Integrated Approaches to Reduce Use of Animals in Biocompatibility Testing

Medical device manufacturers face the familiar challenge of demonstrating patient safety and meeting regulatory expectations without creating avoidable development delays. What’s changing is that more organizations are moving toward an integrated approach to biocompatibility testing to reduce reliance on animal (in vivo) testing.

Biocompatibility evaluation is moving away from a prescribed battery of tests and toward an evidence-based assessment of biological risk. In vitro methods (testing outside of living animals) are a major part of that transition, but they’re not the whole story. Chemical characterization, toxicological risk assessment (TRA), literature, material knowledge, and manufacturing information can help determine whether more testing is needed and which method can best address any remaining questions.

ISO Changed the Question

For years, medical device teams approached biocompatibility by selecting studies from a testing matrix based on the device category, then working through the list. The 2018 revision of ISO 10993-1 made the shift away from that mindset clear. In its evaluation tables, the emphasis moved from an “X” associated with testing to an “E” for biological effects that must be evaluated. The evaluation may draw on existing information or targeted testing. Teams may also provide a scientific rationale explaining why additional data isn’t warranted.

The latest updates to ISO 10993 move biocompatibility further away from a list of tests. The 2025 edition places biological safety within the device’s risk management process. ISO 10993-2:2022 focuses more specifically on animal welfare and the principles of replacing, reducing, and refining animal use.

Teams should begin by reviewing what’s already known about the device and its materials. If a biological question remains, they determine which type of evidence can answer it. An animal study may still be appropriate, but the rationale should explain why it’s needed and how it addresses the risk associated with patient contact.

The FDA’s partial recognition of ISO 10993-1:2025 is also important. The agency will continue accepting declarations of conformity to the 2018 edition during a transition period ending July 1, 2029. Method acceptance still depends on the device, biological effect, and submission context, so sponsors should align their plans with current FDA guidance and communicate with the appropriate review office when the path is unclear. The recognition nonetheless gives U.S. manufacturers a reason to build the newer risk-based framework into their planning now.

What In Vitro Methods Can Show

In vivo testing evaluates a response in a living animal. In vitro testing is performed outside a living organism, typically with cell cultures, reconstructed tissues, or laboratory models. Common in vitro methods used in medical device biocompatibility testing include cytotoxicity testing, certain genotoxicity assays, and irritation testing with reconstructed human epidermis models.

Compared to animal studies, in vitro methods can offer faster turnaround times, lower study costs, more controlled and reproducible test systems, and human-relevant or mechanistic information (in appropriate applications).

An animal study may show the outcome after exposure, while an in vitro assay can focus on a specific mechanism in a biological pathway. This gives scientists better insight into how or why a medical device or a test-article extract produced a response. That information can be used to select materials or investigate unexpected results. It can also speed up the team’s next development decision because in vitro testing is faster, easier, and more affordable than in vivo testing. In vitro testing provides a quick method to check a material first, then move forward with the device’s development and further testing.

In vitro tests cannot answer every biocompatibility question. A cell model doesn’t show everything that happens throughout the body or over an extended period. Systemic effects may require evidence beyond a single laboratory assay. The same may be true for implantation and the way surrounding tissue responds to a device. Manufacturers also need to confirm that regulators accept the method for its intended use because validation for one biological effect or device doesn’t automatically apply to another.

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Not a One-for-One Replacement

Moving away from animal studies isn’t as simple as choosing an in vitro test instead. Often, there is no direct substitute. 

The more effective model is an integrated evidence system. A manufacturer may combine device and material history with a literature review, chemical characterization, exposure assessment, TRA, and one or more in vitro methods. Together, those sources may answer a testing requirement without a direct substitute for the traditional animal study. 

Chemical characterization deserves a point of clarification—it’s not classical in vitro testing. Neither is TRA. Both are non-animal approaches that can reduce testing by showing what may migrate from a device, estimating patient exposure, and determining whether the exposure presents an unacceptable risk. Medical device manufacturers need to connect chemistry, exposure, toxicology, and clinical use into one clear, defensible story.

This is where the quality of interpretation matters more than the sheer quantity of data. A long extractables list doesn’t prove that every detected compound creates patient risk. The assessment must consider concentration, route, and duration of exposure, relevant populations, and the uncertainties in the underlying information.

Margins of safety can help show whether another animal study would add useful information. If estimated patient exposure is well below a level of toxicological concern, the chemistry and exposure data may be enough to address some biological effects. If questions remain, the team can choose a test designed to answer them instead of ordering a broad panel of studies.

Europe Is Turning Policy into Practice

Europe has been pressing for fewer animal studies for years. Directive 2010/63/EU requires researchers to replace, reduce, and refine the use of animals wherever possible. Medical device manufacturers may be asked why an animal study was needed and why the available non-animal evidence couldn’t answer the same question.

On June 1, 2026, the European Commission set out its plan to phase out animal testing for chemical safety assessments. The effort focuses on chemical safety rather than medical device testing, so it doesn’t create a deadline for device manufacturers. For the device industry, the larger impact is the push to move non-animal methods toward broader regulatory use.

The Medical Device Coordination Group was more direct in its MDCG 2025-9 guidance for breakthrough devices. Animal testing, it said, should be used only when existing scientific data and in vitro studies cannot provide enough safety information. The guidance applies only to breakthrough devices, but manufacturers should be prepared to show what they reviewed before deciding an animal study was needed.

Put the Strategy Up Front

Manufacturers will gain more from alternative methods when they consider them during the biological evaluation plan and gap analysis, not after a testing program has already been ordered. Early planning can identify whether an in vitro assay is appropriate for material screening, a design change, or an internal development decision. A faster assay may allow a team to reject problematic material before investing in a finished-device study.

A good strategy should define intended use and patient contact; review materials, processing, sterilization, and existing evidence; identify unresolved biological questions; and, select the evidence or methods needed to address them. For a device intended for use in U.S. and EU markets, manufacturers may need different supporting evidence; however, the scientific rationale should remain consistent.

Planning early can save time and money. A familiar animal study may seem the quickest route, but if it does not answer the question at hand, it can lead to more testing and delays. In some cases, a targeted in vitro method will be more useful, especially after a material change or when the team is trying to understand a specific biological response. 

U.S. manufacturers should not interpret a cautious regulatory path as a reason to ignore in vitro data. Where an alternative method is scientifically appropriate, it may support internal decisions, strengthen the weight of evidence, or supplement a submission even when another study remains necessary. It also helps build the body of device-relevant information that standards developers and regulators need when evaluating newer methods.

What This Means for Manufacturers

Modern biocompatibility assessments are risk-based and science-driven. Animal testing is no longer the starting point. It’s important to identify what evidence best answers the question and then choose the test that gets you there, whether it’s in vivo, in vitro, or a combination of other tests.

Non-animal evidence is becoming more influential. In vitro methods, chemical characterization, and toxicological risk assessments are playing a larger role in EU regulatory submissions and can also inform internal studies and strengthen FDA submissions.

Integrated evidence is the future. The strongest strategy is integrated evidence generation that combines the most relevant methods for each biological question, reducing unnecessary animal testing while improving science, efficiency, and patient safety.

As we seek to advance science and deliver the next generation of safe, effective devices that save and improve lives, it’s critical to look beyond the familiar testing matrix and consider what each method can provide. Taking an integrated approach can shorten development cycles, reduce avoidable costs, and limit animal use. More importantly, it produces a biological evaluation grounded in how the device is used and what patients may experience.

More from Hohenstein Medical: A Practical Guide to Toxicological Risk Assessment for Medical Devices

Katie Brinkman leads the development and strategic positioning of Hohenstein Medical’s medical device biocompatibility program, with a focus on chemical characterization, ISO 18562 gas pathway testing, and ethical, non-animal assays. Brinkman has over 15 years of experience in biological sciences, authoring numerous biocompatibility and toxicological risk assessment reports supporting global regulatory submissions. She’s an active member of the Society of Toxicology and the Regulatory Affairs Professionals Society. She is also certified as a Biological Safety Specialist by NAMSA.

Dr. Isabel Groh, ERT, DABT, is a senior toxicologist and biocompatibility expert at Hohenstein Medical, where she leads toxicological and biocompatibility evaluations and supports the strategic development of Hohenstein’s medical device safety services. With dual board certifications as a European Registered Toxicologist (ERT) and Diplomate of the American Board of Toxicology (DABT), Dr. Groh brings extensive experience in toxicology, biocompatibility and pharmacology. Dr. Groh also lectures in experimental clinical pharmacology and toxicology at the University Hospital Tübingen.