Engineered Multi-Functional Nanofibrous Meniscus Implants

工程设计的多功能纳米纤维半月板植入物

• 批准号: 9379800
• 负责人: John Esterhai
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-01 至 2019-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9379800
• 关键词: Address; Adjuvant; Adult; Anatomy; Animal Model; Animals; Anisotropy; Biochemical; Biological Factors; Blood Vessels; Cartilage; Cell Differentiation process; Cell Mobility; Cells; Cellular Infiltration; Cellularity; Chemotactic Factors; Clinical; Clinical Treatment; Collagen; Data; Defect; Degenerative Disorder; Deposition; Development; Devices; Doctor of Philosophy; Drug Delivery Systems; Encapsulated; Engineering; Evaluation; Excision; Extracellular Matrix; Extracellular Matrix Degradation; Femur; Fiber; Funding; Grant; Growth Factor; Health; Heterogeneity; Histology; Human; Implant; In Vitro; Individual; Injury; Intervention; Kinetics; Knee; Mechanics; Meniscus structure of joint; Methodology; Methods; Microspheres; Military Personnel; Mission; Modeling; Musculoskeletal System; Natural regeneration; Operative Surgical Procedures; Orthopedics; Pathology; Phase; Phenotype; Population; Procedures; Process; Production; Property; Quality of life; Recombinants; Recruitment Activity; Research; Research Design; Sheep; Site; Stromal Cells; Structure; Surgical sutures; System; Technology; Time; Tissues; Transforming Growth Factor beta; Trauma; Ursidae Family; Veterans; Work; X-Ray Computed Tomography; base; cartilage degradation; cartilaginous; cell motility; cell type; clinical translation; collagenase; healing; health administration; improved; in vivo; injury and repair; mechanical properties; migration; mobility enhancement; nanofiber; new technology; novel; novel strategies; prevent; progenitor; public health relevance; release factor; repaired; scaffold; soft tissue; standard of care; stem cells; success; targeted agent; tibia; tissue repair; treatment effect; treatment strategy; wound; wound healing

DESCRIPTION: Objective: Fibrous tissues of the musculoskeletal system are plagued by their poor intrinsic healing capacity. In this proposal, we focus on the knee meniscus, a tissue critical for proper load transfer, and for which current repair strategies do not restore function. To address this clinical need, we have devised a novel strategy employing anisotropic biodegradable composite nanofibrous scaffolds that serve as an inter- positional device and enhance meniscus repair. The objective of this study is to develop nanofibrous scaffolds capable of releasing multiple agents over different temporal scales, and thus, positively impact the entire healing process. Research Design: This proposal will utilize a novel class of composite nanofibrous scaffolds (developed during the first funding cycle) that have varying degradation profiles and release kinetics of bioactive agents targeted to different phases of healing and repair. These release profiles will be tuned to first 'enable' repair by rapidly and locally degrading the dense extracellular matrix at the injury site to allow cell migration and new tissue formation. Second, these scaffolds will selectively recruit progenitor cells to the wound interface, to accelerate and sustain the repair process. Finally, the scaffold will provide biochemical factors over a longer-term to 'direct' cell phenotype and promote matrix production. The synergistic interactions of these different adjuvants to repair will be investigated in a large animal meniscus defect model. Methodology: We will develop and characterize composite nanofibrous scaffold systems that permit release of factors from the fibers themselves or from encapsulated microspheres. This novel scaffolding technology allows for the inclusion of several fiber populations with different degradation profiles and for the release of multiple bioactive factors with varying temporal release profiles. Scaffolds will be utilized in a model of meniscus repair in adult sheep and compared to suture repair controls at early (2, 4, and 8 weeks) and longer term (16 and 48 week) time points. Evaluation criteria will include meniscus and cartilage histology, micro-computed tomography, and mechanical properties. Findings: We will develop composite nanofiber-based engineered scaffolds to enhance meniscus repair in an ovine model. We will show enhanced cellularity and integration with local matrix degradation at the injury site. We will also show increased recruitment of progenitor cells as well as improved matrix production with staged biofactor delivery. The synergistic effects of these treatments will be assessed relative to the current standard of care. Clinical Relationships: If successful, these studies and new technologies will set the stage for clinical translation and treatment of human meniscal pathology. These novel scaffolds can be directly utilized in clinical procedures to enhance meniscus repair. Impact/Significance: The proposed research is highly relevant to the mission of the Veterans Health Administration since it will advance the health of veterans suffering from meniscus injuries resulting from military trauma, injury or from degenerative diseases. If successful, the proposed therapy will improve the quality of life of such individuals.

描述： 目的：肌肉骨骼系统的纤维组织因其内在愈合能力差而受到困扰。在本提案中，我们重点关注膝关节半月板，这是一种对于适当的负荷转移至关重要的组织，目前的修复策略无法恢复其功能。为了满足这一临床需求，我们设计了一种新策略，采用各向异性可生物降解复合纳米纤维支架作为插入装置并增强半月板修复。本研究的目的是开发能够在不同时间尺度释放多种药剂的纳米纤维支架，从而对整个愈合过程产生积极影响。研究设计：该提案将利用一类新型复合纳米纤维支架（在第一个资助周期中开发），该支架具有不同的降解特性和针对不同愈合和修复阶段的生物活性剂的释放动力学。这些释放曲线将通过快速局部降解损伤部位的致密细胞外基质来调整，以首先“实现”修复，以允许细胞迁移和新组织形成。其次，这些支架将选择性地将祖细胞募集到伤口界面，以加速和 维持修复过程。最后，支架将长期提供生化因子来“指导”细胞表型并促进基质产生。将在大型动物半月板缺陷模型中研究这些不同佐剂修复的协同相互作用。方法：我们将开发并表征复合纳米纤维支架系统，该系统允许从纤维本身或从封装的微球中释放因子。这种新颖的支架技术允许包含具有不同降解曲线的多种纤维群，并允许释放具有不同时间释放曲线的多种生物活性因子。支架将用于成年羊半月板修复模型，并在早期（2、4和8周）和长期（16和48周）时间点与缝合修复对照进行比较。评估标准将包括半月板和软骨组织学、微型计算机断层扫描和机械性能。研究结果：我们将开发基于复合纳米纤维的工程支架，以增强绵羊模型中的半月板修复。我们将展示损伤部位细胞结构的增强以及与局部基质降解的整合。我们将 还显示祖细胞的招募增加以及通过分阶段生物因子递送改善基质生产。这些治疗的协同效应将根据 目前的护理标准。临床关系：如果成功，这些研究和新技术将为人类半月板病理学的临床转化和治疗奠定基础。这些新型支架可直接用于临床手术以增强半月板修复。影响/意义：拟议的研究与退伍军人健康管理局的使命高度相关，因为它将改善因军事创伤、受伤或退行性疾病而遭受半月板损伤的退伍军人的健康。如果成功，所提出的疗法将改善这些人的生活质量。