Tag Archive for: GARDskin Medical Device

Evaluation of the applicability of GARDskin to predict skin sensitizers in extracts from medical device materials

Peer-reviewed article in Frontiers in Toxicology.

The application of GARD®skin to predict potential skin sensitizers in extracts from Medical Device materials has recently been published in a peer-reviewed article in Frontiers in Toxicology.

The study results provide evidence recognizing the GARD®skin Medical Device assay as a scientifically sound and ethical alternative to conventional animal methods, compatible with both polar and non-polar extraction vehicles, in line with the ISO 10993-12:2021 standard.

We are proud to provide the only OECD-validated in vitro assay for sensitization that is fully compatible with testing requirements specified in ISO 10993-12.

Jenvert Rose-Marie, Larne Olivia, Johansson Angelica, Berglin Mattias, Pedersen Emma, Johansson Henrik
Frontiers in Toxicology, Volume 6, 2024,ISSN 2673-3080
DOI=10.3389/ftox.2024.1320367

Keywords

GARD™; In vitro; Skin sensitisation; NAMs; Medical Device, ISO 10993, Biocompatibility

Abstract

Biocompatibility testing of medical devices is governed by the ISO 10993 series of standards and includes evaluation of skin sensitization potential of the final product. A majority of all medical devices are tested using in vivo methods, largely due to the lack of in vitro methods validated within the applicability domain of solid materials. The GARDskin method for assessment of chemical skin sensitizers is a validated method included in the OECD Test Guideline 442E, based on evaluation of transcriptional patterns of an endpoint-specific genomic biomarker signature in a dendritic cell-like cell, following test chemical exposure. The current study aimed to evaluate the applicability of GARDskin for the purpose of testing solid materials by incorporation of extraction procedures described in ISO 10993-12:2021, as well as to demonstrate the functionality of the proposed protocols, by testing of custom-made materials spiked with sensitizing agents. It was shown that GARDskin is compatible with both polar and non-polar extraction vehicles frequently used for the purpose of medical device biological testing. Further, exploring three different material types spiked with up to four different sensitizing agents, as well as three unspiked control materials and commercial reference products, it was shown that the method correctly classified all evaluated test materials. Taken together, the data presented suggest that GARDskin may constitute a valid alternative to in vivo experimentation for the purpose of skin sensitization assessment of medical devices.

 

Regulatory approval of medical devices according to MDR using in vitro data from GARDskin Medical Device for skin sensitization assessment

Presented at Eurotox 2023

Regulatory approval of medical devices according to MDR using in vitro data from GARDskin Medical Device for skin sensitization assessment

​Anna Chérouvrier Hansson1, Lisa Theorin1, Andy Forreryd1, Monica Grekula2 and Anneli Johansson3  1SenzaGen AB, 2Limulus Bio (Veranex), 3Duearity AB

 

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Conclusion

  • The GARDskin Medical Device assay is a novel method for assessment of skin sensitizing properties in leachables from solid materials, according to ISO 10993 standards.
  • Here, we demonstrate how GARDskin Medical Device data, combined with endpoint data from skin irritation and cytotoxicity testing, were successfully used in a data package for biocompatibility assessment of a novel medical device.
  • Following review by a notified body, an obtained CE-mark for the medical device Tinearity® G1 highlights unique opportunities to comply with the European Medical Device Regulation 2017/745 (MDR) using only in vitro data sources.

Abstract

Skin sensitizers in medical device extracts are conventionally assessed in vivo, primarily using the Guinea Pig Maximization Test and the Buehler Occluded Patch Test. However, there is a shift in the medical device toxicology field towards an increased use of in vitro methods for the evaluation of the biological safety of medical devices. Recently, in vitro methods for the endpoints skin irritation and skin sensitization have been included in the ISO 10993 standard, what makes it possible to perform this testing in vitro. The GARDskin assay is one of the in vitro methods for assessment of skin sensitization described in ISO 10993-10 and is the first OECD TG 442 method that has been adapted to work with oil, the non-polar extraction vehicle often used in in vivo studies for testing medical devices.

Here we share an example of how in vitro testing results, including results from the GARDskin Medical Device assay, were submitted to obtain CE-marking according to the European Medical Device Regulation 2017/745 (MDR) for Tinearity® G1, an innovative tinnitus treatment medical device. Tinearity® G1 was classified as a non-sensitizer in both polar and non-polar extracts in the GARDskin Medical Device assay. This result was used together with in vitro cytotoxicity and in vitro skin irritation results as weight of evidence together with review of chemical data in the risk assessment and biological evaluation of the medical device.

In vitro assays for assessment of the skin sensitization hazard and potency of isobornyl acrylate

Presented at SOT 2023

In vitro assays for assessment of the skin sensitization hazard and potency of isobornyl acrylate

Rose-Marie Jenvert1, Olivia Larne1, Ulrika Mattson1, Robin Gradin1, Kelly P Coleman2 and Andy Forreryd1  1SenzaGen, Lund, Sweden, 2Medtronic, Minneapolis, USA

 

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Conclusion

The GARDskin Medical Device assay can be used

  • with the extraction vehicles saline and oil as described 
    in ISO 10993. 
  • to detect low concentrations of skin sensitizers in a mixture and have the potential to replace in vivo tests 
    for risk assessment of skin sensitizers in medical devices. 
  • as risk assessment tool in combination with the 
    GARDskin Dose-Reponse assay during development of medical devices containing acrylates. 

Abstract

Acrylates have a wide range of applications for medical devices as they can bring several advantages  such as transparency, super-absorbency and hardness in combination with flexibility. The manufacturing of acrylic materials typically involves using at least one monomer of either acrylate or methacrylate which react to form a polymer. Several methodologies can be used for polymerization and the degree of polymerization of the final material can vary, hence some products can contain more residual monomers than others, and human exposure to these well-known skin sensitizers may increase the risk of developing the adverse immunological response, allergic contact dermatitis.

In 2020, the acrylate monomer, isobornyl acrylate (IBOA; CAS 5888-33-5), was named allergen of the year by American Contact Dermatitis Society due to the increased number of patients that were sensitized to IBOA found in glucose sensors and glucose pumps. IBOA is also present in other medical devices as plastic materials, coatings, sealants, glues, adhesives and inks. As a result, it is important to find alternatives to the animal methods used today to assess skin sensitization to properly identify the skin sensitizing potential of IBOA in medical devices and avoid the risk of sensitizing more individuals to this chemical.

The GARDskin (OECD TG 442E) assay, initially developed for hazard identification of a wide range of skin sensitizers, has been adapted for use with polar and non-polar solvents as described in ISO 10993-12:2021 and can be applied to assess the skin sensitization of medical devices. Further development of the GARDskin protocol has also enabled the prediction of skin sensitization potency by using a dose-response measurements. The cDV0 value derived from the assay corresponds to the lowest concentration required to exceed a binary classification threshold in GARDskin, and this concentration correlates significantly with LLNA EC3 and human NOEL values.  Linear regression models have been established to exploit these relationships for potency predictions.

In this study, we explored the ability of GARDskin Medical Device assay to detect the skin sensitizing potential of IBOA in a mixture of chemicals extracted from a silicone material (Nunsil MED-2000) in both saline and oil extract. Additionally, the skin sensitizing potency of IBOA was also investigated using the novel GARDskin Dose-Response assay. The acrylate monomer, IBOA, was correctly classified as a skin sensitizer in extracts of the silicon material spiked with IBOA using the GARDskin Medical Device assay. The correct classification of IBOA as a skin sensitizer provides evidence that the GARDskin Medical Device assay is sensitive enough to detect low concentrations of device-related skin sensitizers in a mixture of extracted chemicals and hence has the potential to replace in vivo tests for risk assessment of medical devices. Furthermore, IBOA was classified as a strong to moderate skin sensitizer (HP 2) with a predicted LLNA EC3 value of 0.848% and human NOEL value of 230 µg/cm2 using the GARDskin Does-Response assay. These predictions agree with existing human data and information from the ECHA registration dossier, illustrating the potential of the GARDskin Dose-Response assay to replace in vivo tests for quantitative potency assessment of potential skin sensitizers.

Ability of the GARDskin assay to Predict Skin Sensitization Response in the Guinea Pig Maximization Test

Joint poster with Risk Science Consortium,
Presented at the 2022 SOT

Rose-Marie Jenvert1, Alexandra Zambriczki Lee2, Ronald P Brown2
1SenzaGen, Lund, Sweden, 2Risk Science Consortium, LLC, Arnold, MD USA

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Conclusion

  • The GARD®skin assay is able to predict skin sensitization potential in humans with a level of accuracy that is equal to or exceeds that of GPMT and the LLNA.
  • As a result, the GARDskin assay serves as a promising alternative to assess the skin sensitization potential of medical devices.

Abstract

The preclinical safety assessment of medical devices typically involves an evaluation of the skin sensitization potential of the device. The GARDskin assay is being proposed as an in vitro alternative to the animal-based tests, Local Lymph Node Assay (LLNA) and Guinea Pig Maximization Test (GPMT), that are typically used to assess the skin sensitization potential of medical devices. The ability of the GARDskin assay to replace LLNA for prediction of skin sensitization response has been evaluated (e.g., Johansson et al., 2019) but since GARDskin has also been proposed as an alternative to the GPMT, it is important to compare the concordance of the prediction of the GARDskin assay with the in vivo response obtained in both of the animal-based tests.  Based on the results of the GARDskin assay for 122 compounds, this in vitro assay shows a high concordance with the predicted results of the LLNA (87.5%); however, the concordance for results obtained in the GPMT is much lower (71.2%). The concordance of the GARDskin assay and the GPMT is impacted by the relatively high number of false positive results (15 out of 73) compared to the false positives seen in the comparison between GARDskin and LLNA (2 out of 80).   The high number of false positives found when comparing the results from GARDskin and the GPMT results from the inaccurate characterization of the human skin sensitization potential of these compounds by the GPMT. Therefore, the low concordance between the GARDskin assay and the GPMT is due largely to inaccurate predictions of human skin sensitization potential by the GPMT and not by shortcomings of the GARDskin assay. Notably, the GARDskin assay (88.7% accuracy) outperforms the GPMT (83.0% accuracy) in the ability to predict the human sensitization response of compounds in this dataset. The results of this project show that the GARDskin assay is able to predict skin sensitization potential with a level of accuracy that is equal to or exceeds that of the currently accepted animal-based tests, suggesting that the GARDskin assay can serve as a promising alternative to the GPMT and the LLNA, and provide a more human relevant result for assessment of the skin sensitization potential of medical devices.

In vitro method for quantitative potency assessment of skin sensitizers during development of novel materials for intended use in medical devices

Joint poster with Sonova,
Presented at the 2022 SOT

Andy Forreryd1, Ulrika T Mattson1, David Waeckerlin2, Karla Lienau2, Robin Gradin1, Rose-Marie Jenvert1
1SenzaGen, Lund, Sweden, 2Sonova AG, Staefa, Switzerland

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Conclusion

The GARD®skin Dose-Response assay can be used as a tool for:

  • quantitative potency information of chemicals that might leach out of materials or medical devices.
  • internal decision-making during development of new materials for use in medical devices.

Abstract

New innovative materials for use in medical devices based on acrylates can bring several advantages such as super-absorbency, transparency, flexibility, toughness and hardness.

The manufacturing of acrylates typically involves using a monomer of either acrylate or methacrylate that is polymerized into the final product. The polymerization or hardening of material makes the monomers inert, however several methodologies can be used for polymerization, and they differ in the degree to which they result in a fully polymerized final product. Some products therefore contain more residual monomers than others and human exposure to these well-known skin sensitizers may increase the risk of skin sensitization and allergic contact dermatitis. To assess the risks resulting from exposure to these chemicals, potentially found in medical device material, it is necessary to accurately identify and characterize their skin sensitizing potential.

The GARDskin (OECD TGP 4.106) assay was initially developed for hazard identification of skin sensitizers. To derive potency information, a modification of the standard GARDskin protocol based on dose-response measurements has been proposed. The readout of the assay is a cDV0 value, which corresponds to the lowest concentration required to exceed a binary classification threshold in GARDskin. This concentration correlates significantly with LLNA EC3 and human NOEL values and linear regression models have been established to exploit these relationships for potency predictions. In this study, we explore the potential to use this novel assay for quantitative potency assessment of two acrylate monomers.

The GARDskin Dose-response assay classified both acrylate monomers as skin sensitizers with predicted LLNA EC3 values and human NOEL values of 0.848% and 22.4%, and 230 µg/cm2and 12200 µg/cm2, resulting in final classifications as a strong to moderate skin sensitizer (HP 2) and a moderate to weak sensitizer (HP 5), respectively. The results agreed with information in the ECHA registration dossiers and gathered human data evidence for the respective monomers, illustrating that GARDskin Dose-Response has the potential to replace the in vivo LLNA method for quantitative potency assessment of potential skin sensitizers during development of novel materials for use in medical devices.

Applicability domain of the GARD™skin Medical Device test for in vitro skin sensitization testing of medical devices

Poster presented at SOT 2021

Joshua Schmidt, Ron Brown and Rose-Marie Jenvert
SenzaGen Inc., Raleigh, NC, USA, Risk Science Consortium LLC, Arnold, MD, USA, SenzaGen AB, Lund, Sweden.

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Conclusion

  • The chemical space of compounds tested in GARD closely approximates the chemical space of compounds known to be released from medical device materials.
  • GARDskin is able to predict the skin sensitization potential of compounds released from medical device materials with a high degree of sensitivity and specificity, including: metals, lipophilic compounds and pre/pro haptens.

Abstract

Medical device toxicology is undergoing an exciting evolution; transitioning from a process that largely relied on the results of animal testing to evaluate the biological safety of devices in patients to one which is increasingly focused on the use of in vitro methods for the safety assessment of device materials.

Recently, in vitro methods to assess endpoints such as skin irritation and pyrogenicity have been validated and proposed for medical device testing, but a method to assess the potential for device-related skin sensitization to occur has not been sufficiently qualified. A number of in vitro skin sensitization test methods have been shown to have acceptable predictive ability for known skin sensitizers with structures that span a broad range of chemical classes, but the predictive ability of these methods has not been specifically evaluated using compounds typically found in materials used to manufacture medical devices. As a result, the need exists to qualify in vitro methods to assess the skin sensitization of compounds that may be released from medical devices, taking into account the applicability domain of known or potential skin sensitizers, including metals.

To address this challenge, the predictive ability of the GARD assay has been evaluated using a dataset of compounds known to be released from device materials.  Against these data, the assay correctly predicted 19 out of 21 lipophilic and pre-/pro-hapten compounds (90.5% accuracy), with one false positive (95.2% sensitivity) and one false negative (95.2% specificity) being predicted, thus increasing the confidence in use of this in vitro assay to assess the skin sensitization potential of medical devices.  Furthermore, we have also demonstrated that the GARD assay correctly predicts the skin sensitization response of nickel and cobalt salts (sensitizers) and a zinc salt (non-sensitizer). Overall, our data support the use of the GARDskin Medical Device assay as an in vitro alternative for the in vivo methods (e.g., GPMT, LLNA) that are typically used to assess skin sensitization as part of the biological safety assessment of medical devices.

Tag Archive for: GARDskin Medical Device

Webinar: Advancing NAMs for Skin Sensitization Testing

Spotlight on Applicability Domain, Quantitative Potency Assessment and Medical Devices

In case you missed SenzaGen’s poster presentations and scientific session at this year’s SOT, we are pleased to offer you a new opportunity to participate on April 23, 2024!

In this webinar Dr Andy Forreryd, SenzaGen’s in vitro toxicology expert, will summarize the latest GARD data from industry collaborations:

Corteva Agriscience | ExxonMobil Biomedical Sciences | L’Oréal | IFF | RIFM | Inotiv | Johnson Matthey | Sonova | Duearity

The webinar will last around 50 minutes, followed by a live Q&A. If you cannot attend the live event, make sure to register to get access to the recording.

Key topics

  • Agrochemical Formulations
  • UVCBs and Formulated Lubricant Products
  • Complex Mixtures
  • Metals
  • PoD for Quantitative Risk Assessment
  • NESILs for Fragrance Materials
  • Regulatory Acceptance According to MDR
  • Early-stage screening of materials intended for use in Medical Devices


Speakers