An integrated benefit-risk assessment of cobalt-containing alloys used in medical devices: Implications for regulatory requirements in the European Union.

In 2017, the European Union (EU) Committee for Risk Assessment (RAC) recommended the classification of metallic cobalt (Co) as Category 1B with respect to its carcinogenic and reproductive hazard potential and Category 2 for mutagenicity but did not evaluate the relevance of these classifications for patients exposed to Co-containing alloys (CoCA) used in medical devices. CoCA are inherently different materials from Co metal from a toxicological perspective and thus require a separate assessment. CoCA are biocompatible materials with a unique combination of properties including strength, durability, and a long history of safe use that make them uniquely suited for use in a wide-range of medical devices. Assessments were performed on relevant preclinical and clinical carcinogenicity and reproductive toxicity data for Co and CoCA to meet the requirements under the EU Medical Device Regulation triggered by the ECHA re-classification (adopted in October 2019 under the 14th Adaptation to Technical Progress to CLP) and to address their relevance to patient safety. The objective of this review is to present an integrated overview of these assessments, a benefit-risk assessment and an examination of potential alternative materials. The data support the conclusion that the exposure to CoCA in medical devices via clinically relevant routes does not represent a hazard for carcinogenicity or reproductive toxicity. Additionally, the risk for the adverse effects that are known to occur with elevated Co concentrations (e.g., cardiomyopathy) are very low for CoCA implant devices (infrequent reports often reflecting a unique catastrophic failure event out of millions of patients) and negligible for CoCA non-implant devices (not measurable/no case reports). In conclusion, the favorable benefit-risk profile also in relation to possible alternatives presented herein strongly support continued use of CoCA in medical devices.

A hazard evaluation of the reproductive/developmental toxicity of cobalt in medical devices.

Cobalt (Co) is an essential element with human exposure occurring from the diet, supplement ingestion, occupational sources, and medical devices. The European Chemical Agency (ECHA) recently voted to classify Co metal as a Reproductive Hazard Category 1B; presumed human reproductive toxicant due to adverse testicular effects in male rodents. A weight of evidence evaluation of the preclinical reproductive and developmental toxicity studies and available clinical data was performed to critically evaluate the relevance of this proposed classification for Co in medical devices. Reproductive responses to Co are limited to the male testes and sperm function following high systemic exposure in rodents, only at Co concentrations/doses that result in overt toxicity (i.e., above the maximum tolerable dose (MTD)). The potential mechanisms of Co reproductive/developmental toxicity, including its indirect mode of action in the testes and relevance to humans, are discussed. The available preclinical and clincial evidence suggests that it would be more appropriate to classify Co as a Reproductive Hazard Category 2 compound: suspected human reproductive toxicant and, in the case of Co-containing medical devices, it should not be considered a reproductive hazard.

Carcinogenic hazard assessment of cobalt-containing alloys in medical devices: Review of in vivo studies.

Cobalt (Co) alloys have been used for over seven decades in a wide range of medical devices, including, but not limited to, hip and knee implants, surgical tools, and vascular stents, due to their favorable biocompatibility, durability, and mechanical properties. A recent regulatory hazard classification review by the European Chemicals Agency (ECHA) resulted in the classification of metallic Co as a Class 1B Carcinogen (presumed to have carcinogenic potential for humans), primarily based on inhalation rodent carcinogenicity studies with pure metallic Co. The ECHA review did not specifically consider the carcinogenicity hazard potential of forms or routes of Co that are relevant for medical devices. The purpose of this review is to present a comprehensive assessment of the available in vivo preclinical data on the carcinogenic hazard potential of exposure to Co-containing alloys (CoCA) in medical devices by relevant routes. In vivo data were reviewed from 33 preclinical studies that examined the impact of Co exposure on local and systemic tumor incidence in rats, mice, guinea pigs, and hamsters. Across these studies, there was no significant increase of local or systemic tumors in studies relevant for medical devices. Taken together, the relevant in vivo data led to the conclusion that CoCA in medical devices are not a carcinogenic hazard in available in vivo models. While specific patient and implant factors cannot be fully replicated using in vivo models, the available in vivo preclinical data support that CoCA in medical devices are unlikely a carcinogenic hazard to patients.

Grafting of calcium chelating functionalities onto PLA monofilament fiber surfaces.

Polymer surface grafting is widely used in the field of bone regeneration to increase calcium phosphate (CaP) adhesion, with the intent of improving mechanical properties of CaP-polymer composite cements. Reinforcement can be achieved using multiple combined functional groups and/or complex surface geometries that, however, concurrently influence multiple effects such as wetting, roughness, and interfacial strengthening. This study focused on the influence of a chelating group, namely aspartic acid, on the adsorption of divalent ions such as Ba2+ or Ca2+ onto poly-l-lactic acid (PLA) films. The films were analyzed using contact angle measurements and X-ray photoelectron spectroscopy. The adsorption of CaP and its interfacial mechanical properties were investigated using functionalized PLA monofilaments whose surface roughness was analyzed using white light interferometry. Mechanical analysis was conducted by performing pull-out tests. The surfaces were analyzed using scanning electron microscopy and energy dispersive X-ray spectroscopy. Using aspartic acid as a chelating group resulted in a 50 % increased adsorption of barium, an almost threefold increase in calcium coverage of the fiber compared to the control group and a twofold increase in interfacial stiffness. No significant increase in interfacial strength was determined, most likely due to the weakness of the CaP matrix, which was partially visible as residues on the monofilaments in the postfracture imaging. This study shows the potential of surfaces functionalized with aspartic acid as a simple alternative to complex polypeptide based functional groups for the adsorption of divalent ions such as calcium on poly-lactic acid in bone regenerating applications.

Rings, chains and helices: new antimicrobial silver coordination compounds with (iso-)nicotinic acid derivatives.

Complexes with silver ions have great potential for applications in medicine. Appropriate bidentate ligands, binding to silver ions, are able to generate coordination polymers as well as molecular entities as a function of ligand flexibility, conformation and length. Here we present the continuation of our previous studies in this field with ligands based on oligomers of polyethylene glycol, functionalized at both ends with either nicotinic or isonicotinic acid. The structures of three ligands and nine new coordination compounds are presented. A large variety of structures are obtained as a function of counterion, solvent and ligand-to-metal ratio, such as isolated rings, offset stacked rings, parallel chains and entangled chains, and their antimicrobial properties as well as biocompatibility are assessed.