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: 7750954
• 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: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2012-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7750954
• 关键词: Address; Adult; Aging; Anatomy; Angiogenic Factor; Animal Model; Animal Testing; Animals; Anisotropy; Beryllium; Biodegradable microsphere; Biological Preservation; Biomimetics; Blood Vessels; Cartilage; Cell-Matrix Junction; Cells; Cellular Infiltration; Characteristics; Clinical; Collagen; Collagen Fiber; Collection; Defect; Deposition; Development; Disease; Doctor of Philosophy; Elements; Engineering; Ethylene Oxide; Excision; Extracellular Matrix; Femur; Fiber; Goals; Growth Factor; Healed; Heterogeneity; Implant; In Vitro; Infiltration; Intervertebral disc structure; Joints; Kinetics; Knee; Knee Osteoarthritis; Ligaments; Mechanics; Meniscus structure of joint; Methodology; Methods; Microspheres; Military Personnel; Mission; Modeling; Monitor; Musculoskeletal; Musculoskeletal System; Natural regeneration; Operative Surgical Procedures; Pathology; Patients; Pattern; Pharmaceutical Preparations; Physiological; Plague; Polymers; Population; Porosity; Process; Production; Property; Proteins; Rattus; Recovery of Function; Research Design; Shapes; Sheep; Spatial Distribution; Structure; System; Techniques; Technology; Tendon structure; Testing; Time; Tissue Engineering; Tissues; Transforming Growth Factor beta; Translations; Trauma; Variant; Vascular Endothelial Growth Factors; Vascularization; Vertebral column; Veterans; Water; Work; abstracting; angiogenesis; animal model development; articular cartilage; base; caprolactone; clinically relevant; controlled release; density; efficacy testing; functional restoration; healing; implantation; improved; in vivo; interstitial cell; nanofiber; non-drug; novel; public health relevance; repaired; scaffold; soft tissue; subcutaneous; tibia

DESCRIPTION (provided by applicant): Abstract Objective: Fibrous tissues of the musculoskeletal system are plagued by their poor healing capacity. Tissue engineering (TE) strategies combine cells and biodegradable scaffolds to fabricate new tissues for implantation. In this proposal, we focus on the knee meniscus, a tissue critical for proper load transfer between the femur and the tibia, and for which current repair strategies do not restore the function. Meniscus damage leads inexorably to cartilage erosion, and in the adult, meniscus healing is limited. The most common surgical procedure is removal of the damaged portion. To address this clinical need, we have devised a novel TE strategy employing anisotropic biodegradable nanofibrous scaffolds to generate constructs for meniscus repair. The objective of this study is to develop and test the efficacy of these novel scaffolds in a large animal meniscus defect model. Research Design: We have developed a novel fabrication process to create dynamic multi-component electrospun scaffolds that promote cellular infiltration while at the same time provide mechanical functionality and direct tissue organization. Here, we introduce three novel features to further their application. First, we include a biomimetic collagen fiber population to enhance cell attachment, invasion, and construct remodeling. Secondly, we improve integration with native tissue via a microsphere-based growth factor delivery system to promote matrix production and angiogenesis. We also employ a new methodology to fabricate scaffolds into the meniscus shape. These scaffolds are tested in a subcutaneous animal model to assess the enhancement of tissue development and vascular invasion. Next, they formed into anatomic shape and tested in a large animal meniscus repair model. In this clinical translation step, we evaluate the construct maturation, as well as their capacity to preserve the underlying articular cartilage. Methodology: Electrospun scaffolds will be fashioned in a novel tri-polymer electrospinning system we recently developed. VEGF and/or TGFbeta will be delivered from co-embedded micropsheres and vascular invasion and matrix development evaluated in a subcutaneous rat model. Next, scaffolds will be formed into anatomic shapes, and used to repair subtotal meniscectomies in a sheep model. We have developed this sheep model over the last two years to evaluate new meniscus formation as well as the mechanical and histological features of the underlying articular cartilage. Findings: Our novel scaffolds are tailored to address the mechanical, biologic, and anatomic requirements of meniscus repair, and will be rigorously evaluated in a large animal defect model. Findings from this study will include degree of vascular invasion, as well as the mechanical properties of the engineered construct and articulating cartilage. Clinical Relationships: This application is focused on the clinical translation of engineered meniscus constructs. We will make significant progress in this translational space, from scaffold production, through to small animal testing, and ultimately to testing of efficacy in a large defect animal model. This work will provide new clinical options for meniscus repair, an otherwise untreatable and prevalent musculoskeletal condition in our active military personnel, and a causative factor for the development of knee osteoarthritis in our aging veteran populations. PUBLIC HEALTH RELEVANCE: Project Narrative This project develops a clinically-relevant approach to fabricate anatomically shaped meniscus constructs that possess several enabling technologies. First, a sacrificial element is engineered into the system to enhance porosity while maintaining fiber alignment critical to meniscus function. Second, a stabilized collagen fiber population is co-electrospun into the network to promote cellular infiltration. Third, a method for placing biodegradable microspheres throughout the fibrous structure is developed to deliver pro-angiogenic growth factors to promote vascular invasion and integration. This highly engineered system provides controlled and direction dependent mechanical properties, tailored degradation to enhance infiltration and integration, and directed neo- vascularization. These enabling technologies culminate in the formation of anatomic shaped implants that are then evaluated in a large animal sub-total meniscus defect model. If successful, this approach would surmount a major hurdle in meniscus tissue engineering to provide an architecturally and biologically relevant template for new tissue formation and with enhanced mechanical properties to support the intense loads found in the joint. This meniscus tissue engineering technique could aid in the treatment of millions of patients afflicted with debilitating joint pathology and degeneration due to trauma or disease, and may be extended for application in other dense fibrous tissues such as tendons and ligaments and the intervertebral disk.

描述（由申请人提供）： 摘要目的：肌肉骨骼系统的纤维组织因其愈合能力差而受到困扰。组织工程（TE）策略将细胞和可生物降解的支架结合起来，制造用于植入的新组织。在本提案中，我们重点关注膝关节半月板，这是一种对于股骨和胫骨之间适当的负荷传递至关重要的组织，目前的修复策略无法恢复其功能。半月板损伤不可避免地导致软骨侵蚀，并且在成人中，半月板愈合受到限制。最常见的外科手术是切除受损部分。为了满足这一临床需求，我们设计了一种新颖的 TE 策略，采用各向异性可生物降解纳米纤维支架来生成半月板修复结构。本研究的目的是开发和测试这些新型支架在大型动物半月板缺陷模型中的功效。研究设计：我们开发了一种新颖的制造工艺来创建动态多组分电纺支架，促进细胞浸润，同时提供机械功能和直接组织组织。在这里，我们介绍三个新颖的功能来进一步推动其应用。首先，我们采用仿生胶原纤维群来增强细胞附着、侵袭和构建重塑。其次，我们通过基于微球的生长因子传递系统改善与天然组织的整合，以促进基质产生和血管生成。我们还采用了一种新方法将支架制造成弯月面形状。这些支架在皮下动物模型中进行测试，以评估组织发育和血管侵袭的增强作用。接下来，它们形成解剖形状并在大型动物半月板修复模型中进行测试。在这个临床转化步骤中，我们评估了构建体的成熟度，以及它们保存底层关节软骨的能力。方法：静电纺丝支架将在我们最近开发的新型三聚合物静电纺丝系统中制成。 VEGF 和/或 TGFbeta 将从共同嵌入的微球中递送，并在皮下大鼠模型中评估血管侵袭和基质发育。接下来，支架将被制成解剖形状，并用于修复绵羊模型的半月板次全切除术。我们在过去两年中开发了这种绵羊模型，以评估新的半月板形成以及底层关节软骨的机械和组织学特征。研究结果：我们的新型支架专为满足半月板修复的机械、生物和解剖学要求而定制，并将在大型动物缺陷模型中进行严格评估。这项研究的结果将包括血管侵入的程度，以及工程结构和关节软骨的机械特性。临床关系：该应用程序专注于工程半月板结构的临床转化。我们将在这个转化领域取得重大进展，从支架生产到小动物测试，最后到大型缺陷动物模型的功效测试。这项工作将为半月板修复提供新的临床选择，半月板修复是我们现役军人中一种无法治疗且普遍存在的肌肉骨骼疾病，也是我们老龄化退伍军人中膝骨关节炎发展的致病因素。 公共卫生相关性： 项目叙述该项目开发了一种临床相关的方法来制造具有多种支持技术的解剖形状的半月板结构。首先，系统中设计了牺牲元件，以增强孔隙率，同时保持对半月板功能至关重要的纤维排列。其次，将稳定的胶原纤维群共静电纺丝到网络中以促进细胞浸润。第三，开发了一种将可生物降解的微球放置在整个纤维结构中的方法，以递送促血管生成生长因子，以促进血管侵袭和整合。这种高度工程化的系统提供受控和方向依赖的机械特性、定制的降解以增强渗透和整合，以及定向新血管形成。这些使能技术最终形成解剖形状的植入物，然后在大型动物半月板次全缺损模型中进行评估。如果成功，这种方法将克服半月板组织工程中的主要障碍，为新组织的形成提供结构和生物学相关的模板，并具有增强的机械性能以支撑关节中的强烈负载。这种半月板组织工程技术可以帮助治疗数百万因创伤或疾病而遭受关节衰弱和退化的患者，并且可以扩展到其他致密纤维组织，例如肌腱、韧带和椎间盘。