After ten years without a major update, ISO 10993‑6:2026 has officially been published, replacing the 2016 edition and reshaping how manufacturers evaluate local tissue responses to medical devices. The standard has been expanded from 29 to 41 pages in total, with two new Annex, and numerous additional paragraphs. This new 4th edition is not a cosmetic refresh but a substantial scientific, methodological, and regulatory overhaul.
The revision aligns ISO 10993‑6 with the broader modernization of the ISO 10993 series, especially the landmark ISO 10993‑1:2025 update, and reflects a decisive shift toward risk‑based, evidence‑driven biological evaluation, taking into account the increasingly complex medical device landscape and ensuring alignment with current scientific knowledge.
A Broadened Scope
ISO 10993‑6 retains its title — Tests for local effects after implantation — but its scope is now broader and more explicit. Of note, the 2026 edition also introduces several important definitions that clarify expectations and reduce ambiguity. This new version states that ISO 10993-6:
- Is applicable to devices used where skin or mucosa is breached, making it directly relevant to certain product categories. This creates a natural link to the broader “local effects after tissue contact” category introduced in ISO 10993-1:2025. Annex A (subcutaneous implantation) also refers to the testing of devices with long term contact with mucosal membranes.
- Is applicable to tissue‑engineered medical products (TEMPs) when relevant.
- Pays significantly more attention to non-solid, absorbable, and novel materials -reflecting their growing prevalence in modern devices.
- Details the applicability of the standard to neurological devices with the introduction of Annex E for peripheral nerve‑contacting devices while expanding the scope of Annex D to all devices in contact with the central nervous system, including the brain, spinal cord, dura mater, and cerebrospinal fluid.
Key Change
ISO 10993-6:2026 extends its scope, aligning with ISO 10993 1:2025’s broader category of “local effects after tissue contact”, and tightens and clarifies guidance for specific categories such as neural implants.
Risk-Based Approach
The new ISO 10993-6 is fully embedded in the ISO 14971 risk management framework – a hallmark of the broader 2025 revision to the whole ISO 10993 series. The revised standard requires manufacturers to conduct a structured biological risk evaluation before deciding whether in vivo implantation testing is even necessary.
Before any implantation study, manufacturers must:
- Develop a Biological Evaluation Plan (BEP) that justifies whether in vivo testing is needed
- Identify biological hazards and evaluate risks
- Consider chemical characterization, clinical history, and toxicological data before selecting tests
- Document every decision in the risk management file
Key Change
A formal document should address whether in vivo testing is necessary, with scientific rationale. For well‑characterized materials with strong existing evidence, implantation studies may be reduced or waived – but only with robust justification.
Stronger 3R Requirements: Replace, Reduce, Refine
Animal welfare provisions have been substantially strengthened in alignment with ISO 10993-2:2022 and the broader ethos of ISO 10993-1:2025. The 3R principle – Replace, Reduce, Refine – is more explicitly operationalized in the new Part 6. In vivo implantation studies should only be performed when no adequate alternative approach exists. The standard does not mention the use of validated in vitro replacements, but it opens the door more clearly than ever before.
When in vivo studies are necessary, ISO 10993-6:2026 requires:
| Replace | Reduce | Refine |
|---|---|---|
| Non-animal alternatives must be evaluated and documented as insufficient before any in vivo study is initiated. | Use the minimum number of animals needed for statistically meaningful data. Combine endpoints across studies as possible (e.g. ISO 10993-4, -11, -16 or vertical standard) to maximize information per animal. | Compliance with GLP and institutional ethics oversight. Study design must be strongly justified, with addition of specific endpoints to optimize use of each animal. |
Key Change
Manufacturers must demonstrate that alternatives were evaluated and found insufficient before any animal study is initiated. When an in vivo study is conducted, the design of the study should be strongly justified, and addition of specific endpoints to optimize the use of each animal is encouraged.
Sample Design and Control Selection
Test Article Design
- The new standard tightens the requirements around test article design. The implant must reflect the final finished form of the device, including any surface treatments, sterilization and geometry as possible (unless justified otherwise).
- A major addition is the formal acceptance of coupons (smaller, compositionally representative portions of complex devices) for multi-material devices. When used, coupons must represent the final device composition, include all tissue contacting materials and surface finishes, and be able to capture multi-material interactions.
Comparative / Reference Control Article
- The updated standard emphasizes the influence of physical characteristics that may influence tissue response and provides clearer guidance on control article selection and justification.
- While the use of a reference control such as the historical High-Density- Polyethylene (HDPE) may still be acceptable in some situations, it may not always be the best choice for a control and should be justified.
- A commercially available material that is clinically established and closely matches the test material in class, surface, and form is recommended to be used as a comparative control. If it does not exist, a control that is as close as possible should be selected and justified. Deviations from ideal matches should be justified.
- Comparative controls for degradable materials should also be selected to match the degradation kinetics of the test article as closely as possible. The use of a non-absorbable reference control, such as HDPE, is still recommended when appropriate, in addition to the comparative degradable control article.
Key Change
Device should be tested in its final finished form; representative coupons may be used if justified. The use of a commercially available comparative control matching as closely as reasonably possible to the test article is encouraged, so that the tissue reaction is compared to what has been clinically proven.
Test Methods and Annex Update
ISO 10993‑6:2026 tightens implantation site selection and expands annex guidance to ensure clinically relevant, anatomically precise, and scientifically robust testing across a wider range of device types.
Study designs must justify the chosen implantation site with explicit linkage to the device’s intended clinical use. Selection should consider local anatomy, function, expected exposure time, and whether the site will capture relevant degradation or device‑tissue interactions. ISO 10993-6 explicitly allows the use of implantation sites other than those listed in the normative annexes, if scientifically justified and documented.
| Annex | Site / Scope | Key Update | Status |
| A (normative) | Subcutaneous Tissue | Now applicable to long-term mucosal contact devices | UPDATED |
| B (normative) | Muscle | New guidance on trocars and verifying implant placement | UPDATED |
| C (normative) | Bone | Clear distinction between cancellous and cortical sites; expanded implant size ranges; emphasis on skeletal maturity and bone densitometry | UPDATED |
| D (normative) | Central Nervous System (CNS) | Scope expanded – now covers all CNS-contacting devices: brain parenchyma, spinal cord, dura mater, and cerebrospinal fluid (CSF) spaces. New technical details on histological biomarkers, sampling methodology, and clinical observations | UPDATED |
| E (informative) | Peripheral Nerve | Entirely new dedicated methods for peripheral nerve-contacting devices, with approach analogous to Annex D | NEW |
Neurology Spotlight
Manufacturers of devices contacting brain, dura mater, CSF of peripheral nerves should conduct a comprehensive review of their study protocol including – but not limited to – implantation site selection, in-life and terminal procedures, histopathological processing and evaluation as well as scientific justifications in light of the updates to ISO 10993-6 and new Annex D and E requirements.
Of note, ASTM F 2901 (Standard Guide for Neurotoxicity Evaluation and Additional Biocompatibility Assessment for Medical Devices Contacting the Nervous System) was also updated in 2026.
Key Change
Standard test methods were partially updated to include some helpful technical details. Main technical changes related to neurological devices: neurotechnology manufacturers should review their preclinical protocols to ensure study design and planned technical procedures meet the new, device‑specific requirements.
Histopathological Evaluation Refinements: Addition of a NEW Annex G
10993-6:2026 introduces Annex G, a new informative annex on microscopic evaluation, in addition to updates of Annex F and the main body of the standard describing the general methodology of evaluation of tissue response.
Main topics covered by Annex G:
- Methods for tissue harvesting, processing and histopathological evaluation have been described to reflect current best practice
- The revised standard emphasizes the use of semi-quantitative scoring systems (described in Annexes F and G), allowing comparisons to be made between test materials and appropriate controls
- It should be noted that the scoring systems provided in these Annexes are merely examples and should be adapted based on the type of device and implant site, in order to accurately reflect the tissue response observed under the microscope
- Scientific interpretation of the scores by the expert pathologist as well as qualitative differences in tissue response types should be reported, scores alone are not sufficient
- The inclusion of microphotographs illustrating the implant-tissue interface and peri-implant tissue response is recommended
- Lymph nodes collection and evaluation is described
- Information is given on methodology to evaluate absorption or degradation of an implant, including two semi-quantitative scoring system examples
- Again, these scoring systems are examples and should be adapted based on the type of device and implant site
Key Change
This update highlights the importance of histological endpoints in this type of study and puts a strong emphasis on scientific approach and expertise of the study pathologist. Annexes F and G are informative only, highlighting the flexibility afforded by pathologists in interpreting tissue responses, which can be highly complex and difficult to standardize depending on the implant site and device characteristics.
Enhanced Requirements for Degradable or Absorbable Materials
The revised standard pays significantly more attention to degradable or absorbable materials, reflecting their growing prevalence in modern implantable devices. These changes are visible all through the document. Expectations in terms of study duration, evaluation, and grading system were updated in the new version.
Manufacturers must address the following:
- Degradation Characterization: Description of the degradation characteristics (e.g. fragmentation, debris generation, remnants, etc.) and kinetics (using a standardized histological semi-quantitative scoring system) and their correlation with tissue response
- Control Article Justification: Justification of the choice of appropriate control, based on its degradation characteristics and kinetics
- Multiple Time Points: Study design must include multiple time points covering the full degradation profile and steady state (now defined as a “biologically stable condition wherein change in the test system’s cellular activity, morphology or features is no longer detected over a period of time”) or beyond if needed
Key Change
Manufacturers working with degradable or absorbable materials will face heightened expectations, whereas requirements are largely unchanged for stable, non-absorbable materials with established clinical history, provided chemical characterization is comprehensive.
Conclusion
ISO 10993‑6:2026 is one of the most complex and scientifically demanding parts of the ISO 10993 series. The new edition provides a structured framework while preserving the flexibility needed for diverse device types.
The revision pushes manufacturers toward scientific justification, risk‑based decision‑making, and modern biological evaluation methods – ensuring that implantation studies remain relevant, ethical, and aligned with current scientific understanding.
The Value of Partnering with an Experienced CRO
Navigating these new expectations demands both technical depth and strategic regulatory insight. Designing a compliant implantation study is a scientific exercise that directly influences the success of global submissions, thereby saving time and resources.
At NAMSA, we understand the challenges manufacturers face when defining the optimal preclinical strategy under the new ISO 10993‑6 framework. Our teams combine preclinical scientific expertise, regulatory experience, and deep familiarity with the ISO 10993 series to help you design studies that are not only compliant, but scientifically robust and defensible.
NAMSA supports manufacturers at every stage of the process:
- BEP development aligned with ISO 14971 and ISO 10993‑1:2025
- Regulatory strategy, ensuring alignment with FDA, EU, and global expectations for all device types
- Study design optimization, consistent with the new ISO 10993-6 and other appropriate standard requirements
- Execution of all type of GLP‑compliant implantation studies, including neural and degradable‑material models
- Advanced histopathology evaluation, leveraging toxicologic pathologists experienced with Annex G expectations
By prioritizing scientific rigor, ethical study design, and regulatory compliance manufacturers can confidently navigate the evolving landscape of biological evaluation. NAMSA is ready to guide you through these challenges with precision, expertise, and a commitment to accelerating safe, effective medical devices to market.
Related Reading – Published May 2026
The FDA’s Recognition of ISO 10993-1:2025: What Does It Mean?
On 25 May 2026, the FDA officially recognized ISO 10993-1:2025. Understanding the scope of that recognition — including what is not recognized (partial recognition for skin-contacting materials) — is essential context for manufacturers navigating the full ISO 10993 series update alongside ISO 10993-6:2026. NAMSA’s biological safety experts break down the practical implications for daily biocompatibility work.
Frequently Asked Questions (FAQs)
What is the most significant change in this version?
The addition of Annex G on microscopic evaluation is the most significant change of this new version. While the evaluation of local tissue effects has always relied on microscopic assessment, the methodology has not been described until now. Although primarily informative, this annex provides valuable guidance on how to perform histological tissue preparation and how the pathologists should conduct the evaluation in local tissue effects studies.
For non-specialists, it offers useful guidance and highlights key points to consider when initiating such a study. Annex G – as well as Annex F – also emphasizes the central role of the study pathologist in the evaluation process. Indeed, although tables of parameters to be assessed (in Annex F) and scoring criteria for material absorption (in Annex G) are provided, these are intended only as examples. The study pathologist must determine any necessary adaptations to the evaluation criteria based on the study design, the type of device, and the implantation site.
When should I start using this new version of the standard?
ISO 10993-6 was published in April 2026, closely followed by the EN ISO version in May. As of June 2026, neither the US nor the EU had published this new version on their list of recognized standards; recognition would then be followed by a transition period. Nevertheless, the scientific approach outlined in this version can be regarded as the ‘state of the art’ and is already being adopted by regulators such as the FDA and EU Notified Bodies, as evidenced by some recent feedback and interactions.
Manufacturers preparing submissions should engage with their regulatory affairs teams early on, justifying their chosen approach and taking into account the framework of this new version, while also including appropriate scientific justification in their study design. Manufacturers who adapt early will be better placed to ensure smooth regulatory interactions and future‑proof biological evaluations.
I have a long-term mucosal contact device. Do I have to perform a subcutaneous tissue implantation study?
Although this is one of the major modifications to Annex A, the answer is NO. This category of devices has been introduced to provide a broader perspective on the model. Indeed, for certain devices, subcutaneous tissue represents an appropriate site for local tissue evaluation. However, this is not the case for all long-term mucosal contact devices and some of them may be more appropriately evaluated using alternative implant sites.
For example, urinary catheters may be evaluated using a standard intramuscular implantation as this approach is more relevant and closer to clinical use. Other clinically relevant sites not listed in Annex A may also be used for some mucosal contacting devices.
In addition, several device-specific vertical ISO standards exist for certain families of devices, providing tailored recommendations that should be followed. It is essential to ensure that the device under evaluation complies with these specific standards alongside ISO 10993-6.
Working with an experienced contract research organization that is familiar with both the models and the relevant standards can help develop the most appropriate study protocol, thereby saving time and resources.
Why are there only a limited number of models described in the Annexes?
The market for implantable devices is a dynamic and rapidly evolving field. Although ISO 10993-6 provides key principles for designing local tissue effects studies, the standard cannot cover all device types. As it allows for the use of implantation sites beyond those explicitly listed, this new version remains open to alternative models.
For example, no annex has been developed that specifically addresses wound healing devices. Discussions regarding this addition took place within the ISO working group, however it was concluded that the standard is sufficiently flexible to accommodate the use of other appropriate models.
