Biodegradable Piezoelectric Nanocomposite Scaffold with Physical Exercise to Heal Major Cartilage Defects in Large Animals

摘要 骨关节炎(OA)是一种与关节内软骨损伤有关的疾病，影响着数百万人 每年都有。目前的药物，包括止痛药和消炎药，只是减轻症状 但不能治愈这种疾病，因为外科方法使用自体或同种异体软骨替代移植难以治愈 感染、供体部位发病率、免疫排斥和有限的组织供应等问题。在这方面， 基于生物材料支架、干细胞和生物生长的再生工程方法 构建人工替代软骨组织的因素已经成为一个重要的领域。虽然增长因素 这些化学物质都很强大，但它们的毒性和副作用令人严重担忧。或者， 已知电刺激(ES)在促进骨和软骨生长方面具有显著效果。 由于生物电是生物体内在的生理信号，ES的使用可能提供了更多的 诱导软骨生长的自然方法。然而，虽然体外电刺激器不是 有效的植入式设备依赖有毒电池，需要进行侵入性手术才能移除，这很容易 破坏愈合组织。在这方面，我们开发了一种新型的可生物降解的压电纳米纤维 由聚乳酸(聚-L-丙交酯)制成的支架，表明该支架在施加关节的情况下可以自生成ES 在小动物模型中强制修复软骨缺陷。然而，仍然需要解决的重要问题是 地址。这些问题是(1)什么是最好的刺激和最好的压电生物降解 支架是用来修复软骨的；(2)运动后的支架能否修复主要软骨 大型动物的缺陷。在这里，我们首次提出了一种新的可生物降解的压电材料 纳米复合软骨移植(含聚乳酸和氧化镁-氧化镁纳米颗粒)及其研究 一种最佳的体育锻炼，以获得一种新的可治愈临界尺寸的再生方法 大型动物的软骨缺陷。因此，这项工作有三个具体目标；目标1是 对所提出的可生物降解的压电复合支架进行体外表征，以获得良好的替代物 软骨移植。目标2是研究和评估最佳体育锻炼(持续时间、频率和强度)和 兔软骨缺损最佳修复的最佳复合支架。目标3是研究和演示 大动物模型(绵羊)的软骨愈合。第一个里程碑(在1.5年内)是找出最好的 体外具有所需性能的压电支架。3.5年后的第二个里程碑是找出 修复兔软骨缺损的最佳体能训练和支架材料。最后一个里程碑(5年后)是 演示具有推导出的最佳关节载荷(N/m2)和跑步机训练的MgO/PLLA支架的能力 修复绵羊临界大小的软骨缺陷。

Abstract Osteoarthritis (OA), a disease associated with cartilage damages inside the joints, affects millions of people every year. The current medicines, including analgesics and anti-inflammation drugs only alleviate symptoms but do not cure the disease while surgical methods to use replacement cartilage auto- or allo-grafts struggle with the problems of infection, donor-site morbidity, immune-rejection and limited tissue supply. In this regard, regenerative engineering approaches which are based on biomaterial scaffolds, stem cells and biological growth factors to construct artificial replacement cartilage tissues have become an important field. While growth factors are powerful, these chemicals pose a significant concern regarding to their toxic and side effects. Alternatively, electrical stimulation (ES) has been known to exhibit a significant effect on promoting bone and cartilage growth. As bioelectricity is an intrinsic physiological signal of living organisms, the use of ES presumably, offers a more natural approach for inducing cartilage growth. However, while extracorporeal electrical stimulators are not effective, implanted devices rely on toxic batteries, requiring invasive surgery for removal, which can easily damage the healing tissues. In this regard, we have developed a novel biodegradable piezoelectric nanofiber scaffold, made of PLLA (Poly-L-lactide) and shown that this scaffold can self-generate ES under applied joint force to heal cartilage defects in small animal models. Yet remaining important questions still need to be addressed. These questions are (1) what the optimal stimulation and the best piezoelectric biodegradable scaffold are for cartilage healing and (2) whether the scaffold with physical exercise can heal the major cartilage defects in large animals. Here, we propose, for the first time, a new biodegradable piezoelectric nanocomposite cartilage-graft (containing PLLA and magnesium oxide – MgO nanoparticles), and study an optimal physical-exercise to obtain a novel regenerative approach which can heal critical-sized cartilage defects in large animals. Accordingly, the work is designed with three specific aims; Aim 1 is to characterize the proposed biodegradable piezoelectric composite scaffold in vitro to obtain a good replacement cartilage graft. Aim 2 is to study and assess optimal physical exercise (duration, frequency, and intensity) and optimal composite scaffolds for the best healing of cartilage defects in rabbits. Aim 3 is to study and demonstrate cartilage healing in large animal model (sheep). The first milestone (in 1.5 years) is to find out the best piezoelectric scaffold with desired properties in vitro. The second milestone after 3.5 years is to find out the optimal physical training and scaffold to heal cartilage defects in rabbits. The final milestone (after 5 years) is to demonstrate the ability of the MgO/PLLA scaffold with derived optimal joint load (N/m2) and treadmill training to heal critical-sized cartilage defects in sheep.