Biodegradable Matrices with Structural and Physical Cues for Interface Engineering

具有界面工程结构和物理线索的可生物降解基质

• 批准号: 10265488
• 负责人: Syam Nukavarapu
• 金额: $ 36.37万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-17 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10265488
• 关键词: 3-Dimensional; Allografting; Architecture; Arthroscopy; Autologous Transplantation; Beds; Biocompatible Materials; Biomedical Engineering; Biophysics; Bone Regeneration; Cartilage; Cell Communication; Cell Lineage; Cells; Chemistry; Clinical; Complex; Cues; Defect; Development; Elasticity; Engineering; Failure; Fibrocartilages; Gene Expression; Goals; Growth Factor; Histologic; Histology; Image Analysis; Immunohistochemistry; Immunologics; Implant; In Vitro; Knee; Knowledge; Lead; Length; Literature; Maps; Measures; Mechanics; Mediating; Mesenchymal Stem Cells; Methodology; Microfabrication; Modeling; Modulus; Myosin Type II; Natural regeneration; Oryctolagus cuniculus; Outcome; Phase; Polymers; Porosity; Procedures; Property; Publications; Role; Sampling; Stimulus; Structure; Surface; System; Technology; Testing; Tissue Engineering; Tissues; Vascular blood supply; Work; adult stem cell; analytical tool; blebbistatin; bone; design; engineered stem cells; healing; implantation; in vivo; innovation; interfacial; mechanical signal; non-muscle myosin; novel; osteochondral repair; osteochondral tissue; osteogenic; protein expression; receptor; regenerative approach; repaired; response; scaffold; sex; standard care; stem cell differentiation; stem cell fate; stem cells; tissue regeneration; tissue repair; tool; unpublished works

Stem cell lineage commitment in response to biomaterial cues offer attractive alternative means for complex tissue regeneration. The goal of this project is to design, develop, and evaluate a scaffold platform that can instruct stem cells in a 3D micro-environment through material stiffness and bio-physical cues. We propose to evaluate this scaffold technology to study osteochondral (OC) tissue development with an interface as a potential solution to complex tissue repair, an unment clinical need. The OC tissue regeneration continues to be a major clinical hurdle and despite many merits, current biological and tissue engineered grafts fail to provide successful long-term clinical outcomes. Incomplete tissue regeneration, quality of newly formed cartilage (fibrocartilage/hyaline), and lack of zonal structure formations lead to poor host tissue integration. The current knowledge in tissue engineering elucidates the role of biomaterials and their cues in the form of surface chemistry, topography, and matrix stiffness in regulating stem cell fate and lineage commitment in 2D cultures. However, limited efforts have been made to incorporate material and structural cues in 3D-scaffolds to induce stem cell lineage commitment. The primary objective of this proposal is to develop a scaffold platform with imbued structural and material cues to drive mesenchymal stem cell (MSC) lineage commitment, differentiation, and zonal structure formation to regenerate OC tissue. Our recent publications and unpublished work suggest layered OC tissue formation within the scaffold structure by the cultured MSCs under controlled in vitro and in vivo conditions. The current scaffold technology is innovative because it uses a single material to create pore gradients in zonal configurations to avoid material compatibility issues and delamination. Additionally, the literature lacks methodology to characterize a zonal tissue such as OC and scaffolds presented in this application. We propose to develop and validate a heat map methodology as a new analytical tool to measure material stiffness and validate quantitatively with histological findings of regenerated tissue from in vitro and in vivo samples. We hypothesize that scaffold architecture imbued with varied matrix stiffness and growth factors will promote implanted adult stem cell differentiation towards complete OC tissue regeneration with zonal structure. The specific aims of this project are: Aim 1: Optimization of a 3D-scaffold platform embedded with structural and physical cues for interface engineering. Aim 2: Elucidate biomaterial-cell interactions and the mechanistic role of local matrix stiffness and structure in influencing MSC lineage commitment in vitro. Aim 3: Assess the engineered scaffold system with bio-physical cues for OC interface formation in a rabbit model. The outcomes of this project may lead to (i) development of an enabling scaffold technology to engineer stem cells, and (ii) development of an OC test-bed scaffold platform that promotes zonal structure formation leading to host tissue integration. The scaffold technology, tools, and methodologies developed through this project will be applicable to build scaffold-driven regenerative strategies for interface engineering.

响应生物材料提示的干细胞谱系承诺为复合物提供了有吸引力的替代方法 组织再生。该项目的目的是设计，开发和评估一个可以 通过材料刚度和生物物理提示，指导3D微环境中的干细胞。我们建议 评估这种脚手架技术以研究骨软骨（OC）组织的发展，并具有界面的潜力 解决复杂组织修复的解决方案，这是一种临床需求。 OC组织再生继续是主要的 临床障碍，尽管有很多优点，但目前的生物和组织工程移植物无法提供成功 长期临床结果。不完整的组织再生，新形成的软骨的质量 （纤维球杆菌/透明），缺乏纬向结构的形成导致宿主组织的整合不良。电流 在组织工程方面的知识以表面形式阐明了生物材料及其线索的作用 在2D培养物中调节干细胞命运和谱系承诺的化学，地形和基质刚度。 但是，已经做出了有限的努力，以将材料和结构提示纳入3D型属性以诱导 干细胞谱系承诺。该提案的主要目的是开发一个脚手架平台 填充结构和材料提示，以驱动间充质干细胞（MSC）谱系承诺，分化， 和区域结构形成以再生OC组织。我们最近的出版物和未发表的作品暗示 由培养的MSC在受控的体外和IN中由培养的MSC在支架结构内的分层OC组织形成 体内条件。当前的脚手架技术具有创新性，因为它使用单个材料来创建毛孔 区域配置中的梯度，以避免物质兼容性问题和分层。另外， 文献缺乏表征诸如OC和脚手架等区域组织的方法论 应用。我们建议开发和验证热图方法作为测量的新分析工具 材料刚度和验证从体外和中的再生组织的组织学发现定量验证 体内样品。我们假设脚手架结构充满了不同的基质刚度和生长因子 将促进植入的成年干细胞分化朝着Zonal的完全OC组织再生 结构。该项目的具体目的是：目标1：嵌入的3D-Scabdold平台的优化 接口工程的结构和物理提示。目标2：阐明生物材料 - 细胞相互作用和 局部基质刚度和结构在影响MSC谱系承诺中的机械作用。目标3： 用兔模型中的OC界面形成的生物形态提示评估工程脚手架系统。这 该项目的结果可能会导致（i）开发启用脚手架技术，以设计干细胞， （ii）开发促进区域结构形成的OC测试床脚手架平台 组织整合。通过该项目开发的脚手架技术，工具和方法将是 适用于建立脚手架驱动的接口工程的再生策略。