Graduate School of Peking Union Medical College, Beijing 100730, China.
Department of Reproduction and Physiology, National Research Institute for Family Planning, Beijing 100081, China.
Acta Biomater. 2021 Jul 1;128:523-539. doi: 10.1016/j.actbio.2021.04.037. Epub 2021 Apr 24.
Copper intrauterine device is one of the most adopted contraceptive methods with high effectiveness (over 99 %), low cost, spontaneous reversibility and long-lasting usage. However, the side effects induced from the initial burst release of copper ions (Cu) hinder the continuation of the Cu-IUD made of Coarse-Grained Copper (CG Cu). We proposed to tailor the bio-corrosion behaviors of better control of Cu release via the addition of bioactive Mg into the Ultra-Fine Grained (UFG) Bulk Cu. Thus, UFG bulk Cu with 0.4 wt.% Mg was produced via equal-channel angular pressing. The microstructures of the UFG Cu-0.4Mg was observed using electron backscatter diffraction and transmission electron microscopy techniques. The in vitro long-term corrosion behaviors in simulated uterine fluid, cytotoxicity to four cell lines, in vivo biocompatibility and contraceptive efficacy were all studied on CG Cu, UFG Cu and UFG Cu-0.4Mg materials. The results demonstrate that both the ultrafine grains and the addition of bioactive Mg into Cu contribute to the suppression of the burst release of Cu in the initial stage and the maintenance of high level Cu in long-term release. Moreover, the UFG Cu-0.4Mg also exhibited much improved cell and tissue biocompatibility from both the in vitro and in vivo evaluations. Therefore, the contraceptive efficacy of UFG Cu-0.4Mg is still maintained as high as the CG Cu and UFG Cu while the side effects are significantly eased, suggesting the high potential of the UFG Cu-0.4Mg alloy as a new upgrading or alternative material for Cu-IUD. STATEMENT OF SIGNIFICANCE: The side effects from burst release of Cu at the initial implantation stage of Cu-containing intrauterine devices (Cu-IUD) is one of the main drawbacks of these devices. In this work, an ultra-fine-grained Cu (UFG Cu) alloyed with a low amount of bioactive Mg was used for a Cu-IUD. The UFG Cu-0.4Mg alloy exhibited suppressed burst release of Cu at initial implantation, while active Cu release for long-term usage was maintained, comparable to coarse-grained pure Cu. Furthermore, the UFG Cu-0.4Mg alloy displayed significantly improved biocompatibility with human uterus cells and a much decreased inflammatory response within the uterus. Therefore, the side effects from Cu-IUD were eased, while high antifertility efficacy of the UFG Cu-0.4Mg alloy was maintained. The UFG Cu-0.4Mg alloy is promising for Cu-IUD.
铜宫内节育器是最常采用的避孕方法之一，具有高效性（超过 99%）、低成本、自发可逆性和长效性。然而，由于铜离子（Cu）的初始爆发释放引起的副作用，阻碍了由粗晶粒铜（CG Cu）制成的 Cu-IUD 的继续使用。我们提出通过向超细晶粒（UFG）块状铜中添加生物活性 Mg 来定制更好的生物腐蚀行为，从而控制 Cu 的释放。因此，通过等径角挤压生产了含有 0.4wt.%Mg 的 UFG 块状 Cu。使用电子背散射衍射和透射电子显微镜技术观察 UFG Cu-0.4Mg 的微观结构。在 CG Cu、UFG Cu 和 UFG Cu-0.4Mg 材料上研究了在模拟子宫液中的长期体外腐蚀行为、对四种细胞系的细胞毒性、体内生物相容性和避孕效果。结果表明，超细晶粒和向 Cu 中添加生物活性 Mg 都有助于抑制初始阶段 Cu 的爆发释放，并维持长期释放中高水平的 Cu。此外，UFG Cu-0.4Mg 还表现出从体外和体内评估都明显改善的细胞和组织生物相容性。因此，UFG Cu-0.4Mg 的避孕效果仍然保持在 CG Cu 和 UFG Cu 一样高，而副作用明显减轻，这表明 UFG Cu-0.4Mg 合金作为 Cu-IUD 的新型升级或替代材料具有很大的潜力。
含铜宫内节育器（Cu-IUD）在植入初期 Cu 爆发释放引起的副作用是这些装置的主要缺点之一。在这项工作中，使用含有少量生物活性 Mg 的超细晶粒 Cu（UFG Cu）来制造 Cu-IUD。UFG Cu-0.4Mg 合金在初始植入时表现出抑制 Cu 的爆发释放，同时维持长期使用的活性 Cu 释放，与粗晶粒纯 Cu 相当。此外，UFG Cu-0.4Mg 合金与人体子宫细胞具有明显改善的生物相容性，并且子宫内的炎症反应大大降低。因此，Cu-IUD 的副作用得到缓解，而 UFG Cu-0.4Mg 合金的高抗生育效果得到维持。UFG Cu-0.4Mg 合金有望用于 Cu-IUD。
