Injectable Fibrous Scaffolds for Meniscal Repair

用于半月板修复的可注射纤维支架

• 批准号: 10311622
• 负责人: Karen Xu
• 金额: $ 5.1万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311622
• 关键词: Address; Adolescent; Adult; Animal Model; Animals; Biocompatible Materials; Biological Assay; Bypass; Cartilage; Cell Nucleus; Cells; Chemotactic Factors; Child; Clinical; Conceptions; Cues; Defect; Degenerative polyarthritis; Dense Connective Tissue; Deposition; Development; Electrospinning; Engineering; Environment; Enzymes; Excision; Exhibits; Extracellular Matrix; Family suidae; Fellowship; Fiber; Formulation; Future; Goals; Hyaluronic Acid; In Situ; In Vitro; Incidence; Individual; Infiltration; Injectable; Injections; Injury; Investigation; Kinetics; Knee; Lead; Light; Meniscus structure of joint; Miniature Swine; Modeling; Nuclear; Nude Rats; Operative Surgical Procedures; Pain; Patients; Physicians; Pilot Projects; Population; Porosity; Procedures; Process; Property; Prothrombin; Rattus; Rehabilitation therapy; Research; Scientist; Site; Structure; Surgical sutures; System; Technology; Therapeutic; Thinness; Time; Tissue Engineering; Tissues; Translating; Trichostatin A; Weight-Bearing state; Work; aged; alternative treatment; articular cartilage; career; cartilage degradation; cell motility; clinical application; connective tissue growth factor; density; design; fetal; healing; improved; in vivo; in vivo Model; innovation; meniscal tear; migration; novel strategies; pre-clinical; recruit; release factor; repaired; response; scaffold; skeletal; skills; subcutaneous; therapeutic development; tissue regeneration; wound

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.

项目摘要/摘要 半月板是一个重要的承重结构，它保护着下面的关节软骨，因此 减少骨关节炎(OA)的发生率。不幸的是，它对成年人的治愈能力有限，所以眼泪 通常需要手术治疗。目前的治疗方法包括部分半月板切除术；然而，切除部分 半月板暴露软骨，切除的程度与软骨的大小有关。 退化。与成人半月板不同，胎儿和青少年半月板表现出内在修复，这降低了 其中儿童出现半月板撕裂。因此，组织工程学方法概括了 年轻的半月板可能为治疗半月板撕裂提供新的方法。多纤维支架，其 以前已经开发出了模拟低密度胎儿细胞外基质(ECM)的孔道 提供多种因素来促进最初的愈合。然而，这些刚性的电纺支架已经减少了 可控制单个纤维组件，不能通过关节镜提供。这项提案针对的是 通过利用后处理策略，其中支架由碎裂的纤维制成 它可以被注入到缺陷中，注入后重建，并用光稳定。通过组合不同的 纤维种群，该组件允许通过调节的方式对各种释放因子进行单独调节 纤维降解率不同。拟建的支架将释放一种核软化剂(曲古菌素A ‘TSA’)，进一步模仿了胎儿半月板比成人更柔软的核，以及一个 趋化剂(结缔组织生长因子，CTGF)持续数周。这两个因素是 有望协同促进细胞渗透和细胞外基质沉积到支架中。要演示 对于这份材料的翻译能力，将进行三个目标。目标1将面向制造 材料和支架生物因子单独和释放时的释放活性 同时在体外。支架纤维组件将被定制为具有精确的动力学调谐。目标2 A将 证明已开发的碎片化多纤维组件(FMA)在皮下大鼠中的疗效 模型，从而证实释放的因子继续促进细胞迁移和细胞外基质沉积 一个活体环境。目标2B将涉及将FMA插入尤卡坦的半月板缺损处 小猪。这项大型动物先导研究将证明设计的材料留在其注射部位。 它与周围的半月板在细胞水平上相结合。因此，这个子目标将设置 评估该方法和其他拟议的组织工程方法的有效性的未来研究框架 在一个大型动物模型中半月板撕裂。这些目标的成功实现将绕过当前的 临床实施纤维支架的障碍，从而提供了一种替代治疗方案 修复半月板。