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阻塞（主动脉缩窄）或主动脉阻塞。 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、 以及基于导管的干预措施，例如支架。对于对药物没有反应的儿科患者， 手术后风险增加，不建议使用支架，因为成长中的儿童需要支架 要么与孩子一起成长，要么在组织重塑后生物降解，以便发育中的组织可以与孩子一起成长 身体的其余部分。不幸的是，大多数正在研发的生物可吸收支架（BRS）都是聚合物支架 专为冠状动脉设计。因此，这些支架太软，无法承受主动脉和肺动脉压力， 而且太小了。可生物吸收的金属是 BRS 的一个有吸引力的替代品。金属具有较高的机械性能 其强度和韧性优于聚合物，而且许多材料在体内都具有经过验证的生物相容性。这样的一位 金属是锌。作为基本生物功能的必需元素，锌被活体组织良好耐受，并且 最近的体内研究表明，锌具有稳定的腐蚀速率，没有严重的不良事件。 此外，与其他常用的支架金属相比，锌的断裂伸长率更高——这一点很重要 用于展开可扩张支架。这些特性使锌成为儿科 BRS 的绝佳候选者。 然而，纯锌的机械性能较弱，需要合金化以增加其强度。不幸的是，这 通常是以牺牲其他有利性能为代价的，例如腐蚀速率、延展性和/或生物相容性。 最近，用纳米颗粒增强金属材料已显示出作为一种策略的巨大潜力 显着提高机械性能。通过使用纳米颗粒分散体，锌的机械性能 可以显着改善，同时保留锌的有利特性。因此，我们的假设是 锌纳米复合材料可用于制造适用于儿科应用的 BRS， 4-6 个月内具有足够的结构完整性，然后完全降解为无毒副产品。的 开发使用锌纳米复合材料制造的用于治疗先天性心脏病的儿科 BRS 疾病将通过追求以下目标来实现： 目标 1 – 优化锌和纳米粒子的组合 强化锌纳米复合材料，用于制造功能性儿科 BRS。目标 2 – 体外表征锌纳米复合材料的生物相容性和机械性能。目标 3 – 评估 锌纳米复合材料支架在快速生长的猪动物模型中的体内功效和生物相容性。的 预期结果将为进一步微调核心材料提供急需的指导。最终，一个 机械坚固、生物相容且可生物降解的支架有可能彻底改变以下疾病的治疗 通过消除婴儿和老年人开胸手术的需要来治疗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技术的发展产生广泛的影响。 适用于许多临床应用的安全有效的生物可吸收金属植入物。

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.