Dynamic Fibrous Scaffolds for Engineering Dense Connective Tissues

用于工程致密结缔组织的动态纤维支架

• 批准号: 7626527
• 负责人: Jason A Burdick
• 金额: $ 34.14万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-20 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7626527
• 关键词: 3-Dimensional; Address; Anatomy; Animal Model; Anisotropy; Architecture; Award; Benchmarking; Biocompatible; Biomedical Engineering; Bioreactors; Caliber; Cartilage; Cells; Cellular Infiltration; Clinical; Coupled; Coupling; Custom; Defect; Dense Connective Tissue; Deposition; Development; Doctor of Philosophy; Drug or chemical Tissue Distribution; Elements; Engineering; Environment; Esters; Exhibits; Extracellular Matrix; Fiber; Foundations; Funding; Grant; Growth; Healed; Homeostasis; In Vitro; Individual; Infiltration; Intervertebral disc structure; Investigation; Kinetics; Knee; Lead; Libraries; Ligaments; Maintenance; Manuscripts; Mechanical Stimulation; Mechanics; Meniscus structure of joint; Methods; Modeling; Muscle; Musculoskeletal; Musculoskeletal System; Natural regeneration; Orthopedic Surgery procedures; Outcome; Pattern; Pennsylvania; Plague; Polymer Chemistry; Polymers; Positioning Attribute; Process; Production; Property; Publishing; Regenerative Medicine; Research; Research Personnel; Structure; Students; System; Techniques; Technology; Tendon structure; Time; Tissue Engineering; Tissue Model; Tissues; Translations; Treatment Protocols; Universities; Work; Wound Healing; abstracting; biodegradable polymer; clinically relevant; flexibility; healing; implantation; improved; in vivo; innovation; nanofiber; novel; novel strategies; preconditioning; predictive modeling; public health relevance; repaired; response; scaffold; scale up; technology development; tissue regeneration

DESCRIPTION (provided by applicant): When endogenous repair fails, as is often the case with dense fibrous musculoskeletal tissues (like the knee meniscus), novel strategies and enabling technologies must be developed to enhance tissue regeneration. While numerous tissue engineering therapies have been developed for the engineering of fiber-reinforced tissues, one persistent limitation is the ability to fabricate scaffolds that maintain structural integrity and direct appropriate tissue architecture, while simultaneously promoting cellular infiltration throughout the regeneration period. In this proposal, we address these limitations with the production of a novel multi-polymer composite nanofibrous scaffold that provides a 3-dimensional micropattern for neo-tissue formation. These scaffolds, with fiber diameters on the order of the native extracellular matrix, can be produced with defined fiber anisotropies that mimic the structural arrangement of fiber-reinforced tissues. Further, by introducing flexibility in polymer properties via a library of photocrosslinkable macromers that exhibit a range of mechanical and degradation properties when polymerized, we propose to tailor temporal pore formation within the scaffold through the controlled degradation of individual polymer components. We hypothesize that these nanofibrous multipolymer photocrosslinked meshes will have controlled mechanical properties reflective of the stiffest and slowest degrading component and show a time dependent increase in void space while maintaining their overall mechanical properties. Further, we hypothesize that the controlled increase in void space within these scaffolds, via the erosion of sacrificial elements, will promote cellular infiltration into the multi-polymer mesh and will result in a more uniform functional tissue structure. Additionally, as the mechanical environment of the meniscus is paramount in its maturation and homeostasis, we hypothesize that tailored mechanical preconditioning regimens will likewise promote functional maturation of infiltrated meniscus constructs. To this end, a novel dynamic loading bioreactor that applies compression and tension is developed to promote tissue maturation. The first Aim of this proposal is to develop technology to electrospin multi-component nanofibrous scaffolds and compare properties to the native tissue using a predictive fiber-reinforced composite model. In the second Aim, the interaction and infiltration of cells and ultimate mechanical properties will be explored in single- and tri-polymer cell-laden nanofibrous scaffolds. The third Aim involves the development of a bioreactor for pre-conditioning scaffolds and evaluating the impact of mechanical stimulation on tissue formation in the short and long term. If successful, this innovative approach will provide several new enabling technologies for the functional regeneration of damaged fiber-reinforced musculoskeletal tissues. Public Health Relevance Statement (provided by applicant): This project develops a novel multi-polymer nanofiber fabrication system to exert control over polymer chemistry and overall scaffold mechanics and degradation with time to improve cellular infiltration and uniform tissue deposition in fibrous tissue-engineered constructs. If successful, this approach would surmount a major hurdle in the tissue engineering of dense structures of the musculoskeletal system and provide a mechanically functional, structurally anisotropic 3D micro-pattern for directed neo-tissue formation while promoting full cellular colonization and eventual replacement of the polymer structure after complete dissolution. This innovative approach, coupling scaffold fabrication, mechanical loading, and in vivo assessments, will aid in the development of tissue engineered therapies for fiber-reinforced musculoskeletal tissues such as the knee meniscus that otherwise fail to heal and have few clinically viable repair strategies.

描述（由申请人提供）： 当内源性修复发生故障时，浓密的纤维肌肉骨骼组织（例如膝盖弯木板）通常会发生这种情况，必须开发出新的策略和能力技术来增强组织再生。尽管已经开发了用于纤维增强组织的工程的许多组织工程疗法，但一种持续的限制是制造脚手架的能力，这些脚手架能够保持结构完整性和直接适当的组织结构，同时在整个再生期间同时促进细胞浸润。在此提案中，我们通过生产新型的多聚合物复合纳米纤维支架来解决这些局限性，该纳米纤维支架为新组织形成提供了三维微图案。这些脚手架的直径在天然细胞外基质的顺序上，可以用定义的纤维各向异性产生，这些纤维各向异性模仿纤维增强组织的结构排列。此外，通过通过可光叠式链接宏的库引入聚合物性能的柔韧性，在聚合聚合时，它们表现出一系列机械和降解性能，我们建议通过单个聚合物成分的受控降解来定制支架内的颞孔孔形成。我们假设这些纳米纤维聚合物光链接网的网格将具有反映最僵硬和最慢的降解成分的机械性能，并显示出空间的时间依赖性，同时保持其整体机械性能。此外，我们假设通过牺牲元素的侵蚀，这些支架内的空隙空间的受控增加将促进细胞浸润到多聚合物网格中，并将导致更均匀的功能组织结构。此外，由于半月板的机械环境至关重要，因此我们假设量身定制的机械预处理方案同样将促进浸润式半月板结构的功能成熟。为此，开发了一种应用压缩和张力的新型动态加载生物反应器，以促进组织成熟。该提案的第一个目的是开发用于静电素多组分纳米纤维支架的技术，并使用预测纤维增强的复合模型将特性与天然组织进行比较。在第二个目标中，将在单次和三聚合物细胞细胞的纳米纤维支架中探索细胞的相互作用和浸润和最终的机械性能。第三个目的涉及生物反应器的发展，用于预先调节支架，并评估机械刺激对短期和长期内组织形成的影响。如果成功，这种创新方法将为受损纤维增强肌肉骨骼组织的功能再生提供几种新的促成技术。 公共卫生相关性声明（由申请人提供）：该项目开发了一种新型的多聚合物纳米纤维制造系统，以控制聚合物化学和整体支架力学和降解，以改善细胞浸润和纤维化组织工程构造的均匀组织浸润和均匀的组织沉积。如果成功，这种方法将克服肌肉骨骼系统致密结构的组织工程中的主要障碍，并提供机械提供 功能性，结构各向异性3D微图案，用于定向新组织形成，同时促进完全溶解后的全细胞定植和最终替代聚合物结构。这种创新的方法，耦合脚手架制造，机械负荷和体内评估，将有助于开发用于纤维增强的肌肉骨骼组织的组织工程疗法，例如膝盖弯面试，否则否则无法愈合，几乎没有临床可行的维修策略。