheng M.H. et al. and Behrens P. et al. reported that the histologic change after matrix-associated
[1-3 ]autologous chondrocyte implantation/transplantation (MACI/MACT) () ) was a hyaline-like cartilage.
The knee articular cartilage couldcan also be repaired or regenerated via other tissue engineering
approaches using other seed cells such as mesenchymal stem cells or even by tissue regeneration free
[4-6 ]of external seed cells ( ). . MACI and other approaches lead to a maturation of the cartilage matrix
over time with the development of an organized collagen architecture. For long-term follow-up of
regenerative cartilage, clinical scores and morphological evaluations are commonly used. Furthermore,
histological evaluation from arthroscopic biopsies provides a gold standard for morphological and
biochemical assessments of regenerative cartilage tissue. However, this process is invasive and
unacceptable for patients after cartilage repair surgery. Magnetic resonance (MR) is a noninvasive
technique that can be used for the evaluation of a cartilage microstructure. Xu X and other researchers
reported that MR-based biochemical imaging techniques, such as delayed gadolinium-enhanced MRI of
the cartilage (dGEMRIC) and T2 mapping, show the capability of evaluating the biochemical character of
[7-12 ]articular cartilage ( ). . The T2 relaxation time is sensitive to the content of effective hydrogen atoms,
[13 ]and thus to the concentration of collagen, the main component of cartilage extracellular matrix ( ). .
Besides, the orientation changes in the collagen network of articular cartilage produce the depthwise T2
[14 ]anisotropy through the magic angle effect ( ). . The dGEMRIC technique enables an indirect estimation
of the fixed charge density (FCD) of cartilage, which mainly arises from the aggregated proteoglycan
[15 ]biomacromolecules ( ). . Since both collagen and proteoglycan components are important for
determining the functional characteristics of cartilage, a combination of T2 mapping and dGEMRIC
techniques provides a better evaluation of articular regenerative cartilage. Therefore, standardization
of T2 mapping and dGEMRIC techniques is needed for the evaluation of regenerative articular cartilage.
This document is intended to guide the clinical biochemical evaluation of regenerative articular
cartilage with MR. dGEMRIC and T2 mapping are recommended for the clinical evaluation of
regenerative cartilage. These techniques have been used for patients who received tissue-engineered
cartilage implantation or transplantation (MACI/MACT). The validation data from different hospitals
wereare provided in this document as an annexAnnex A.This document provides general principles for imaging and the measurement method of T2 mapping
and dGEMRIC of knee cartilage using 1,5 T or 3,0 T MRI equipment. These techniques are also
applicable for other articular cartilage, such as the ankle joint, hip joint, and shoulder joint, but the
imaging parameters should be adjusted and modified for better image quality.The International Organization for Standardization (ISO) draws attention to the fact that it is claimed
that compliance with this document may involve the use of a patent.ISO takes no position concerning the evidence, validity and scope of this patent right.
The holder of this patent right has assured ISO that he/she is willing to negotiate licences under
reasonable and non-discriminatory terms and conditions with applicants throughout the world. In this
respect, the statement of the holder of this patent right is registered with ISO. Information may be
obtained from the patent database available at www.iso.org/patents.8 © ISO 2022 – All rights reserved
viii © ISO 2022 – All rights reserved
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ISO/TS 24560-1:2022(E)
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights other than those in the patent database. ISO shall not be held responsible for identifying
any or all such patent rights.© ISO 2022 – All rights reserved 9
© ISO 2022 – All rights reserved ix
---------------------- Page: 8 ----------------------
TECHNICAL SPECIFICATION ISO/TS 24560-1:2022(E)
Tissue Engineered Medical Products –-engineered medical
products — MRI Evaluationevaluation of Cartilage–cartilage —
Part 1: Clinical Evaluation of Regenerative Knee Articular
Cartilage Using Delayed Gadolinium-Enhancedevaluation of
regenerative knee articular cartilage using delayed gadolimium-
enhanced MRI of the Cartilagecartilage (dGEMRIC) and T2
Mappingmapping
1 Scope
This document provides a principle to determine the parameter settings and operating methods for the
evaluation of the composition and structure of articular cartilage by dGEMRIC and T2-mapping MRI in
humans with a typical example of the methods; each are distinct MRI technologies that allow for
noninvasive observation of soft tissue characteristics.The methods provided in this document are intended for application in the evaluation of the clinical
effects of tissue -engineered cartilage or other cartilage regeneration products used in the knee joint,
and are also applicable for the evaluation of regenerative cartilage in other joints, although some
modification of parameters is needed.This document recommendsdescribes a longitudinal evaluation of the water content, the
glycosaminoglycan (GAG) concentration, and the concentration and orientation of collagen fibersfibres
in regenerative cartilage when using dGEMRIC and T2-mapping techniques in 1,5 T or 3,0 T magnetic
resonance imaging equipment.32 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/TR 16379:2014, Tissue-engineered medical products — Evaluation of anisotropic structure of
articular cartilage using DT (Diffusion Tensor)-MR ImagingISO/TS 21560:2020, Tissue-engineered medical products — General requirements of tissue-engineered
medical productsThere are no normative references in this document.
43 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
ISO and IEC maintain terminologicalterminology databases for use in standardization at the following
addresses:— ISO Online browsing platform: available at https://www.iso.org/obphttps://www.iso.org/obp
© ISO 2022 – All rights reserved 1---------------------- Page: 9 ----------------------
ISO/TS 24560-1:2022(E)
— IEC Electropedia: available at http://www.electropedia.org/https://www.electropedia.org/
3.1pulse sequences
train of programmed radio frequency pulses and gradient pulses, in MRI, it is a time protocol for
encoding images to obtain k-space dataNote 1 to entry: In MRI, it is a time protocol for encoding images to obtain k-space data.
3.2number of averages
number of repeated acquired identical MR signals from the same programedprogrammed pulse
sequence3.3
voxel
three-dimensional cuboid representing the minimum unit comprising a three-dimensional image
3.4pixel
two-dimensional cuboid representing the minimum unit comprising an image
3.5
field of view
FOV
width and height of an imaged region (expressed in cm by cm or mm by mm)
Note 1 to entry: It is expressed in cm by cm or mm by mm.
3.6
matrix
array of scalars arranged in frequency encoding direction and phase encoding direction in a two-
dimensional MR image (Note 1 to entry: It is typically expressed in number of pixels in frequency encoding direction by number of
pixels in phase encoding direction).Note 12 to entry: In MRI, the scalars in the array are called pixel of the matrix.
3.7in-plane resolution
capability of the sensor to observe or measure the smallest object clearly with distinct boundaries,
given by = FOV/matrix size (typically expressed in mm by mm)3.8
slice thickness
thickness of the imaging plane (
Note 1 to entry: It is expressed in cm or mm).
2 © ISO 2022 – All rights reserved
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ISO/TS 24560-1:2022(E)
3.98
signal-to-noise ratio
SNR
a single number obtained by dividing the image signal by the image noise
3.109
region of interest
ROI
a user -defined area on an image in which parameter of interested is calculated
3.1110
echo time
the time from the centercentre of the 90-degree excitation RF-pulse to the centercentre of the echo (
Note 1 to entry: It is expressed in ms).3.1211
repetition time
time interval for repetition of the basic unit of magnetic resonance pulse sequences (expressed in ms)
Note 1 to entry: It is expressed in ms.3.1312
proton density-weighted image
PDWI
magnetic resonance image reflecting the concentration of protons in tissue
3.1413
matrix-associated autologous chondrocyte implantation/transplantation
MACI/MACT
procedure involving expansion of autologous chondrocytes and seeding the cells onto a three-
dimensional biomaterial scaffold3.1514
scaffold
support or structural component or delivery vehicle, or matrix, consisting of synthetic and/or naturally-
derived material(s), for modulating the biological properties (including, but not limited to, adhesion,
migration, proliferation, and differentiation) or transport of administered and/or endogenous cells
and/or binding/transport of bioactive agentsNote 1 to entry: Biological properties include (but are not limited to) adhesion, migration, proliferation, and
differentiation.[SOURCE: ASTM F2312-11:2020, Clause 4]
3.15
gradient recalled3.16
gradientrecalled echo
© ISO 2022 – All rights reserved 3
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ISO/TS 24560-1:2022(E)
GRE
MR sequence that generates gradientsgradient echoes as a consequence of echo refocusing
3.173.16
delayedgadolinium enhanced MRI of the cartilage
dGEMRIC
pre-contrast and post contrast T1 mapping of cartilage
3.1817
longitudinal relaxation time
the time taking for the longitudinal magnetization to recover approximately 63 % of its initial value
after being flipped into the magnetic transverse plane by a 90° radiofrequency pulse
Note 1 to entry: It is expressed in ms.3.18
transverse relaxation time
time taking for the magnetic resonance signal to irreversibly decay to 37 % of its initial value after
being flipped into the magnetic transverse plane by a 90° radiofrequency pulse (expressed in ms)
3.19Note 1 to entry: It is expressed in ms.
3.19
transverse relaxation time
the time taking for the magnetic resonance signal to irreversibly decay to 37% of its initial value after
being flipped into the magnetic transverse plane by a 90° radiofrequency pulse (expressed in ms)
3.20T1 mapping
two -dimensional spatial distributions of T1 value of tissue
3.2120
T2 mapping
two -dimensional spatial distributions of T2 value of tissue
3.2221
longitudinal relaxation rate calculated as 1/T1
54 Principles
Articular cartilage is a type of hyaline cartilage that is characterized by an extracellular matrix that
[16 ]contains a fine network of collagen and proteoglycan etc. ( ). . In regenerative articular cartilage, it is
important to evaluate whether the implanted tissues regenerate to hyaline or hyaline-like cartilage with
4 © ISO 2022 – All rights reserved4 © ISO 2022 – All rights reserved
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ISO/TS 24560-1:2022(E)
time. MRI is a noninvasive technique that can provide an indirect method for assessing the composition
and microstructure of articular regenerative cartilage, including content and organization of the
[12 ],[17 ]collagen network and the proteoglycan, as the main component in the extracellular matrix ( , ). .
dGEMRICDelayedgadolinium enhanced MRI of the cartilage (dGEMRIC) is a technique pertinent to the
T1 relaxation-time measurement that uses the negative ionic charge of gadopentetate dimeglumine
2- 2-(Gd-DTPA ) to map the fixed charge density of the cartilage GAG. Gd-DTPA is repelled by negatively
charged GAGs and, is therefore, is thus negatively related to the local proteoglycan concentration.
Consequently, Gd-DTPA accumulates in areas of low GAG content, and a cartilage will have a shorter
T1 relaxation time in these regions. The ability to measure spatial variations in the cartilage GAG
concentration in vitro with dGEMRIC has been validated biochemically and histologically using both
bovine and human cartilage. The feasibility of using dGEMRIC in vivo washas also been demonstrated,
and the interpretation of MR images as representing a GAG distribution wasis supported by literature
[18-21 ]evidence ( ). . The GAG is a component of normal hyaline cartilage that is critical to its mechanical
strength. Thus, as a non-invasivenoninvasive method of indirectly monitoring the GAG concentration in
cartilage, dGEMRIC is a potentially useful method for assessing regenerative cartilage.
[22 ]T2 mapping usually involves imaging at several echo times along the T2 decay curve ( ) and T2
relaxation time of different tissues can be calculated after data processing. In cartilage, changes in the
T2-relaxation times are dependent upon the quantity of water and the integrity of the proteoglycan–
collagen matrix. T2 relaxation time mapping provides an indirect assessment of the collagen structure
and orientation as it relates to the free water content. The presence of unbound water molecules slows
the loss of transverse magnetization following an RF pulse, such that regions of cartilage with more free
water have higher T2 relaxation times. In healthy cartilage, the collagen matrix traps and immobilizes
water molecules. When this structured matrix breaks down, the extra space is filled with free, unbound
water, and leads to elevated T2 relaxation times. The correlation between T2 relaxation time mapping
[23 ],[24 ]and the collagen content has been validated, both in vitro and in vivo ( , ). . The T2 value of cartilage
is a dipolar interaction due to the slow anisotropic motion of water molecules in the collagen matrix
[14 ],[25 ]and varies as a function of the collagen arrangement in the static magnetic field ( , ), , the strength
of this interaction is orientation-dependent and reaches its minimum at an angle of 54.,7 (between the
static field and the axis of interacting protons, the so-called “magic angle”. Consequently, T2 changes
along cartilage thickness are reported to follow the orientational changes in the collagen fibril network.
Using appropriate arrangement of the articular surface with respect to the B0 field the resulting
laminated appearance in T2 maps approximately corresponds to the histological collagenous zones: the
superficial zone (orientation of collagen fibrils parallel to the articular surface), the transitional zone
(random fibril orientation) and the deep or radial zone (fibrils perpendicular to the articular surface
and perpendicular to the bone), which reveals the spatial collagen architecture in articular cartilage.
This spatial variation is a marker for hyaline-like matrix organization after cartilage repair.
MACI/MACT uses biomaterial scaffolds (natural or synthetic materials) as a carrier and seeds cells of
autologous chondrocytes. The repaired tissue may be able tocan develop an organized collagen
network, which is the basis for histological characterization of normal hyaline articular cartilage over
[1-3 ],[26 ],[27 ]time ( , , ). . It is possible to longitudinally evaluate the water content, the GAG concentration,
and the concentration and orientation of collagen fibersfibres in regenerative cartilage after
MACI/MACT by using the dGEMRIC and T2 mapping techniques.In this document, T2 mapping and dGEMRIC data obtained from subjects who received MACI using
different MRI equipment are included in the Annex A.© ISO 2022 – All rights reserved 5
© ISO 2022 – All rights reserved 5
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ISO/TS 24560-1:2022(E)
65 T2 mapping evaluation in human knee articular cartilage
6.15.1 Characterization parameters and methods
The 1,5 T or 3,0 T magnetic resonance imaging equipment and multichannel phased-array knee coil are
recommended for T2 mapping examination of knee cartilage. It is recommended to use the same field
strength equipment for longitudinal evaluation to avoid the influence of static magnetic field B0 on the
relaxation time of the tissue. Before MRI examinations, the subject should rest for more than 30
minutes min to avoid mechanical loading by exercise, which can influence the T2 value of knee cartilage.
B0 and B1 shimming is highly recommended before scanning the T2-mapping sequence for every
patient. Sagittal proton density -weighted images with fat saturation (FS-PDWI) and three-
dimensional GRE gradient recalled echo (3D-GRE) pulse sequences are recommended for
morphological evaluation of cartilage. 3D-GRE pulse sequences with spoiled gradient (such as SPGR,
FLASH, and VIBE) or steady-state free precession (such as DESS) can be chosen in different MR
manufactures. The pixel size in plane of the 3D-GRE pulse sequence should be consistent with pixel size
in plane of the T2 mapping seq...
TECHNICAL ISO/TS
SPECIFICATION 24560-1
First edition
Tissue-engineered medical
products — MRI evaluation of
cartilage —
Part 1:
Clinical evaluation of regenerative
knee articular cartilage using delayed
gadolimium-enhanced MRI of
cartilage (dGEMRIC) and T2 mapping
Produits médicaux issus de l'ingénierie tissulaire — Évaluation du
cartilage par IRM —
Partie 1: Évaluation clinique de la régénération du cartilage
articulaire du genou par séquences IRM tardives après injection de
gadolinium (dGEMRIC) et cartographie T2
PROOF/ÉPREUVE
Reference number
ISO/TS 24560-1:2022(E)
© ISO 2022
---------------------- Page: 1 ----------------------
ISO/TS 24560-1:2022(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2022
All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may
be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting on
the internet or an intranet, without prior written permission. Permission can be requested from either ISO at the address below
or ISO’s member body in the country of the requester.ISO copyright office
CP 401 • Ch. de Blandonnet 8
CH-1214 Vernier, Geneva
Phone: +41 22 749 01 11
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
PROOF/ÉPREUVE © ISO 2022 – All rights reserved
---------------------- Page: 2 ----------------------
ISO/TS 24560-1:2022(E)
Contents Page
Foreword ........................................................................................................................................................................................................................................iv
Introduction .................................................................................................................................................................................................................................v
1 Scope ................................................................................................................................................................................................................................. 1
2 Normative references ..................................................................................................................................................................................... 1
3 Terms and definitions .................................................................................................................................................................................... 1
4 Principles ..................................................................................................................................................................................................................... 3
5 T2 mapping evaluation in human knee articular cartilage ................................................................................... 4
5.1 Characterization parameters and methods ................................................................................................................. 4
5.2 T2 value measurement process ............................................................................................................................................... 6
5.2.1 Post-processing of imaging ....................................................................................................................................... 6
5.2.2 Measurement method .................................................................................................................................................... 6
5.2.3 ROIs of regenerative cartilage ................................................................................................................................ 7
5.2.4 ROIs of normal control cartilage .......................................................................................................................... 8
5.3 T2 value evaluation ............................................................................................................................................................................ 8
5.3.1 Purpose of evaluation .................................................................................................................................................... 8
5.3.2 In vivo evaluation of regenerative cartilage with T2 value ......................................................... 8
6 dGEMRIC evaluation in human knee articular cartilage .......................................................................................... 9
6.1 Characterization parameters and methods ................................................................................................................. 9
6.2 T1 value measurement process ............................................................................................................................................ 11
6.2.1 Post-processing of imaging .................................................................................................................................... 11
6.2.2 Measurement method ................................................................................................................................................. 11
6.2.3 ROIs of regenerative cartilage .............................................................................................................................12
6.2.4 ROIs of normal control cartilage .......................................................................................................................12
6.3 ΔR1 value calculation .................................................................................................................................................................... 12
6.4 ΔR1 value evaluation .....................................................................................................................................................................12
6.4.1 Purpose of evaluation .................................................................................................................................................12
6.4.2 In vivo evaluation of regenerative cartilage with ΔR1 values ................................................13
7 Acceptable standard for MR evaluation ...................................................................................................................................14
7.1 Requirements for MR equipment ........................................................................................................................................ 14
7.2 Requirements for MR parameters...................................................................................................................................... 14
7.3 Requirements for the MR longitudinally evaluation ......................................................................................... 14
7.4 Exclusion criteria .............................................................................................................................................................................. 14
8 Limitation .................................................................................................................................................................................................................15
Annex A (informative) Example of measurement results ..........................................................................................................16
Annex B (informative) Introduction of T1ρ MR Imaging technology ............................................................................26
Bibliography .............................................................................................................................................................................................................................28
iii© ISO 2022 – All rights reserved PROOF/ÉPREUVE
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ISO/TS 24560-1:2022(E)
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 of 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
www.iso.org/iso/foreword.html.This document was prepared by Technical Committee ISO/TC 150, Implants for surgery, Subcommittee
SC 7, Tissue-engineered medical products.Any feedback or questions on this document should be directed to the user’s national standards body. A
complete listing of these bodies can be found at www.iso.org/members.html.PROOF/ÉPREUVE © ISO 2022 – All rights reserved
---------------------- Page: 4 ----------------------
ISO/TS 24560-1:2022(E)
Introduction
Tissue-engineered cartilage has shown desirable results for the repair of cartilage defects, and histologic
findings indicate that the repaired tissue has a hyaline-like cartilage structure. Kang H.J. et al., Zheng
M.H. et al. and Behrens P. et al. reported that the histologic change after matrix-associated autologous
[1-3]chondrocyte implantation/transplantation (MACI/MACT) was a hyaline-like cartilage. The knee
articular cartilage can also be repaired or regenerated via other tissue engineering approaches using
other seed cells such as mesenchymal stem cells or even by tissue regeneration free of external seed
[4-6]cells . MACI and other approaches lead to a maturation of the cartilage matrix over time with the
development of an organized collagen architecture. For long-term follow-up of regenerative cartilage,
clinical scores and morphological evaluations are commonly used. Furthermore, histological evaluation
from arthroscopic biopsies provides a gold standard for morphological and biochemical assessments
of regenerative cartilage tissue. However, this process is invasive and unacceptable for patients after
cartilage repair surgery. Magnetic resonance (MR) is a noninvasive technique that can be used for the
evaluation of a cartilage microstructure. Xu X and other researchers reported that MR-based biochemical
imaging techniques, such as delayed gadolinium-enhanced MRI of the cartilage (dGEMRIC) and T2
[7-12]mapping, show the capability of evaluating the biochemical character of articular cartilage . The
T2 relaxation time is sensitive to the content of effective hydrogen atoms, and thus to the concentration
[13]of collagen, the main component of cartilage extracellular matrix . Besides, the orientation changes
in the collagen network of articular cartilage produce the depthwise T2 anisotropy through the magic
[14]angle effect . The dGEMRIC technique enables an indirect estimation of the fixed charge density (FCD)
[15]of cartilage, which mainly arises from the aggregated proteoglycan biomacromolecules . Since both
collagen and proteoglycan components are important for determining the functional characteristics
of cartilage, a combination of T2 mapping and dGEMRIC techniques provides a better evaluation of
articular regenerative cartilage. Therefore, standardization of T2 mapping and dGEMRIC techniques is
needed for the evaluation of regenerative articular cartilage.This document is intended to guide the clinical biochemical evaluation of regenerative articular
cartilage with MR. dGEMRIC and T2 mapping are recommended for the clinical evaluation of
regenerative cartilage. These techniques have been used for patients who received tissue-engineered
cartilage implantation or transplantation (MACI/MACT). The validation data from different hospitals
are provided Annex A.This document provides general principles for imaging and the measurement method of T2 mapping
and dGEMRIC of knee cartilage using 1,5 T or 3,0 T MRI equipment. These techniques are also applicable
for other articular cartilage, such as the ankle joint, hip joint, and shoulder joint, but the imaging
parameters should be adjusted and modified for better image quality.© ISO 2022 – All rights reserved PROOF/ÉPREUVE
---------------------- Page: 5 ----------------------
TECHNICAL SPECIFICATION ISO/TS 24560-1:2022(E)
Tissue-engineered medical products — MRI evaluation of
cartilage —
Part 1:
Clinical evaluation of regenerative knee articular cartilage
using delayed gadolimium-enhanced MRI of cartilage
(dGEMRIC) and T2 mapping
1 Scope
This document provides a principle to determine the parameter settings and operating methods for the
evaluation of the composition and structure of articular cartilage by dGEMRIC and T2-mapping MRI
in humans with a typical example of the methods; each are distinct MRI technologies that allow for
noninvasive observation of soft tissue characteristics.The methods provided in this document are intended for application in the evaluation of the clinical
effects of tissue-engineered cartilage or other cartilage regeneration products used in the knee joint,
and are also applicable for the evaluation of regenerative cartilage in other joints, although some
modification of parameters is needed.This document describes a longitudinal evaluation of the water content, the glycosaminoglycan (GAG)
concentration, and the concentration and orientation of collagen fibres in regenerative cartilage when
using dGEMRIC and T2-mapping techniques in 1,5 T or 3,0 T magnetic resonance imaging equipment.
2 Normative referencesThere are no normative references in this document.
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
ISO and IEC maintain terminology databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at https:// www .iso .org/ obp— IEC Electropedia: available at https:// www .electropedia .org/
3.1
pulse sequences
train of programmed radio frequency pulses and gradient pulses
Note 1 to entry: In MRI, it is a time protocol for encoding images to obtain k-space data.
3.2number of averages
number of repeated acquired identical MR signals from the same programmed pulse sequence
3.3voxel
three-dimensional cuboid representing the minimum unit comprising a three-dimensional image
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ISO/TS 24560-1:2022(E)
3.4
pixel
two-dimensional cuboid representing the minimum unit comprising an image
3.5
field of view
FOV
width and height of an imaged region
Note 1 to entry: It is expressed in cm by cm or mm by mm.
3.6
matrix
array of scalars arranged in frequency encoding direction and phase encoding direction in a two-
dimensional MR imageNote 1 to entry: It is typically expressed in number of pixels in frequency encoding direction by number of pixels
in phase encoding direction.Note 2 to entry: In MRI, the scalars in the array are called pixel of the matrix.
3.7slice thickness
thickness of the imaging plane
Note 1 to entry: It is expressed in cm or mm.
3.8
signal-to-noise ratio
SNR
single number obtained by dividing the image signal by the image noise
3.9
region of interest
ROI
user-defined area on an image in which parameter of interested is calculated
3.10
echo time
time from the centre of the 90-degree excitation RF-pulse to the centre of the echo
Note 1 to entry: It is expressed in ms.3.11
repetition time
time interval for repetition of the basic unit of magnetic resonance pulse sequences
Note 1 to entry: It is expressed in ms.3.12
proton density-weighted image
PDWI
magnetic resonance image reflecting the concentration of protons in tissue
3.13
matrix-associated autologous chondrocyte implantation/transplantation
MACI/MACT
procedure involving expansion of autologous chondrocytes and seeding the cells onto a three-
dimensional biomaterial scaffoldPROOF/ÉPREUVE © ISO 2022 – All rights reserved
---------------------- Page: 7 ----------------------
ISO/TS 24560-1:2022(E)
3.14
scaffold
support or structural component or delivery vehicle, or matrix, consisting of synthetic and/or naturally-
derived material(s), for modulating the biological properties or transport of administered and/or
endogenous cells and/or binding/transport of bioactive agentsNote 1 to entry: Biological properties include (but are not limited to) adhesion, migration, proliferation, and
differentiation.[SOURCE: ASTM F2312 -11: 2020, Clause 4]
3.15
gradient recalled echo
GRE
MR sequence that generates gradient echoes as a consequence of echo refocusing
3.16
delayedgadolinium enhanced MRI of the cartilage
dGEMRIC
pre-contrast and post contrast T1 mapping of cartilage
3.17
longitudinal relaxation time
time taking for the longitudinal magnetization to recover approximately 63 % of its initial value after
being flipped into the magnetic transverse plane by a 90° radiofrequency pulseNote 1 to entry: It is expressed in ms.
3.18
transverse relaxation time
time taking for the magnetic resonance signal to irreversibly decay to 37 % of its initial value after
being flipped into the magnetic transverse plane by a 90° radiofrequency pulseNote 1 to entry: It is expressed in ms.
3.19
T1 mapping
two-dimensional spatial distributions of T1 value of tissue
3.20
T2 mapping
two-dimensional spatial distributions of T2 value of tissue
3.21
longitudinal relaxation rate calculated as 1/T1
4 Principles
Articular cartilage is a type of hyaline cartilage that is characterized by an extracellular matrix that
[16]contains a fine network of collagen and proteoglycan . In regenerative articular cartilage, it is
important to evaluate whether the implanted tissues regenerate to hyaline or hyaline-like cartilage
with time. MRI is a noninvasive technique that can provide an indirect method for assessing the
composition and microstructure of articular regenerative cartilage, including content and organization
[12],[17]of the collagen network and the proteoglycan, as the main component in the extracellular matrix .
Delayedgadolinium enhanced MRI of the cartilage (dGEMRIC) is a technique pertinent to the T1
relaxation-time measurement that uses the negative ionic charge of gadopentetate dimeglumine (Gd-
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2- 2-
DTPA ) to map the fixed charge density of the cartilage GAG. Gd-DTPA is repelled by negatively
charged GAGs and is therefore negatively related to the local proteoglycan concentration. Consequently,
Gd-DTPA accumulates in areas of low GAG content, and a cartilage will have a shorter T1 relaxation
time in these regions. The ability to measure spatial variations in the cartilage GAG concentration in
vitro with dGEMRIC has been validated biochemically and histologically using both bovine and human
cartilage. The feasibility of using dGEMRIC in vivo has also been demonstrated, and the interpretation
[18-21]of MR images as representing a GAG distribution is supported by literature evidence . The GAG is a
component of normal hyaline cartilage that is critical to its mechanical strength. Thus, as a noninvasive
method of indirectly monitoring the GAG concentration in cartilage, dGEMRIC is a potentially useful
method for assessing regenerative cartilage.[22]
T2 mapping usually involves imaging at several echo times along the T2 decay curve and T2
relaxation time of different tissues can be calculated after data processing. In cartilage, changes in the
T2-relaxation times are dependent upon the quantity of water and the integrity of the proteoglycan–
collagen matrix. T2 relaxation time mapping provides an indirect assessment of the collagen structure
and orientation as it relates to the free water content. The presence of unbound water molecules slows
the loss of transverse magnetization following an RF pulse, such that regions of cartilage with more free
water have higher T2 relaxation times. In healthy cartilage, the collagen matrix traps and immobilizes
water molecules. When this structured matrix breaks down, the extra space is filled with free, unbound
water, and leads to elevated T2 relaxation times. The correlation between T2 relaxation time mapping
[23],[24]and the collagen content has been validated, both in vitro and in vivo . The T2 value of cartilage is
a dipolar interaction due to the slow anisotropic motion of water molecules in the collagen matrix and
[14],[25]varies as a function of the collagen arrangement in the static magnetic field , the strength of this
interaction is orientation-dependent and reaches its minimum at an angle of 54,7 (between the static
field and the axis of interacting protons, the so-called “magic angle”. Consequently, T2 changes along
cartilage thickness are reported to follow the orientational changes in the collagen fibril network.
Using appropriate arrangement of the articular surface with respect to the B0 field the resulting
laminated appearance in T2 maps approximately corresponds to the histological collagenous zones: the
superficial zone (orientation of collagen fibrils parallel to the articular surface), the transitional zone
(random fibril orientation) and the deep or radial zone (fibrils perpendicular to the articular surface
and perpendicular to the bone), which reveals the spatial collagen architecture in articular cartilage.
This spatial variation is a marker for hyaline-like matrix organization after cartilage repair.
MACI/MACT uses biomaterial scaffolds (natural or synthetic materials) as a carrier and seeds cells of
autologous chondrocytes. The repaired tissue can develop an organized collagen network, which is the
[1-3],[26],[27]basis for histological characterization of normal hyaline articular cartilage over time . It is
possible to longitudinally evaluate the water content, the GAG concentration, and the concentration and
orientation of collagen fibres in regenerative cartilage after MACI/MACT by using the dGEMRIC and T2
mapping techniques.In this document, T2 mapping and dGEMRIC data obtained from subjects who received MACI using
different MRI equipment are included Annex A.5 T2 mapping evaluation in human knee articular cartilage
5.1 Characterization parameters and methods
The 1,5 T or 3,0 T magnetic resonance imaging equipment and multichannel phased-array knee coil
are recommended for T2 mapping examination of knee cartilage. It is recommended to use the same
field strength equipment for longitudinal evaluation to avoid the influence of static magnetic field B0
on the relaxation time of the tissue. Before MRI examinations, the subject should rest for more than
30 min to avoid mechanical loading by exercise, which can influence the T2 value of knee cartilage. B0
and B1 shimming is highly recommended before scanning the T2-mapping sequence for every patient.
Sagittal proton density-weighted images with fat saturation (FS-PDWI) and three-dimensional gradient
recalled echo (3D-GRE) pulse sequences are recommended for morphological evaluation of cartilage.
3D-GRE pulse sequences with spoiled gradient (such as SPGR, FLASH, and VIBE) or steady-state free
precession (such as DESS) can be chosen in different MR manufactures. The pixel size in plane of the
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3D-GRE pulse sequence should be consistent with pixel size in plane of the T2 mapping sequence, which
can ensure the accuracy of the image fusion registration.A regularly repeated phantom test is recommended to ensure the status and stability of the MR system.
Phantom-based quality control is required after any change in the MR system hardware and software.
The protocol of T2 mapping consists of a sagittal, multi-echo spin echo pulse sequence for T2
measurement. Table 1 lists the recommended imaging parameters of T2 mapping in 1,5 T and 3,0 T MR
equipment, as a reference.Table 1 — Recommended Magnetic resonance parameters of T2 mapping evaluation
T2 mapping
Parameters
1,5 T 3,0 T
FOV (mm x mm) 160 × 160 160 × 160
TR (ms) range 1 200 to 2 000 range 1 200 to 2 000
multiple TE (no less than 4 echo times), more multiple TE (no less than 4 echo times), more
echo times corresponds to more accurate echo times corresponds to more accurateTE (ms)
T2 calculation, and the maximum echo time T2 calculation, and the maximum echo time
should be shorter than 80 ms should be shorter than 80 msParallel acquisi- the acceleration factor should be no larger the acceleration factor should be no larger
tion than 2 than 2Matrix no less than 256 × 256 no less than 320 × 320
Pixel size in plane
no larger than 0,6 × 0,6 no larger than 0,5 × 0,5
(mm )
Number of aver-
1 or 2 1 or 2
ages (NA)
Slice thickness
3 is recommended (ranging 3,0 to 4,0) 3 is recommended (ranging 3,0 to 4,0)
(mm)
Image plane sagittal plane sagittal plane
Number of slices no more than 30 slices no more than 30 slices
NOTE The parameters were suggested to be adjusted with different MR equipment and different signal-receiving coil.
MR examination of PDWI and T1-weighted 3D-GRE pulse sequences should achieve the following
standards:a) the field of view (FOV) should be no larger than 160 mm × 160 mm and no smaller than 140 mm ×
140 mm;b) the pixel size in plane of the PDWI pulse sequence should not be larger than 0,5 mm × 0,5 mm in 3,0
Tesla MRI equipment and should not be larger than 0,6 mm x 0,6 mm in 1,5 Tesla MRI equipment;
c) a 3,0-4,0 mm slice thickness is suggested in the PDWI pulse sequence;d) for image matching, some parameters, such as FOV, the scanning centre and slice thickness, are
suggested to be kept the same for both PDWI and T2 mapping;e) the voxel size of the 3D-GRE pulse sequence should be isotropic and not larger than 0,5 mm ×
0,5 mm × 0,5 mm in 3,0 Tesla MRI equipment and should not be larger than 0,6 mm × 0,6 mm ×
0,6 mm in 1,5 Tesla MRI equipment;f) the fat-saturation technique is suggested in PDWI and 3D-GRE pulse sequences, such as water-
excitation or fat water separation methods;g) imaging with high resolution can require multiple signal averages in 1,5 Tesla MR equipment for a
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h) if images are acquired with fat suppression, lowering the imaging bandwidth improves the overall
SNR.5.2 T2 value measurement process
5.2.1 Post-processing of imaging
Post-processing of the multiple images generated by the T2 mapping sequences can be performed
online on the scanner or offline using algorithms written in separate programs, such as MATLAB (the
MathworksInc, Natick, MA). Automated processing on the scanner typically generates a pixel-by-pixel
map of T2 relaxation times, and the T2 maps can be overlain on anatomical images through image
registration. Generally, sagittal PDW images and 3D-GRE images are recommended for morphological
evaluation of regenerative cartilage and native cartilage. PDW images are sensitive to the signal
abnormality of regenerative tissue, and 3D-GRE pulse sequence is used to obtain anatomical images for
its high resolution. T2 map images can be registered to 3D GRE images for verification of regenerative
cartilage and native cartilage (see Figure 1).5.2.2 Measurement method
T2 relaxation time is obtained by pixel-wise mono-exponential fitting of signal decay at different echo
times, and discarding the first echo for curve fitting is recommended in post-processing to minimize
[28]the error in T2 . If the regenerative cartilage showed longer T2 component not covered by the entire
ETL, bi-exponential curves including the offset as an additional parameter should be applied and the
corresponding model can be manually selected in the MATLAB software for imaging processing.
The SE pulse sequence signal intensity (S) shall be calculated by Formula (1).SM=×()11−−expT()RT//×−expT()ET2 (1)
where
S is the SE pulse sequence signal intensity;
M is equilibrium longitudinal magnetization;
TR is the repetition time;
T1 is the longitudinal relaxation time;
TE is the echo time;
T2 is the transverse relaxation time.
When TR>>T1, (1-exp(-TR/T1)) approaches 1. When TR is not much longer than T1(mo
...
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