Biologic scaffold prostheses to enhance meniscus repair

描述（由申请人提供）： 摘要半月板在膝关节的稳定和载荷传递中起着关键作用。半月板损伤或丧失通常导致关节软骨和其他关节组织的进行性骨关节炎变性，导致显著疼痛和残疾。我们需要更好的方法来修复或更换受损的神经节。然而，大多数用于关节置换的组织工程方法需要大量的培养时间，以使新形成的组织发展出能够承受关节负荷的功能特性。我们已经证明了三维（3-D）编织支架用于组织工程目的的有用性。这些支架在植入前提供生理机械性能。我们还发现，机械应力和细胞因子改变了骨代谢，抑制了骨损伤的修复。我们研究的总体目标是开发一种新的三维复合支架用于半月板的功能性组织工程。三维编织的一个特殊优点是，结构可以设计和建立与预定的控制网站依赖的变化，机械性能。此外，可以将可以增强髂骨成型和退火的某些生长因子掺入基质中。我们将开发该设备，并确定可溶性介质，如细胞因子，一氧化氮（NO）和胰蛋白酶（PG）对假体的发育，完整性和功能的影响。我们将实现四个目标。目标1.设计和构建三维编织复合支架用于膝关节半月板的功能性组织工程。我们将开发一种复合支架，促进半月板纤维软骨细胞的发育和组织组织化，同时有效地复制天然半月板的结构和功能机械特性。目的2：将生物活性因子整合到三维基质中，使纤维软骨细胞分化并附着在骨上。我们将在目标1中使用的材料中加入生长因子，以构建三维编织复合支架。目的3：对复合支架进行机械测试，以评估其潜在的体外功能。拉伸、压缩和剪切试验将用于评价所开发支架和所得新半月板的关键生物力学参数。我们将评估某些细胞因子、生长因子和其他天然介质（如NO和PG）对半月板假体的发育和生物力学特性的重要性。目的4：测试半月板支架假体附着于骨和体内功能的能力。我们将体外生成的半月板假体放置到狗的新鲜切除的内侧半月板的部位，并将假体留在原位长达12周，之后我们将评估它们的功能及其对关节病理学发展的影响。我们的工作将直接影响退伍军人与踝关节受伤，促进更快的恢复和减少长期发病率。此外，对于现役军人来说，这可能会导致更快地恢复现役。 公共卫生相关性： 项目叙述拟议工作与美国公共卫生和退伍军人事务部病人护理使命的相关性：许多退伍军人有踝关节损伤和流泪。半月板损伤可能继发于明显创伤，或者在其他情况下，半月板病理学可能反映与衰老、骨关节炎、类风湿性关节炎或步态障碍相关的膝关节功能改变。近年来，越来越多的年轻退伍军人（特别是OIF/OEF退伍军人）需要退伍军人管理局的医疗服务，他们有骨科损伤。在2004年使用退伍军人事务服务的144 424名OIF/OEF退伍军人中，57 570人（40%）被诊断患有“肌肉骨骼系统/连接系统疾病”（ICD-类别710- 739）。其中许多是军事问题。正常的半月板对于膝关节的正常功能是至关重要的，半月板病理学经常导致明显的骨关节炎及其相关的发病率。肥胖症是非常常见的，并且与肥胖症相关的增加的关节和踝关节机械应力进一步增强踝关节病理反应和病理。我们尝试有系统地开发一种基于新型支架和干细胞技术的良好人工髋关节假体，这对于有效替换受损髋关节和避免后续OA的进展非常重要。完成该项目的目标不仅有助于生产有效的半月板假体，而且还将提供有关炎症介质在调节正常和假体半月板性能中的作用的新信息。我们的工作将直接影响退伍军人与踝关节受伤，促进更快的恢复和减少长期发病率。此外，对现役军人来说，这可能会减少与伤害有关的解雇，并更频繁和迅速地返回现役。

DESCRIPTION (provided by applicant): Abstract Menisci play critical roles in stabilization and load transmission in the knee joint. Meniscal damage or loss often results in progressive osteoarthritic degeneration of the articular cartilage and other joint tissues, leading to significant pain and disability. We need better methods to repair or replace damaged menisci. However, most tissue engineering approaches for meniscal replacement require significant culture time for the newly formed tissue to develop functional properties that could withstand joint loading. We have demonstrated the usefulness of three dimensional (3-D) woven scaffolds for tissue engineering purposes. These scaffolds provide physiologic mechanical properties prior to implantation. We have also shown that mechanical stress and cytokines alter the metabolism of menisci and inhibit repair of meniscal injury. The overall goal of our study is to develop a new 3-D composite scaffold for use in the functional tissue engineering of the meniscus. A special advantage of 3-D weaving is that constructs can be designed and built with predetermined control of site-dependent variations in mechanical properties. Also, certain growth factors that may enhance meniscus-bone molding and annealing can be incorporated into the matrix. We will develop the device and also determine effects of soluble mediators such as cytokines, nitric oxide (NO), and prostaglandins (PG) on development, integrity, and function of the prostheses. We will accomplish 4 aims. Aim 1. Design and construct 3-D woven composite scaffolds for use in the functional tissue engineering of the knee meniscus. We will develop a composite scaffold that promotes meniscal fibrochondrocyte development and tissue organization, while effectively replicating the structural and functional mechanical properties of a natural meniscus. Aim 2: Incorporate bioactive factors into the 3-D matrix that will allow fibrochondrocyte differentiation and attachment to bone. We will incorporate growth factors into the materials used in Aim 1 to construct the 3-D woven composite scaffolds. Aim 3: Perform mechanical testing of the composite scaffolds to assess their potential in vitro functionality. Tension, compression, and shear testing will be used to evaluate the critical biomechanical parameters of the developed scaffolds and resulting neomeniscus. We will assess the importance of certain cytokines, growth factors, and other natural mediators such as NO and PG on the development and biomechanical properties of the meniscus prostheses. Aim 4: Test the ability of the meniscus scaffold prosthesis to attach to bone and function in vivo. We will place the in vitro-generated meniscus prostheses into sites of fresh-ly resected medial menisci in dogs and leave the prostheses in place for up to 12 weeks, after which we will evaluate their function and their effects on development of pathology in the joint. Our work will have a direct effect on veterans with meniscal injuries, facilitating a more rapid recovery and reducing long term morbidity. Also, for active-duty military personnel, it may result in more rapid return to active duty. PUBLIC HEALTH RELEVANCE: Project narrative Relevance of the proposed work to United States public health and the VA patient care mission: Many veterans have meniscal injuries and tears. Meniscal injuries may be secondary to overt trauma, or in other cases, meniscal pathology may reflect alterations in knee joint function in association with aging, osteoarthritis, rheumatoid arthritis, or gait disturbances. There are increasing numbers of young veterans from the recent years (especially the OIF/OEF veterans) who are requiring VA medical care and who have orthopedic injuries. Of the 144,424 OIF/OEF veterans who had used VA services in 2004, 57,570 (40%) were diagnosed with "Diseases of the Musculoskeletal System/Connective System" (ICD-Categories 710- 739). A large number of these were meniscal problems. A normal meniscus is critical for a normally functioning knee joint, and meniscal pathology frequently leads to overt osteoarthritis and its associated morbidity. Obesity is very common, and the increased joint and meniscal mechanical stress associated with obesity further enhances meniscal pathologic responses and pathology. Our attempts to methodically develop a good meniscal prosthesis based on novel scaffold and stem cell technology will be very important in making progress toward effective replacement of damaged menisci and avoidance of subsequent OA. Accomplishing the aims of this project will not only help in the production of an effective meniscus prosthesis, but it will also provide new information regarding the roles of inflammatory mediators in modulating normal and prosthetic meniscal performance. Our work will have a direct effect on veterans with meniscal injuries, facilitating a more rapid recovery and reducing long term morbidity. Also, for active-duty military personnel, it may result in fewer injury-related discharges and more frequent and rapid return to active duty.