The new ISO/ TS 37137-1:2021 (E) released in March 2021 provides much-needed guidance on the biological safety of absorbable medical devices/implants. Absorbable medical devices or implants are intentionally designed to degrade and therefore release degradation products into the patient, a feature making these products fundamentally different from other medical devices that are not intended to be absorbed by the patient’s body.
Bioabsorbable implants are used in orthopaedic, cardiovascular, soft tissue reconstruction or augmentation, and dental procedures such as “Guided Tissue Regeneration”. Absorbable collagen membrane is used in dental practice to separate a bony defect from overlying soft tissues, in order to create space in which new bone growth can occur. In orthopaedics, advances in science have allowed the production of implants with bioresorbable metal alloys with the requisite mechanical strength, and load bearing capability necessary for such procedures. A good example is that of metallic bioresorbable orthopaedic bone screws indicated for the fixation of bone after fractures or osteotomies. Bioabsorbable materials have been utilized for the fixation of fractures as well as for soft-tissue fixation. These implants offer the advantages of gradual load transfer to the healing tissue, and reduced need for hardware removal. Other examples are bioresorbable scaffolds or membranes for cardiovascular and soft tissue reconstruction.
Biological materials derived from devitalised allogeneic or xenogeneic tissues are increasingly providing alternative ways to create safer substitutes for synthetics, and provide an extracellular scaffold, a structural support for cell attachment and subsequent tissue development.
In absorbable medical devices, leachables are substances which get incorporated in the product due to manufacturing, cleaning, or other processing, and substances generated and released as consequence of its degradation. These chemical entities can cause unacceptable adverse systemic and/or local effects on surrounding cells or tissues. Therefore, degradation products should be characterized. The initial characterisation can be performed by reference to the literature to estimate the risk if the product has an established history of safe clinical use at the intended anatomical location. This essentially enables the manufacturer to leverage existing data and adequately justify why the literature is applicable to their product. ISO/ TS 37137-1:2021 again highlights that clinical relevance of available data is crucial in supporting the applicability of the literature to your product.
Another important point mentioned in the ISO/ TS 37137-1:2021 is that the standard tests are not designed to gauge the differences in biological response at different stages of degradation. It is not only the device which is decomposing in a particular manner whilst being absorbed, it is also the physiological environment which is changing due to the process of implantation and regeneration. The testing at a single point of extraction can result in the degradation products becoming available in the extraction fluid at once while in real life situation, their in-vivo release could be more gradual. In the case of combination products, extraction at a single timepoint may result in maximum possible load of the pharmaceutical ingredient, which might provide maximum exposure from the safety and toxicity point, but does not necessarily provide information on the local effects of gradual release. Also, the impact of the pharmaceutical ingredients in the test procedures, extractions and observed response should be carefully evaluated to be able to separate the effect or possible risks of the device to those of the active pharmaceutical ingredients. Consideration in ISO/ TS 37137-1:2021 is also given to the presence of particulate matter, the device once absorbed might leave behind particulate residue. This could trigger a certain biological response which needs to be accounted for in the risk assessment. As the in-vitro models are susceptible to the pH, osmolarity changes, the in-vivo response could be studied using suitable animal models. The choice of the animal model is critical in justifying the clinical relevance of the risk. For the skin sensitization test ISO/ TS 37137-1:2021 mentions that if validated invitro alternatives become available which could be used with absorbable medical devices they are preferred.
The physiological process of absorption of a particular degradation product, its possible chemical change, crystallinity, etc., which is very much related to the chemical characteristics of a compound are acknowledged in ISO/ TS 37137-1:2021. Consequently, the focus of this standard goes beyond chemical characterization in a given state, to chemical characterization in a dynamic physiological state, which might be similar or very different to the standard testing spectrum currently available. This also highlights necessity to justify not only the choice of literature, but also the applicability of a certain standard testing method. Therefore, following a test protocol as per the requirements of ISO 10993 series of biocompatibility standards, without justifying the choice would not be straightforward solution in near future. Throughout ISO/ TS 37137-1:2021, the importance of clinical exposure and clinical relevance is highlighted for the biological safety of absorbable medical devices/implants.
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