Ligament engineering; Effect of gene induction and cyclic stretch

韧带工程；

• 批准号: 7544573
• 负责人: Robyn Shaffer
• 金额: $ 3.01万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7544573
• 关键词: Affect; Animal Model; Architecture; Biocompatible; Biocompatible Materials; Caliber; Cell Differentiation process; Cells; Characteristics; Clinical; Condition; Deposition; Development; Embryonic Development; Engineering; Epidemic; Extracellular Matrix; Extracellular Matrix Proteins; Fiber; Fibroblasts; Future; Gene Expression; Genetic Engineering; Goals; Immune response; Individual; Injury; Knee; Knee Injuries; Length; Ligaments; Limb structure; Localized; Mechanics; Mesenchymal Stem Cells; Methods; Modality; Musculoskeletal; Natural regeneration; Numbers; Obesity; Outcome; Patients; Phenotype; Physical activity; Physiological; Polymers; Population; Protein Overexpression; Quality of life; Recruitment Activity; Research Proposals; Signaling Molecule; Site; Source; Sports; Standards of Weights and Measures; Stem cells; Stretching; Sum; Techniques; Tendon structure; Testing; Tissue Engineering; Tissues; Training; United States; Urea; Work; base; gene induction; in vivo; nanofiber; novel; reconstruction; repaired; response; scaffold; scleraxis; transcription factor

DESCRIPTION (provided by applicant): The focus of this research proposal is the development of a tissue engineered ligament graft for ACL regeneration. Currently, ACL injuries are the most common knee injury in the United States. As the population places more emphasis on physical activity to combat the obesity epidemic and the level of intensity in individual sports increases, the number of ACL injuries is likely to rise. Current reconstruction strategies are not sufficient for successful long-term clinical outcomes and a new method to repair the ACL-deficient knee is needed. An ACL reconstruction that results in an increased quality of life for the patient may be possible through tissue engineering techniques. Our cell-based approach utilizes mesenchymal stem cells (MSCs), a progenitor cell source suitable for musculoskeletal tissue engineering strategies. By directing lineage commitment of MSCs, a suitable tissue can be formed. We propose to engineer ligament tissue by combining three techniques: electrospun fiber meshes, mechanical stretch and scleraxis-expresssing MSCs. We hypothesize that the fiber architecture of the biomaterial, namely fiber orientation and diameter, will affect MSC response to mechancial stretch and the subsequent development of extracellular matrix. Further, we postulate that MSCs with constitutive overexpression of the ligament/tendon transcription factor, scleraxis, will act synergistically with electrospun biomaterials to promote ligament tissue development. Therefore, we propose two specific aims: (1) To determine the effect of fiber architecture under mechanical stretch on ligament tissue formation. (2) To determine the potential of scleraxis-modified mesenchymal stem cells (MSCs) cultured on electrospun polymers on the formation of ligament tissue. Stem cell differentiation to ligament tissue phenotype will be characterized by gene expression and extracellular matrix protein deposition. The long term goal of this project is an engineered ligament capable of integration and regeneration once implated at the site of injury. The studies outlined in this proposal will generate a platform for developing functional ligaments using a multidimensional approach involving polymeric biomaterial architecture and mechanical stretch as well as genetic engineering.

描述（由申请人提供）：该研究建议的重点是开发用于ACL再生的组织工程韧带移植。目前，ACL受伤是美国最常见的膝盖受伤。随着人口更加重视体育锻炼以打击肥胖流行的流行和个别运动的强度水平，ACL损伤的数量可能会增加。当前的重建策略不足以成功进行长期临床结果，并且需要一种修复ACL缺陷膝关节的新方法。通过组织工程技术，可能会导致患者的生活质量提高的ACL重建。我们的基于细胞的方法利用间充质干细胞（MSC），这是一种适合肌肉骨骼组织工程策略的祖细胞来源。通过指导MSC的谱系承诺，可以形成合适的组织。我们建议通过结合三种技术来设计韧带组织：电纺纤维网，机械拉伸和硬化表达MSC。我们假设生物材料的纤维结构，即纤维取向和直径，将影响​​MSC对机间延伸的反应以及随后的细胞外基质的发展。此外，我们假设韧带/肌腱转录因子的构型过表达的MSC巩膜将与电纺生物材料协同作用，以促进韧带组织的发育。因此，我们提出了两个具体的目的：（1）确定机械拉伸下纤维结构对韧带组织形成的影响。 （2）确定在韧带组织形成上培养在电纺聚合物上培养的硬化性巩膜改性的间充质干细胞（MSC）的潜力。干细胞与韧带组织表型的分化将以基因表达和细胞外基质蛋白沉积为特征。该项目的长期目标是一种工程韧带，能够在伤害部位隐含地融合和再生。该提案中概述的研究将生成一个平台，使用涉及聚合物生物材料结构和机械延伸以及基因工程的多维方法来开发功能韧带。