A Predictive Toxicokinetic Model for Nickel Leaching from Vascular Stents.

In vitro testing methods offer valuable insights into the corrosion vulnerability of metal implants and enable prompt comparison between devices. However, they fall short in predicting the extent of leaching and the biodistribution of implant byproducts under in vivo conditions. Physiologically based toxicokinetic (PBTK) models are capable of quantitatively establishing such correlations and therefore provide a powerful tool in advancing nonclinical methods to test medical implants and assess patient exposure to implant debris. In this study, we present a multicompartment PBTK model and a simulation engine for toxicological risk assessment of vascular stents. The mathematical model consists of a detailed set of constitutive equations that describe the transfer of nickel ions from the device to peri-implant tissue and circulation and the nickel mass exchange between blood and the various tissues/organs and excreta. Model parameterization was performed using (1) in-house-produced data from immersion testing to compute the device-specific diffusion parameters and (2) full-scale animal in situ implantation studies to extract the mammalian-specific biokinetic functions that characterize the time-dependent biodistribution of the released ions. The PBTK model was put to the test using a simulation engine to estimate the concentration-time profiles, along with confidence intervals through probabilistic Monte Carlo, of nickel ions leaching from the implanted devices and determine if permissible exposure limits are exceeded. The model-derived output demonstrated prognostic conformity with reported experimental data, indicating that it may provide the basis for the broader use of modeling and simulation tools to guide the optimal design of implantable devices in compliance with exposure limits and other regulatory requirements.

On the development of physiologically based toxicokinetic (PBTK) models for cardiovascular implants.

Local and systemic contamination caused by metal ions leaching from medical device materials is a significant and continuing health problem. The increasing need for verification and validation, and the imposition of stringent government regulations to ensure that the products comply with the quality, safety, and performance standards, have led regulatory bodies worldwide to strongly recommend the use of modeling and simulation tools to support medical device submissions. A previously published physiologically based toxicokinetic (PBTK) model, is here expanded and enriched by an additional separate tissue compartment to better resemble normal physiology and by the introduction of time-dependent functions to describe all biokinetic parameters. The new model is exercised in conjunction with state-of-the-art probabilistic, Monte Carlo methodology to calculate the predictions' confidence intervals and incorporate variability associated with toxicological biodistribution studies. The quantitative consistency of the model-derived predictions is validated against reported data following the implantation of nickel-containing cardiovascular devices in humans and minipigs. Finally, a new methodology for compartmental toxicological risk assessment is presented that can be used for forward or reverse dosimetry. Our work is aimed at providing a computational tool to optimize the device design characteristics and safeguard that the substances released do not exceed permissible exposure limits.