Contains Nonbinding Recommendations  
 
Technical Considerations for Non-
Clinical Assessment of Medical 
Devices  Containing Nitinol  
Guidance  for Industry and Food and 
Drug Administration Staff  
 
Document  issued on  July  9, 2021  
 
Document originally issued  on  October 15,  2020  
 
The draft of this document was issued  on  April 19, 2019  
 
 
 
For questions about this document, contact the  Division of Applied Mechanics at (301) 796-2501, or  
Matthew Di Prima, Ph.D. at (301) 796-2507 or by email  matthew.diprima@fda.hhs.gov.    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S.Department of Health and Human Services  
FOOD & DRUG 
Food and Drug Administration  
Center for Devices and Radiological Health  
CENTER FOR DEVICES & RADIOLOGICAL HEALTH  Contains Nonbinding Recommendations  
Preface  
 
Public Comment  
 
You may submit electronic comments and suggestions at any time for Agency consideration to 
https://www.regulations.gov. Submit written comments to the Dockets Management Staff, Food 
and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD 20852. 
Identify all comments with the docket number  FDA-2019-D-1261. Comments may not be acted 
upon by the Agency until the document is next revised or updated.  
 
Additional Copies  
 
Additional copies are  available from the  Internet. You may also send an e-mail request to  
CDRH-Guidance@fda.hhs.gov  to receive  a copy of the guidance.  Please use the document  
number  17013-R1  and complete title of the guidance in  the request.  
  Contains Nonbinding Recommendations  
Table of Contents  
 
I.   Introduction and Scope  ...........................................................................................................  1  
II.   Background .............................................................................................................................  2  
III.   Definitions...........................................................................................................................  3  
IV.   Technical Recommendations ..............................................................................................  4  
A.   General Information ............................................................................................................  5  
B.   Mechanical Testing .............................................................................................................  7  
C.   Corrosion Testing..............................................................................................................  10  
2.   Nickel  Ion Release  ............................................................................................................  12  
3.   Galvanic Corrosion  ...........................................................................................................  14  
D.   Biocompatibility  ...............................................................................................................  14  
E.   Labeling - Warnings  .........................................................................................................  15  
  Contains Nonbinding Recommendations  
 
Technical Considerations for Non-
Clinical Assessment of Medical 
Devices  Containing Nitinol  
Guidance  for Industry and Food and 
Drug Administration Staff  
 
This guidance represents  the current thinking of the Food and Drug Administration (FDA or  
Agency) on this topic.  It does not establish any rights for any person and is not binding on  
FDA or the public.  You  can use an alternative approach if it satisfies the requirements of the  
applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff  
or Office responsible for this guidance as listed on the title page.   
I.   Introduction  and Scope  
 
Nitinol, a near equiatomic alloy of nickel and titanium,  is a commonly used material in the  
medical device industry.  Device manufacturers  have used nitinols unique properties (e.g.,  
pseudoelasticity and shape memory behavior) to design innovative medical devices that  would  
not be possible with conventional materials.   Nitinol has been extensively used in cardiovascular  
devices such  as stents,  heart valves, guidewires, and vena cava  filters.   The use  of nitinol  in other  
device areas is growing,  particularly  for products  intended for  use in minimally invasive  
procedures.1   The thermomechanical behavior  and processing sensitivity of nitinol raise  special  
considerations when compared to conventional  metals  such as stainless steel, titanium  or cobalt-
chrome alloys.   The  Agency has developed this guidance to provide  FDAs  current  thinking on 
technical considerations  specific to devices using nitinol due to the unique properties of nitinol.   
The recommendations  in this document  should be evaluated in conjunction with the intended use  
and technological  characteristics of your device  and any  relevant  device-specific guidances.  The 
purpose of this  guidance is to outline technical considerations associated with medical devices  
that have at least one patient-contacting component comprised of nitinol.  
 
For the current  edition of the FDA-recognized standard(s)  referenced in this document, see the  
FDA Recognized Consensus Standards Database.2   For additional information on the appropriate  
use of consensus standards  in the preparation and evaluation of premarket submissions for  
 
1  Duerig T, Pelton A, Stockel  D. An overview of  nitinol medical applications. Materials Science and Engineering:  
A. 1999;273:149-60  
2  Available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm   
1  
  Contains Nonbinding Recommendations  
 
medical devices, refer  to the Appropriate Use of  Voluntary Consensus Standards in Premarket  
Submissions for Medical Devices Guidance.3  
The contents of this document do not have the force and effect of law  and are not meant to bind 
the public in any way, unless specifically incorporated into a contract. This document is intended 
only to provide clarity to the public regarding existing requirements under the law. FDA  
guidance documents, including this guidance, should be viewed only as recommendations, unless  
specific regulatory or statutory requirements  are  cited. The use of the  word should  in Agency 
guidances means that something is suggested or  recommended, but not required.  
II.   Background  
 
Nitinol is a  nearly equiatomic metal  alloy of nickel and titanium.4,5  Nitinols unique  
thermomechanical  behavior  have made it a  commonly used material in  medical devices.  The use 
of nitinol in medical devices began over three decades ago in product areas such as orthodontic  
archwires, cardiovascular guidewires, and surgical instruments.  Its use has  increased over the 
past two decades into different device areas such  as orthopedic fracture fixation, stents, and 
transcatheter heart valves.  With an increasing trend to treat patients using minimally invasive  
procedures, nitinol has become a popular choice of material due to its ability to return to its  
original shape after being  mechanically  deformed  or after heat is applied.   These properties are 
due to reversible  transformations between the austenite and martensite phases, which may be 
temperature-induced (shape-memory) or stress-induced (pseudoelasticity).   As a result, nitinol 
can  withstand greater  amounts of  reversible  deformations  without plastic deformation  than 
conventional metallic alloys,  such as  stainless steel, titanium, or cobalt-chrome alloys.6  
 
Given the complex properties of nitinol, characterizing the thermomechanical behavior of  nitinol 
devices presents unique  considerations when assessing safety and effectiveness.   Previous  
literature has  described  the impact of manufacturing on transformation temperatures and 
mechanical  performance of nitinol devices.7   In addition, standards  developing organizations,  
such as American Society for Testing and Materials (ASTM),  have produced consensus  
standards to aid the medical device industry in characterizing nitinol.   These consensus  standards  
define terminology associated with nitinol materials, including specifications for  chemical,  
physical, thermomechanical, and metallurgical properties, and test methods  to characterize the 
transformation temperatures and mechanical properties of nitinol.  
 
 
3  Available at  https://www.fda.gov/regulatory-information/search-fda-guidance-documents/appropriate-use-
voluntary-consensus-standards-premarket-submissions-medical-devices  
4  ASTM F2005: Standard Terminology for Nickel-Titanium Shape Memory Alloys  
5  ASTM F2063: Standard Specification for Wrought Nickel-Titanium Shape Memory Alloys for Medical Devices  
and Surgical Implants 
6  Stoeckel D. Nitinol medical devices and implants.  Minimally Invasive Therapy & Allied Technologies.  
2000;9(2):81-88 
7  Pelton AR, Dicello J, Miyazaki S. Optimisation of processing and properties of  medical grade Nitinol wire.  
Minimally Invasive Therapy  & Allied Technologies. 2000;9(2):107-118  
2  
  Contains Nonbinding Recommendations  
 
Previous literature has shown the corrosion resistance of nitinol to be highly dependent on 
surface processing.8,9   In  vivo  corrosion of nitinol may  decrease  the safety profile or performance  
of the device by adversely impacting thermomechanical properties and/or biocompatibility.  To  
obtain stakeholder input  regarding best practices for corrosion testing  and the impact of  
corrosion on the performance  and safety profile of metals (including nitinol),  FDA held a public  
workshop titled Cardiovascular Metallic Implants: Corrosion, Surface Characterization, and  
Nickel Leaching (March 89, 2012).10   The information gathered from this workshop was  
published11  and used to update the FDAs guidance  document for  Non-Clinical Engineering 
Tests and Recommended Labeling for  Intravascular Stents and Associated  Delivery Systems.12   
However, the recommendations in that guidance were specific to intravascular stents and  
delivery systems.  With the expansion of  nitinol to other  product  areas, the  Agency is issuing this  
general guidance document outlining the technical considerations when using nitinol in medical 
devices.  
III.   Definitions  
 
Austenite start  temperature (As)  - the temperature at which the martensite to austenite 
transformation begins on heating in a single-stage transformation or the temperature at which the 
R-phase to austenite transformation begins on heating in a two-stage transformation.13  
 
Austenite finish temperature (Af)  - the temperature at which the martensite to austenite  
transformation is completed on heating in a single-stage transformation or the temperature at  
which the R-phase to austenite transformation is completed on heating in a  two-stage 
transformation.14  
 
Final finished form  - term used for a device or device component that includes all  
manufacturing processes  for the to be marketed  device including packaging and sterilization, if  
applicable.  
 
Martensite start  temperature (Ms)  - the temperature at which  the transformation from 
austenite to martensite begins on cooling in a single-stage transformation or the temperature at  
 
8  Zhu L, Trepanier C, Pelton A, Fino JM. Oxidation of Nitinol and its Effect on Corrosion Resistance.  ASM   
Materials and Processes for Medical Devices  2003  
9  Sullivan SJ, Dreher ML, Zheng J, Chen L, Madamba D, Miyashiro K, et al. Effects of Oxide Layer Composition 
and Radial Compression on Nickel Release in Nitinol Stents. Shape Memory and Superelasticity. 2015;1(3):319-27. 
10http://web.archive.org/web/20130203225843/http://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConfer 
ences/ucm287535.htm  
11  Nagaraja S, Di Prima M, Saylor D, Takai E. Current  practices in corrosion, surface characterization, and  nickel  
leach testing of cardiovascular metallic implants. Journal of  Biomedical Materials Research Part B: Applied  
Biomaterials. 2016;105(6):1330-1341 
12  Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/select-updates-non-
clinical-engineering-tests-and-recommended-labeling-intravascular-stents-and  
13  Reprinted,  with permission,  from  ASTM  F200505 (Reapproved 2015)  Standard Terminology for  Nickel-
Titanium Shape Memory Alloys, copyright ASTM International, 100 Barr Harbor Drive,  West  Conshohocken, PA  
19428.  A copy of the complete standard may be  obtained  from ASTM International,  www.astm.org.  
14  ibid  
3  
  Contains Nonbinding Recommendations  
 
which the transformation from R-phase to martensite begins on cooling in a two-stage 
transformation.15  
 
Martensite finish temperature (Mf)  - the temperature  at which the transformation from 
austenite to martensite is completed on cooling in a single-stage transformation  or the  
temperature at which the  transformation from R-phase to martensite is completed on cooling in a  
two-stage transformation.16  
 
R-phase  - the intermediate phase which may form between austenite and  martensite.17  
 
R'    phase start temperature (R's)    temperature at which the martensite to R-phase 
transformation begins on heating in a two-stage transformation.18   
 
R'    phase  finish  temperature (R'f)   temperature at which the martensite to R-phase 
transformation is completed on heating in a two-stage transformation.19   
 
Shape memory alloy  - a metal which, after an apparent plastic deformation in the  martensitic  
phase, undergoes a thermoelastic change in crystal structure when heated through its  
transformation temperature range resulting in a recovery of the deformation.20  
 
Preconditioning (simulated use)  - loading, tracking and/or deployment of test  devices, as  they  
would occur  in clinical use.  
 
Pseudoelasticity (superelasticity)  - nonlinear  recoverable deformation behavior of Ni-Ti  shape 
memory alloys at temperatures above the austenite finish temperature (Af).21  
IV.   Technical  Recommendations  
 
The following section contains a description of the type of information that we recommend you 
include in a  premarket  submission of a device made  from  nitinol.  The  type of premarket  
submission that is  appropriate  for your nitinol device is determined by the regulatory 
classification of your  device.  The type  and amount of data  necessary  to support  your regulatory 
submission  will vary depending on the  device design, intended use  and classification  of  the 
device type.  For  devices manufactured with multiple types of nitinol (e.g., components with 
different surface finishes), we recommend that you provide the suggested information for each 
type of nitinol.   Where available, device-specific guidance documents may include additional  
technical recommendations  that should be considered.   The Agency encourages manufacturers to 
engage with the Center for Devices  and Radiological Health (CDRH) through the Q-Submission 
 
15  Reprinted,  with permission,  from  ASTM  F200505 (Reapproved 2015)  Standard Terminology for  Nickel-
Titanium Shape Memory Alloys, copyright ASTM International, 100 Barr Harbor Drive,  West  Conshohocken, PA  
19428.  A copy of the complete standard may be  obtained from ASTM International,  www.astm.org.  
16  ibid  
17  ibid  
18  ibid  
19  ibid  
20  ibid  
21  ibid  
4  
  Contains Nonbinding Recommendations  
 
process to obtain more detailed feedback for questions.   For more information on the Q-
Submission  Program, please see Requests for Feedback and Meetings for  Medical Device 
Submissions: The Q-Submission Program  - Guidance for  Industry and Food and Drug 
Administration Staff.22   For more information on when a  device change or modification would 
require a new 510(k) submission, refer to FDA guidance,  Deciding When to Submit a 510(k)  
for a Change to an Existing Device.23  
 
Nitinol is used in a  diverse range of  medical devices,  with  varying durations  of contact.  The 
recommendations in this guidance document vary depending on the anticipated duration of  
contact.   The  anticipated duration of contact in this guidance document  follows  Section 5.3 of  
ISO 10993-1 2009 Biological evaluation of medical devices  -- Part 1: Evaluation and testing 
within a risk management process,24  with  definitions listed below.  
 
a)   Limited exposure    devices whose cumulative single, multiple or repeated use or contact  
is up to 24 hours.  
b)   Prolonged exposure    devices whose cumulative single, multiple or repeated long-term 
use or contact is likely to exceed 24 hours but not 30 days.  
c)   Permanent contact    devices whose  cumulative single, multiple or repeated long-term use 
or contact exceeds 30 days.  
A.  General Information  
 
The performance and behavior of  nitinol depends  on a number of  factors including 
alloy composition, thermal history, surface  processing, and preconditioning.  Based  
on the  device design and intended use of the  device containing nitinol, different  
material behavior  or performance may be desirable.   We recommend  that you 
provide the following general information on your  nitinol-containing  devices  for 
prolonged exposure and permanent contacting devices.   For limited exposure  
devices, some of this information may not be  warranted  based on device design and 
intended use.   For example,  functional testing performed for passive cardiac 
guidewires  may be sufficient in lieu of providing the  information listed below.  
Where device-specific guidances are available, these may be useful to determine 
what  type  of information is  needed.  Alternatively,  sponsors may wish to discuss the  
use of functional testing with FDA early in their device development process.  FDA  
recommends that sponsors use the  Q-Submission process to facilitate these  
discussions.25  
 
22  Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requests-feedback-and-
meetings-medical-device-submissions-q-submission-program  
23  Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/deciding-when-submit-
510k-change-existing-device  
24  Refer to the 2016 Guidance Use of International Standard  ISO 10993-1, "Biological evaluation of medical  
devices  - Part 1: Evaluation and testing within a risk management process" (https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/use-international-standard-iso-10993-1-biological-evaluation-medical-
devices-part-1-evaluation-and) for clarifaction and updated information on the use of this standard.   
25  For more information see Requests for Feedback on Medical Device Submissions: The Pre-Submission Program  
and Meetings with Food and Drug Administration Staff available at https://www.fda.gov/regulatory-
 
5  
  Contains Nonbinding Recommendations  
 
 
1.   Material Composition  
 
The composition of nitinol can be  tuned  to optimize performance for  a 
particular  intended use.  If your nitinol conforms to a recognized consensus  
standard, this information should be included in your submission  (e.g.,  ASTM  
F2063 Standard Specification for  Wrought Nickel-Titanium Shape Memory  
Alloys for Medical  Devices and Surgical  Implants).  If your  nitinol does not  
conform to a recognized consensus standard, we recommend you  provide  the 
nitinol composition and a description of its specific properties.  
 
2.   Manufacturing  
 
Manufacturing method and  parameters  including heat treatments and surface 
processing can alter the behavior and performance of the nitinol device.   
Therefore,  we recommend that you provide  a high-level  flow chart  to identify 
the manufacturing processes leading from your  raw material to  the final device 
sterilization  (if relevant).  Of specific interest are thermal processes (e.g.,  laser  
cutting, annealing, thermal shape  setting).  Additionally, surface processing can  
have a significant effect  on the corrosion/nickel leach performance of  nitinol.   
Therefore, we recommend that you provide a detailed description of any  surface 
processing steps  (e.g.,  honing, microblasting, pickling, polishing, passivation)  
so the risk of corrosion and nickel release can be  evaluated.   In addition, you 
should describe any final post-processing cleaning steps, and discuss how these  
steps are designed to remove any surface residuals that could impact  
biocompatibility.  
 
3.   Pseudoelasticity/Shape Memory Behavior  
 
Nitinol can be tuned via composition and thermal treatments to either have  
pseudoelastic (superelastic) or shape memory behavior at the desired operating 
temperature.   As these two behaviors are different, it should be stated in the  
submission which one is being used.   If neither  behavior  is being employed, that  
also  should be  clarified.   
 
4.   Transformation  Temperatures  
 
As stated previously, variations in transformation  temperatures of nitinol have  
been shown to affect  mechanical properties.  Therefore, we recommend you  
provide  phase transformation  temperatures of your  final finished form (i.e.,  with 
all manufacturing including sterilization, if  relevant).  When  possible, samples  
from  a minimum of three  production lots26  should be used because nitinol  
transformation temperatures  are sensitive to small variations in manufacturing  
 
information/search-fda-guidance-documents/requests-feedback-and-meetings-medical-device-submissions-q-
submission-program  
26  21 CFR 820.3(m)  
6  
  Contains Nonbinding Recommendations  
 
processes,  such as temperature or heating duration.   If the pseudoelastic 
properties are being utilized  to achieve the intended device performance,  we 
recommend providing either  austenite finish (Af) temperature, R-phase finish 
temperature (Rf) if the  R-phase is present,27  or body temperature mechanical  
test data  meeting a pre-specified acceptance criteria.   If shape memory  
properties are  being  utilized,  you should  also provide austenite start (As), 
martensite start (Ms),  and martensite finish (Mf) temperatures  as these 
temperatures govern the  shape memory behavior.   We recommend using the  
methods described in ASTM F2004  Standard Test Method for Transformation 
Temperature of Nickel-Titanium Alloys  by Thermal Analysis,  ASTM F2082  
Standard Test Method for Determination of Transformation Temperature of  
Nickel-Titanium Shape Memory Alloys by Bend and Free Recovery,  or an 
equivalent method.  It should be noted that these test methods do not necessarily 
measure the same Af  temperature  for  a given material or device.28,29   For  
devices that are expected to be load bearing, we recommend ASTM F2082, 
modified to assess the strains the device is expected to  experience  in its final 
finished form (e.g., crimping of a stent or pre-deformation of a bone plate),  as it 
incorporates deformation.  Alternative methods to  assess transformation 
temperatures can be used with  a detailed test protocol and explanation of how  
transformation temperatures are determined.  We recommend you  provide  
specifications for  body temperature,  mechanical performance or  transformation  
temperature ranges  for your  device  to ensure your device will perform as a  
pseudoelastic  or shape memory material.   
B.  Mechanical Testing  
 
Nitinol has unique  thermomechanical  behavior.   When available, device-specific 
guidance or standards  should be used to assess the mechanical performance of your  
device.   If mechanical testing will be performed as part of your non-clinical testing  
plan, the following specific considerations may apply depending on device  design 
and/or intended use.  
 
1.   Experimental Testing Considerations  
a.   The pseudoelastic behavior of nitinol leads to a region of near  constant  
stress over a  range of strains, and,  therefore,  mechanical testing is  
commonly performed  under displacement control,  although other control  
modes may be appropriate  (e.g., pressure  control  with displacement  
monitoring for  radial pulsatile fatigue testing of a  vascular stent per  
ASTM F2477  Standard Test Methods for in vitro Pulsatile Durability  
Testing of Vascular Stents). Given the unique thermomechanical  
 
27  Duerig TW, Bhattacharya K  The influence of the R-phase on  the superelastic behavior of NiTi. Shape Mem  
Superelasticity 2005 
28  Cadelli A, Manjeri RM, Sczerzenie F, Coda A. Uniaxial Pre-strain and Free Recovery (UPFR) as a Flexible 
Technique  for Nitinol Characterization. Shape Memory and Superelasticity. 2016 Mar  1;2(1):86-94. 
29  Duerig TW, Bhattacharya K.  The influence of the R-phase  on the superelastic behavior of NiTi. Shape Memory 
and Superelasticity. 2015 Jun 1;1(2):153-61.  
7  
  Contains Nonbinding Recommendations  
 
behavior of nitinol, we recommend that you provide a rationale for  the 
control mode used for mechanical testing.  
 
b.   Some devices are designed such that they  may  be  exposed to strains  
prior to and/or  during implantation.  For example, cardiovascular stents  
are  compressed to a smaller diameter onto  a delivery system  and tracked  
through vasculature  prior to deployment.   In addition, orthopedic staples  
are extended prior to implantation.  Therefore,  when appropriate, we 
recommend you account  for any clinical deformations/forces  and 
temperature excursions (e.g., sterilization)  as  a preconditioning step  
prior to mechanical testing  of a device.  
 
c.   Due to the thermomechanical response of nitinol, mechanical testing 
should be performed at a clinically relevant temperature  unless  
otherwise justified.  
 
d.   Some devices are exposed to cyclic loading conditions during use  (i.e., 
fatigue loading).   If you conduct  fatigue  tests, we  recommend that you 
use a clinically relevant  liquid  test solution (e.g., phosphate buffered 
saline (PBS)). Since fatigue testing of nitinol in air has been shown to be  
sensitive to test frequency due to heating effects,30  we do not  
recommend that  you conduct fatigue tests of nitinol in air.  If you 
conduct fatigue testing of nitinol  in air, we recommend that you  provide  
a scientific justification  for the  test environment  used.  
 
e.   For devices intended to utilize the shape memory properties of nitinol  
(e.g., cyclic shape  change through thermal cycling), we recommend a 
cyclic shape memory test  at  a clinically relevant temperature range and  
number of cycles.   This testing should  assess functional  performance  and 
device integrity.  
 
2.   Computational Stress/Strain Analyses  
If you plan to conduct  computational analyses,31  we recommend the  following  
to ensure  the unique thermomechanical properties of nitinol are properly 
captured:  
 
a.   The constitutive laws  applicable to nitinol can  differ substantially from 
traditional metals.32,33   Therefore,  you should simulate nitinol material 
 
30  Wagner et al (2004). Structural fatigue of pseudoelastic NiTi shape memory wires. Materials Science and  
Engineering A. Vol 378 pp 105-109.  
31  Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/reporting-
computational-modeling-studies-medical-device-submissions  
32  Ford DS, and White SR. Thermomechanical  behavior of 55Ni45Ti nitinol.  Acta Materialia  1996;44(6):2295-2307.  
33  Tension, compression, and bending of superelastic shape memory alloy tubes, Benjamin Reedlunn, Christopher B.  
Churchill, Emily E.Nelson, John A. Shaw, Samantha H. Daly, Journal  of the Mechanics and Physics of Solids  
Volume 63, February 2014, Pages 506-537  
8  
  Contains Nonbinding Recommendations  
 
with an appropriate  material model.  You  should document and justify 
the parameters used in the material model.  
 
b.   Material model parameters  can  be obtained from  ASTM F2516 
Standard Test Method for Tension Testing of Nickel-Titanium  
Superelastic Materials.   Test specimens should be representative of the 
final manufactured device (e.g., including heat treatment and surface  
processing steps).  Testing should be conducted at  a temperature  
representative of the  clinical use environment (e.g., 37C for implantable 
devices).   
 
c.   Your computational analysis should include the effect of  any shape  
setting steps in  your  manufacturing process  since these will  relieve  pre-
existing stresses.  
 
d.   If your device is subjected to cyclic loading during use, we recommend  
that you calculate fatigue safety factor(s)  using a constant life curve.  
Unlike  traditional metals,  which utilize stress-based fatigue life 
estimates (e.g., Goodman, Soderberg diagrams),  using a constant life  
mean versus alternating strain diagram has been found to provide a good 
model for fatigue life prediction  for nitinol.34   Fatigue life of nitinol is  
sensitive to composition and processing.  Therefore, we recommend that  
you generate a constant life curve  specific to your  device by 
experimental  testing  of nitinol samples  that are representative of  your  
final manufactured device (e.g., including heat treatment and surface  
processing)  rather than leveraging data  not specific to your device.  
Since fatigue life can be adversely or  favorably affected by pre-strain 
(e.g., from crimping of a  stent onto a delivery catheter),35,36  we 
recommend you consider and discuss  the effects of pre-strain.  We 
recommend that you state and justify the method used to calculate  mean  
and alternating strain for  fatigue safety factors  (e.g., scalar or tensor).37    
 
e.   You should validate the computational model used to analyze the  nitinol 
device, and justify the validation  activity  relative to the context of use  
(COU) of the  computational model,  the risk and role of the  
computational model in decision making,38  and range of conditions  
assessed relative to those in the COU. We also recommend that you 
 
34  Nitinol Fatigue: A Review of  Microstructures and Mechanisms, Alan Pelton, Journal  of Materials Engineering 
and  Performance, 2010  
35Gupta et al (2016). High compressive pre-strains reduce the  bending fatigue life of  nitinol  wire. J Mechanical  
Behavior Biomedical Materials  
36  Senthilnathan et al (2019). Effect of Prestrain on the Fatigue Life of Superelastic Nitinol. J Materials Engineering  
and Performance  
37  Marrey et al (2018). Validating Fatigue Safety Factor Calculation Methods for Cardiovascular Stents. Journal of 
Biomechanical Engineering.  140 (6) 
38  ASME V&V 40. Assessing Credibility of Computational Modeling through Verification and Validation:  
Application to Medical Devices  
9  
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justify your choice of parameter measured (e.g., force, strain)  and 
loading path in your validation activities.  
 
We recommend that submission of computational stress/strain analysis reports  
follow  the  Reporting of  Computational  Modeling Studies in Medical Device 
Submissions Guidance.39  
C.  Corrosion Testing  
 
Nitinols corrosion susceptibility is dependent on the manufacturing and surface  
finishing processes40  used to make the final  finished form  as well as potentially the  
geometry of the final finished form.   As corrosion  can lead to nickel ion release or  
even a compromise of the mechanical integrity of  the device, we  recommend  that 
pitting  corrosion testing  of the  nitinol device be performed  for  prolonged exposure  
and permanent contacting  devices  (see below  for  specific recommendations).  If  
pitting corrosion testing results meet pre-specified  acceptance criteria  (for details  on 
acceptance criteria,  see Section C.1.: Corrosion Testing - Pitting Corrosion)  and 
your device is manufactured using established surface finishing  that has been used 
for device(s) with a good clinical history of use (i.e., no history of adverse  events  
associated with  corrosion or  nickel  ion release) such as electropolishing, chemical  
etch, or mechanical polishing,  further testing may not be  warranted.  When  
considering the effect  of  manufacturing processes  (e.g., thermal processing)  on 
surface finish,  comparison of  surface characterization  results (e.g., chemical  
composition vs. depth) to an established surface  finish may provide insight into the  
quality of your protective oxide layer.  Due to the  spot size limitations of surface  
characterization, this approach may not be appropriate to assess phenomena that are 
influenced by the  entire surface (e.g., nickel ion leach) if surface variability was  
established during corrosion testing.    
 
If the results of the testing do not meet pre-specified acceptance criteria  or your  
device is not manufactured using established surface finishing processes  with a  
good clinical history of use, we recommend characterizing the extent of nickel ion 
release.   A flowchart (Figure 1) is provided to illustrate the recommended testing 
paradigm for  corrosion and nickel  ion release susceptibility.  
 
Corrosion testing  is generally  not warranted  for limited contact devices; however, 
such testing may be requested in situations such as  devices  with an  electrically  
active component, a dissimilar metal couple, or  a degradable metal/polymer  
component  where these features  could accelerate nitinol corrosion.   In these cases,  
we recommend you seek  more detailed feedback via the Q-submission process per  
 
39  Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/reporting-
computational-modeling-studies-medical-device-submissions 
40  Sullivan et al (2017). The effect of surface  processing on in-vivo corrosion of Nitinol stents in a porcine  model.  
Acta Biomaterialia. Vol. 16 pp 385  -396  
10  
  Contains Nonbinding Recommendations  
 
the guidance  Requests for Feedback on Medical  Device Submission: The Pre-
Submission Program and Meetings with FDA Staff.41  
Meets acceptance 
TM F2129 
criteria 
NO 
YES 
Established  NO  In vitro nickel 
surface finish?  ion release 
YES 
No further testing 
Risk assessment 
needed 
   
Figure 1. Corrosion testing paradigm flowchart  
 
1.   Pitting Corrosion  
We recommend conducting pitting corrosion testing per ASTM F2129  Standard 
Test Method for Conducting Cyclic Potentiodynamic Polarization Measurements  
to Determine the Corrosion Susceptibility of Small Implant Devices.  
 
Testing should be performed after subjecting the  device to simulated assembly 
and implantation, which includes compression/loading and deployment of the  
device through an in vitro  fixture that mimics  in vivo anatomic conditions (e.g., 
vessel size, tortuosity).  Alternatively,  the device  can be subjected to 
stresses/strains expected  during simulated use without the use of an in vitro  
fixture, with justification.  This device conditioning is intended to simulate the  
clinical conditions of the  device  at the time of implantation.  You should test 
device sizes that are the worst-case in terms of corrosion susceptibility based on 
surface area, size, and/or  geometry.  Considerations should be given to factors  
such as geometry or size that may affect surface finishing such as adequate 
polishing of regions of high curvature.  Test devices should be representative of  
the final finished form  and selected such that potential variations due to 
manufacturing  can be assessed (e.g., by taking samples from  multiple lots).  If the  
nitinol component is coated with a non-conductive material (e.g., polymer), we 
recommend manufacturing an uncoated version that undergoes identical thermal  
processing as the final finished device to serve as  a worst-case sample  for pitting  
corrosion.  If the tested devices did not undergo sterilization, a justification for  
why the sterilization process would not affect the corrosion performance should 
be provided.  In addition, the number of samples  tested and sampling scheme  
 
41Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requests-feedback-and-
meetings-medical-device-submissions-q-submission-program  
11 
  Contains Nonbinding Recommendations  
 
should be justified with consideration of variability in results.  At least 6 samples  
will likely be  warranted  based on known variability of corrosion performance42  
and more samples  could  be warranted  based on the performance of your device  
and your acceptance criteria.43   If your  worst-case  device  size cannot be 
accommodated in the test fixture, alternative device sizes or shortened samples  
could  be used with a scientific rationale.  
Test reports should include corrosion/rest potentials, breakdown potentials, as  
well as polarization curves.   When practical, we recommend that you plot all  
polarization curves in one graph.   You should  discuss any deviations from the  
ASTM F2129 standard (e.g., test setup not meeting the criteria outlined in ASTM  
G5  Standard Reference  Test Method for Making Potentiodynamic Anodic  
Polarization Measurements).   Results should be assessed against your  
acceptance criteria.   ASTM F2129 does not include an acceptance  criterion.   
Therefore, the  acceptance criterion  for the pitting corrosion testing should be  
determined by comparison to a legally U.S. marketed  comparator device  with  
good clinical history of use (i.e., no history of corrosion-related fractures or  
adverse events associated with nickel release).   Alternatively, while there is  
limited  data directly linking in vitro  corrosion testing to in vivo  corrosion 
outcomes, studies  have been  published44,45,46,47,48  that  could  be used to establish 
acceptance criteria  when a comparator device is not available.   The  criteria should 
be justified based on pitting and crevice corrosion performance  as well as  risk of  
nickel leaching  for your  device.   If breakdown occurred, you should include  
results of the visual inspection of your device before and after testing to assess  
evidence of pitting  and location of pits.  Images of  sufficient magnification  should 
be provided to support your assessment.  
2.   Nickel  Ion Release  
If your nitinol device does not  meet your pre-specified acceptance criteria for  
corrosion resistance  or  does not employ an established  surface finishing process,  
we recommend  nickel ion release  testing be performed  per ASTM  F3306 
Standard Test Method for Ion Release Evaluation of Medical Implants.   This  
 
42  Rosenbloom, SN. An assessment of ASTM F2129 Electrochemical Testing of Small Medical Implants    Lessons 
Learned.  Proceedings  of NACE 2007 
43  Eiselstein, L. E. et al. Acceptance Criteria for Corrosion Resistance of Medical Devices: Statistical Analysis of  
Nitinol Pitting in In Vivo Environments. Journal of Materials Engineering and Performance 18, 768-780 (2009). 
44  Corbett RA. Laboratory corrosion testing of medical implants. Proceedings of Materials and Processes for  
Medical Devices Conference;  2004: ASM International, Materials Park, OH  
45  Eiselstein, L. E. et al. Acceptance Criteria for Corrosion Resistance of  Medical Devices: Statistical Analysis of  
Nitinol Pitting in In Vivo Environments. Journal of Materials Engineering and Performance 18, 768-780 (2009) 
46  Lonn, M. K., Metcalf, J. M.  & Choules, B. D. In Vivo and In Vitro Nitinol Corrosion Properties. Shape Memory 
and Superelasticity 1,  328-338 (2015) 
47  Pertile, L. B., Silva, P. M., Peccin, V. B., Peres, R. , Silveira, P. G., Giacomelli, C. , Giacomelli, F. C., Fredel, M. 
C.and Spinelli, A. (In vivo human electrochemical properties of a NiTi Dbased alloy (Nitinol) used for minimally 
invasive implants. Journal of  Biomedical Materials Research Part A, 89A,  1072-1078 (2009) 
48  Stacey J.L. Sullivan, Daniel  Madamba, Shiril Sivan, Katie Miyashiro, Maureen L. Dreher, Christine Trepanier,  
Srinidhi Nagaraja. The effects  of surface  processing on invivo corrosion of Nitinol stents in a porcine model. Acta  
Biornaterialia 16, 385-396 (2017)  
12  
  Contains Nonbinding Recommendations  
 
testing should quantify nickel  over time  by measuring concentrations of nickel  
released  from the device  into a fluid at physiologic temperature and pH.  To avoid  
excursions in pH, we  recommend using a buffered solution, such as  PBS.  For 
prolonged exposures, immersion testing should be conducted for the  entire  
anticipated duration of  contact.  For permanent implants, we recommend  testing  
be conducted for  60 days.   Alternatively, if the testing demonstrates that the  
surface of your nitinol component is stable, i.e.,  equilibrium is being approached, 
testing may be concluded earlier, with a minimum  test duration of 30 days.  
Justification for surface stability may include evidence of monotonically decaying 
release rates over time that become negligible by the end of testing.   Solution  
sampling should be conducted at adequate intervals  to characterize the nickel  
release profile of the device in vitro.  You  should use a sampling regimen that will 
adequately capture  any initial bolus release of nickel  ions.  For  example, sampling 
intervals  for a permanent implant might include at least days 1, 2, 4, 7, 14, 21, and 
28 days for the first month of cumulative exposure time, and at least bi-weekly 
thereafter  to capture the initial bolus release of nickel  followed by the chronic  
release behavior.   Alternative  sampling frequencies may be used with a scientific 
rationale.  
 
Testing should be performed on devices in final finished  form  after subjecting the  
device to  preconditioning that simulates device implantation (e.g.,  tracking and 
deployment).   Test devices should be selected such that potential variations due to 
manufacturing  can be assessed (e.g.,  by taking samples from  multiple lots), with a  
justification  for the  number  and size  of devices  tested.   In  cases where there are 
multiple sizes or different geometries, the devices  should be selected and justified 
such that they represent the worst-case for nickel  ion release  (e.g.,  largest surface 
area, most challenging to surface finish, and/or highest local strains).  
 
Validation testing should be performed and summarized  in the  test report.  This  
validation testing should include validation of the  analytical instrumentation as  
well as  a spike and recovery test to demonstrate that nickel is not lost out of  
solution during testing  (e.g.,  due to adsorption onto the extraction container).   The 
duration should be at least equal to the longest interval during immersion testing.   
The extraction ratio, or  the ratio of the surface area of the tested device to the 
volume of test solution, should be provided along with a  scientific  rationale for 
why the ratio was selected.  Both  the detection limit of the analytical 
instrumentation and nickel solubility in the test solution should be considered in 
your rationale.  For example, a surface to volume ratio of 0.1 to 1  cm2/mL may  be  
appropriate if the nickel released does not approach the nickel solubility limit in 
the test solution and is sufficiently above the  detection limit.  We  recommend that  
you replace the entire test solution at each time point sampled  with fresh  solution.  
 
Test results should be reported as total cumulative release per device in  
micrograms, as well as a per day release (g/day).  In addition, if release rates are 
compared between devices or samples with different geometries, results should 
13  
  Contains Nonbinding Recommendations  
 
also be normalized by device surface area.   These  results should be used as  part of  
your risk assessment as described in Section D: Biocompatibility.  
3.   Galvanic Corrosion   
Similar to pitting corrosion, galvanic corrosion may lead to higher than 
anticipated rates of  nickel ion release or  compromised mechanical integrity.   If 
nitinol is in contact with  dissimilar metals, galvanic corrosion  testing  should be  
considered.   We recommend the  methods described in ASTM F3044 Standard 
Test Method for Evaluating the Potential  for Galvanic Corrosion for Medical  
Implants.   As an alternative to using devices for galvanic corrosion testing, 
coupons representing an expected worst-case galvanic coupling that are subjected  
to identical manufacturing processes  could  be used.  In  addition, a scientific 
justification may be provided, in lieu of testing,  if the expected worst-case 
potential shift due to galvanic coupling is small and if the relative surface ratios of  
the cathodic to  anodic materials are low  (e.g., marker band to stent surface  ratio).  
D.  Biocompatibility  
 
To  assess the  biocompatibility  of  your nitinol device, we recommend that  you follow  
the guidance Use of  International Standard ISO  10993-1, Biological evaluation of  
medical devices  - Part 1:  Evaluation and testing within a risk management process.49   
This guidance  identifies  the types of  biocompatibility assessments  that should be  
considered and recommendations  regarding how to conduct  related  tests.  
 
In addition, if in vitro  nickel  release  testing will be  conducted  (see Figure 1), a risk 
assessment should be performed  to compare the amount of nickel released from the  
device to a Tolerable Intake (TI) value for nickel.  A TI  value is defined in the  ISO  
10993-17:2002/(R)2012  standard  Biological evaluation of medical devices  -- Part  
17:Establishment of allowable limits for leachable substances  as an estimate of the  
average daily intake of a  substance over a specified time period, on the basis of body 
mass, that is considered to be without appreciable  harm to health.  
 
For adverse systemic effects that may occur following  prolonged or permanent  
patient exposure to nickel released  from a nickel-containing device, with the 
exception of hypersensitivity, CDRH recommends a  TI value  for parenteral  (non-
oral) exposure  to nickel of  0.5  g/kg/day  (e.g., 35  g/day for a 70 kg adult).50   This  
value is based on systemic toxicity data  from  experimental animals following  
administration of nickel salts by parenteral routes  of exposure  (e.g., intravenous, 
intraperitoneal)  and derived using the approach outlined in the ISO 10993-17 
standard.  The  FDA has  not established an oral TI for nickel; however, the US  
Environmental  Protection Agency  has  established a Reference Dose (RfD)  of 20  
g/kg/day  (e.g., 1400  g/day for a 70 kg adult)  that is intended to be protective for  
 
49  Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/use-international-
standard-iso-10993-1-biological-evaluation-medical-devices-part-1-evaluation-and  
50http://web.archive.org/web/20130203225843/http://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConfer 
ences/ucm287535.htm   
14  
  Contains Nonbinding Recommendations  
 
lifetime oral exposure to nickel.   It is important to note that the  TI values  are  not  
intended to be protective  for local effects  (e.g.,  necrosis, inflammation, irritation)  that 
may result from nickel release from  an implant into tissues surrounding the implant.   
With regard to carcinogenicity, no increase in tumor incidence has been observed in 
rats or mice following long-term oral or inhalation exposure to soluble nickel  
compounds in well-conducted bioassays;51  therefore, the TI for nickel ion released  
from nitinol is adequately protective  for carcinogenicity.  If any  in vivo  nickel  
exposure data exists for your device, these values should also  be included in your risk 
assessment.  
 
As the  lower limit of nickel exposure  that can  elicit  allergic reactions in some patients  
is not known, it is not possible to derive a hypersensitivity-based TI  for nickel  
released from nitinol.  Therefore, appropriate  labeling is recommended (see Section  
E:  Labeling).   
 
If your  nickel  exposure estimate exceeds the recommended TI  (i.e., 0.5 g/kg/day),  
an alternative TI  may be  derived  in certain cases,  such as  for  significantly shorter  
exposure duration  or other exposure routes  (e.g.,  inhalation).   To support the  
alternative  TI, you should provide  evidence  (e.g.,  literature)  that the  potential  
toxicological risk(s)  will be  adequately  mitigated  or discuss how  the probable benefit  
to health from the use of  the device outweighs any probable risk of injury or illness  
from  such use.  Additional  information on benefit-risk assessments can be  found in 
the Factors to Consider  When Making Benefit-Risk Determinations for Medical 
Device Investigational Device Exemptions  - Guidance for Investigational Device 
Exemption Sponsors, Sponsor-Investigators  and Food and Drug Administration 
Staff52  and Factors to Consider When Making Benefit-Risk Determinations in  
Medical Device Premarket Approval and  De Novo Classifications  - Guidance for  
Industry and FDA Staff.53   If  your nickel  release exceeds the recommended  or  
alternative TI and cannot be justified, device modifications (e.g.,  surface  
optimization) may be  warranted  to mitigate the risk.  
E.  Labeling  - Warnings  
 
Since there is no known lower limit on the amount of nickel  that can  elicit  allergic  
reactions in some patients, we recommend that the risk of potential allergic reaction  
to nickel be mitigated through  labeling for  nitinol containing devices.   Specifically,  
we recommend that the labeling  (e.g., instructions for use)  include a warning  for 
prolonged and permanent contacting devices.  Note  that a contraindication against use  
of nitinol-containing devices may be  appropriate when the risk of use  clearly 
outweigh any probable  benefit.  
 
51  Heim  KE,  Bates HK, Rush RE, Oller AR. (2007) Oral  carcinogenicity  study with  nickel  sulfate hexahydrate in  
Fischer 344 rats.  Toxicology  Applied  Pharmacology.  224(2):126-37.   
52  Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/factors-consider-when-
making-benefit-risk-determinations-medical-device-investigational-device  
53  Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/factors-consider-when-
making-benefit-risk-determinations-medical-device-premarket-approval-and-de   
15  
  Contains Nonbinding Recommendations  
 
 
We recommend the following warning (or similar)  be included in your  labeling:  
 
Warning: This device  contains  nitinol, an alloy of nickel and titanium.  Persons  
with allergic reactions to these metals may suffer an allergic reaction to this  
implant.   Prior to implantation, patients should be counseled on the materials  
contained in the device, as well as potential for allergy/hypersensitivity to these  
materials.  
 
 
16