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相关的疾病，影响着数百万人 每年目前的药物，包括止痛药和抗炎药，只能缓解症状 但不能治愈这种疾病，而使用自体或异体软骨移植物替代的外科方法， 感染、供区发病率、免疫排斥和组织供应有限等问题。在这方面，委员会注意到， 基于生物材料支架、干细胞和生物生长的再生工程方法 因子来构建人工替代软骨组织已成为一个重要领域。虽然生长因子 由于这些化学品的毒性很强，因此它们的毒副作用引起了人们的极大关注。可选择地， 已知电刺激（ES）在促进骨和软骨生长方面表现出显著的效果。 由于生物电是生物体的内在生理信号，因此ES的使用大概提供了更多的 自然方法诱导软骨生长。然而，虽然体外电刺激器不是 有效的植入式设备依赖于有毒电池，需要侵入性手术才能取出， 损伤愈合组织。在这方面，我们开发了一种新型的可生物降解的压电陶瓷， 支架，由PLLA（聚-L-丙交酯）制成，并显示该支架可在应用关节下自生成ES 在小动物模型中的软骨缺损愈合力。然而，剩下的重要问题仍然需要 处理。这些问题是（1）什么是最佳的刺激和最佳的压电生物降解 支架是否用于软骨愈合和（2）支架与体育锻炼是否可以愈合主要软骨 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， 纳米复合软骨移植物（含有PLLA和氧化镁- MgO纳米颗粒），以及研究 一种最佳的身体锻炼，以获得一种新的再生方法，可以治愈临界大小的 大型动物的软骨缺损。因此，这项工作的设计有三个具体目标：目标1是 在体外表征所提出的可生物降解压电复合支架，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）， 最佳的复合支架，以最好的愈合软骨缺损的兔。目标3是研究和论证 在大型动物模型（绵羊）中的软骨愈合。第一个里程碑（1.5年）是找出最好的 压电支架在体外具有所需的性能。3.5年后的第二个里程碑是找出 最佳的物理训练和支架修复兔软骨缺损。最后一个里程碑（5年后）是 证明MgO/PLLA支架在衍生的最佳关节负荷（N/m2）和跑步机训练下 治愈绵羊临界大小软骨缺损。

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.