Injectable Fibrous Scaffolds for Meniscal Repair

项目总结/摘要 半月板是一个重要的承重结构，它保护下面的关节软骨， 降低骨关节炎（OA）的发病率。不幸的是，它对成年人的治疗能力有限，所以眼泪 通常需要手术治疗。目前的治疗方法包括部分椎间盘切除术;然而， 半月板暴露出软骨， 退化与成人脊髓损伤不同，胎儿和青少年脊髓损伤表现出内在修复， 儿童半月板撕裂。因此，组织工程方法，概括的特点， 年轻的半月板可能提供治疗半月板撕裂的新方法。多纤维支架， 孔隙度被定制为模拟低密度胎儿细胞外基质（ECM）， 提供多种因子来促进初期愈合然而，这些刚性静电纺丝支架已经减少了 控制单个纤维成分，不能通过关节镜输送。该提案针对这些 通过利用后处理策略，其中支架由碎片纤维制成， 其可以被注入到缺陷中，在注入之后重建，并且用光稳定。通过组合不同 纤维群体，这种组装允许通过调谐的方式单独调谐各种释放的因子 不同的纤维降解速率。所提出的支架将释放核软化剂（曲古抑菌素A 'TSA'），进一步模拟与成人相比更柔软的胎儿睾丸核， 趋化剂（结缔组织生长因子，CTGF）。这两个因素 预期协同促进细胞浸润和ECM沉积到支架中。以证明 本材料的翻译能力，将进行三个目的。目标1将致力于制造 所述材料和显示支架生物因子单独释放活性和释放时 同时在体外。支架纤维组分将被定制为具有精确调节的动力学。目标2A将 证实了所开发的片段化多纤维组件（FMA）在皮下大鼠中的功效 模型，从而证实释放的因子继续促进细胞迁移和ECM沉积， 体内环境。目标2B将涉及将FMA插入尤卡坦半岛半月板缺损部位 迷你猪这项大型动物初步研究将证明设计的材料留在其注射部位 并且它在细胞水平上与周围的半月板整合。因此，该子目标将设置 未来研究的框架，评估这种和其他拟议的组织工程方法的有效性 半月板撕裂的大型动物模型。成功完成这些目标将绕过当前 临床上实施纤维支架的障碍，从而提供了一种替代治疗选择， 修复半月板

Project Summary/Abstract The meniscus is an important load-bearing structure that protects the underlying articular cartilage and thus reduces the incidence of osteoarthritis (OA). Unfortunately, it has limited healing capacity in adults, so tears often require surgical treatment. Current treatments include partial meniscectomy; however, removing part of the meniscus exposes the cartilage and the extent of removal correlates with the magnitude of cartilage degeneration. Unlike adult menisci, fetal and juvenile menisci exhibit intrinsic repair, which reduces the rate at which children present with meniscus tears. Thus, tissue engineering approaches that recapitulate features of younger menisci may provide novel approaches to treating meniscus tears. Multi-fiber scaffolds, whose porosities are tailored to mimic low density fetal extracellular matrices (ECM), have previously been developed that deliver multiple factors to promote initial healing. However, these rigid electrospun scaffolds have reduced control over individual fiber components and cannot be delivered arthroscopically. This proposal targets these impediments by utilizing a post-processing strategy in which a scaffold is fabricated out of fragmented fibers that can be injected into a defect, reconstructed after injection, and stabilized with light. By combining different fiber populations, this assembly permits the individual tuning of various released factors by way of tuning different fiber degradation rates. The proposed scaffold will release a nuclear softening agent (Trichostatin A ‘TSA’) over several days, further mimicking the softer nuclei of fetal menisci compared to adult, and a chemotactic agent (connective tissue growth factor, CTGF) over several weeks. These two factors are expected to synergistically promote cell infiltration and ECM deposition into the scaffold. To demonstrate the translational capacity of this material, three Aims will be conducted. Aim 1 will be geared towards fabricating the material and demonstrating scaffold biofactor release activity individually and when released simultaneously in vitro. Scaffold fiber components will be tailored to have precisely tuned kinetics. Aim 2A will demonstrate the efficacy of the developed fragmented multi-fiber assembly (FMA) in a subcutaneous rat model, thus confirming that the factors released continue to promote cell migration and ECM deposition within an in vivo environment. Aim 2B will involve insertion of the FMA into a meniscus defect site in Yucatan minipigs. This large animal pilot study will demonstrate that the designed material stays within its injection site and that it integrates with the surrounding meniscus on a cellular level. Thus, this sub-Aim will set the framework for future studies assessing the efficacy of this and other proposed tissue engineering approaches in a large animal model of meniscus tears. Successful completion of these Aims will bypass current impediments to implementing fibrous scaffolds clinically, thus providing an alternative treatment option for repairing the meniscus.