Center for Devices and Radiological Health, FDA, Silver Spring, MD 20993, United States.
Center for Devices and Radiological Health, FDA, Silver Spring, MD 20993, United States.
Acta Biomater. 2018 Apr 1;70:304-314. doi: 10.1016/j.actbio.2018.01.024. Epub 2018 Feb 13.
Many cardiovascular device alloys contain nickel, which if released in sufficient quantities, can lead to adverse health effects. However, in-vivo nickel release from implanted devices and subsequent biodistribution of nickel ions to local tissues and systemic circulation are not well understood. To address this uncertainty, we have developed a multi-scale (material, tissue, and system) biokinetic model. The model links nickel release from an implanted cardiovascular device to concentrations in peri-implant tissue, as well as in serum and urine, which can be readily monitored. The model was parameterized for a specific cardiovascular implant, nitinol septal occluders, using in-vitro nickel release test results, studies of ex-vivo uptake into heart tissue, and in-vivo and clinical measurements from the literature. Our results show that the model accurately predicts nickel concentrations in peri-implant tissue in an animal model and in serum and urine of septal occluder patients. The congruity of the model with these data suggests it may provide useful insight to establish nickel exposure limits and interpret biomonitoring data. Finally, we use the model to predict local and systemic nickel exposure due to passive release from nitinol devices produced using a wide range of manufacturing processes, as well as general relationships between release rate and exposure. These relationships suggest that peri-implant tissue and serum levels of nickel will remain below 5 μg/g and 10 μg/l, respectively, in patients who have received implanted nitinol cardiovascular devices provided the rate of nickel release per device surface area does not exceed 0.074 μg/(cm d) and is less than 32 μg/d in total.
The uncertainty in whether in-vitro tests used to evaluate metal ion release from medical products are representative of clinical environments is one of the largest roadblocks to establishing the associated patient risk. We have developed and validated a multi-scale biokinetic model linking nickel release from cardiovascular devices in-vivo to both peri-implant and systemic levels. By providing clinically relevant exposure estimates, the model vastly improves the evaluation of risk posed to patients by the nickel contained within these devices. Our model is the first to address the potential for local and systemic metal ion exposure due to a medical device and can serve as a basis for future efforts aimed at other metal ions and biomedical products.
许多心血管设备合金都含有镍，如果释放的量足够大，可能会对健康产生不利影响。然而，植入设备后体内的镍释放以及随后的镍离子在局部组织和全身循环中的生物分布尚不清楚。为了解决这一不确定性，我们开发了一个多尺度（材料、组织和系统）生物动力学模型。该模型将植入心血管设备的镍释放与植入部位组织、血清和尿液中的浓度联系起来，这些都可以很容易地监测到。该模型使用特定的心血管植入物（镍钛诺隔瓣闭合器）进行了参数化，使用了体外镍释放测试结果、心脏组织体外摄取研究以及文献中的体内和临床测量数据。我们的结果表明，该模型能够准确预测动物模型中植入部位组织和血清和尿液中的镍浓度。该模型与这些数据的一致性表明，它可能为建立镍暴露限制和解释生物监测数据提供有用的见解。最后，我们使用该模型预测了由于使用广泛的制造工艺生产的镍钛诺设备的被动释放而导致的局部和全身镍暴露，以及释放率与暴露之间的一般关系。这些关系表明，在接受植入镍钛诺心血管设备的患者中，植入部位组织和血清中的镍水平将分别保持在 5μg/g 和 10μg/l 以下，前提是每个设备表面积的镍释放率不超过 0.074μg/（cm•d），总释放量不超过 32μg/d。
评估金属离子从医疗产品中释放的体外测试是否代表临床环境的不确定性是建立相关患者风险的最大障碍之一。我们已经开发并验证了一个多尺度生物动力学模型，该模型将心血管设备体内的镍释放与植入部位和全身水平联系起来。通过提供临床相关的暴露估计，该模型大大提高了对这些设备中镍对患者构成的风险的评估。我们的模型是第一个解决由于医疗设备而导致的局部和全身金属离子暴露的潜在风险的模型，并且可以作为未来针对其他金属离子和生物医学产品的努力的基础。
