Novel Zinc-Nanocomposite Materials for Pediatric Bioresorbable Cardiovascular Stents

摘要 许多患有先天性心脏病的婴儿出生时就有主动脉梗阻(主动脉缩窄)或 肺动脉。患有这些严重血管阻塞的成年人的选择包括药物、手术、 以及支架等基于导管的介入治疗。对于对药物没有反应的儿科患者， 手术会增加风险，不推荐使用支架，因为成长中的儿童需要支架 要么和孩子一起成长，要么在组织重塑后生物降解，这样发育中的组织就可以一起成长 身体的其余部分。遗憾的是，大多数正在研制的生物可吸收支架(BR)都是聚合物支架 专为冠状动脉设计。因此，这些支架太软，不能处理主动脉和肺的压力， 而且太小了。生物可吸收金属是BRS的一种有吸引力的替代品。金属具有更高的机械强度 比聚合物具有更高的强度和韧性，而且许多聚合物在体内具有良好的生物相容性。这样的一个 金属就是锌。作为基本生物功能中的一种基本元素，锌在活组织中具有良好的耐受性，而且 最近的体内研究表明，锌具有稳定的腐蚀速度，没有严重的不良事件。 此外，与其他通常研究的支架金属相比，锌具有更大的失效延伸率--这一点很重要 用于可扩展支架的部署。这些特性使锌成为儿科BR的极佳候选者。 然而，纯锌的机械性能较弱，需要合金化来增加其强度。不幸的是，这 通常以其他良好的性能为代价，例如腐蚀率、延展性和/或生物相容性。 最近，纳米颗粒增强金属材料作为一种策略显示出巨大的潜力 显著提高机械性能。通过使用纳米粒子分散体，锌的机械性能 可以在保持锌的良好性能的同时显著提高。因此，我们的假设是 锌纳米复合材料可用于制造BR，适用于维持以下条件的儿科应用 在完全降解为无毒副产品之前，保持足够的结构完整性4-6个月。这个 应用锌纳米复合材料治疗先天性心脏病的儿科BRS的研制 将通过追求以下目标来实现疾病：目标1-优化锌和纳米颗粒组合 目的：强化锌-纳米复合材料，用于制造儿童功能性脑脊液。目标2- 表征锌纳米复合材料的生物相容性和体外力学性能。目标3-评估 锌纳米复合支架在快速生长猪动物模型中的体内疗效和生物相容性。这个 预期结果将为进一步微调核心材料提供亟需的指导。最终，一个 机械坚固、生物相容和可生物降解的支架具有革命性的治疗 通过消除婴幼儿和老年人开胸手术的需要，儿科患者的动脉阻塞 孩子们。此外，从这项研究中获得的知识将对 安全有效的生物可吸收金属植入物，可用于多种临床应用。

ABSTRACT Many infants with congenital heart disease are born with obstruction in the aorta (aortic coarctation) or in the pulmonary arteries. Options for adults with these severe vascular obstructions include medications, surgery, and catheter-based interventions such as stents. For pediatric patients that do not respond to medications, surgery posts increased risks, and stents are not recommended because growing children require stents that either grow with the child, or biodegrade after tissue remodeling, so that the developing tissues can grow with the rest of the body. Unfortunately, most bioresorbable stents (BRS) in the pipeline are polymer stents designed for coronary arteries. As such, these stents are too soft to handle aortic and pulmonary pressures, and too small. Bioabsorbable metals are an attractive alternative for BRS. Metals have a higher mechanical strength and toughness than polymers, and many have a proven history of biocompatibility in vivo. One such metal is zinc. As an essential element in basic biological functions, zinc is well tolerated by living tissues, and recent in vivo studies have demonstrated that zinc has a steady corrosion rate with no severe adverse events. Furthermore, zinc has greater elongation to failure than other commonly studied metals for stents – important for expandable stent deployment. These properties make zinc an excellent candidate for pediatric BRS. However, pure zinc is mechanically weak, and requires alloying to the increase its strength. Unfortunately, this often comes at the cost of other favorable properties, such as corrosion rate, ductility, and/or biocompatibility. Recently, reinforcing metallic materials with nanoparticles has demonstrated great potential as a strategy to significantly enhance mechanical properties. By using nanoparticle-dispersions, zinc’s mechanical properties can be improved significantly while retaining the favorable properties of zinc. Therefore, our hypothesis is that zinc-nanocomposites can be used to manufacture BRS suitable for pediatric applications that maintain sufficient structural integrity for 4-6 months before completely degrading into non-toxic byproducts. The development of a pediatric BRS fabricated using zinc-nanocomposite for the treatment of congenital heart disease will be achieved by pursuing the following aims: Aim 1 – Optimize zinc and nanoparticle combination to strengthen zinc-nanocomposite materials for manufacturing of functional pediatric BRS. Aim 2 – Characterize the biocompatibility, and mechanical properties of zinc- nanocomposites in vitro. Aim 3 – Assess in vivo efficacy and biocompatibility of zinc-nanocomposite stents in a rapidly growing pig animal model. The anticipated results will provide much needed guidance to further fine tune the core materials. Ultimately, a mechanically robust, biocompatible, and biodegradable stent has the potential to revolutionize the treatment of arterial obstructions in pediatrics patients by eliminating the need for open chest surgeries in infants and older children. Additionally, the knowledge gained from this research will have a broad impact on the development of safe and efficacious bioabsorbable metallic implants for many clinical applications.