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: 10029269
• 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/10029269
• 关键词: 3-Dimensional; Allografting; Architecture; Arthroscopy; Autologous Transplantation; Beds; Biocompatible Materials; Biological; 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; non-muscle myosin; novel; osteochondral repair; osteochondral tissue; osteogenic; protein expression; receptor; regenerative; 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sex; standard care; stem cell differentiation; stem cell fate; stem cells; tissue regeneration; tissue repair; tool; unpublished works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.

响应生物材料线索的干细胞谱系承诺为复杂的治疗提供了有吸引力的替代方法 组织再生。该项目的目标是设计、开发和评估一个脚手架平台，该平台可以 通过材料硬度和生物物理线索在 3D 微环境中指导干细胞。我们建议 评估这种支架技术，以研究骨软骨 (OC) 组织发育，并以界面作为潜在的研究对象 复杂组织修复的解决方案，这是一个未满足的临床需求。 OC组织再生仍然是主要的 临床障碍，尽管有许多优点，但当前的生物和组织工程移植物未能提供成功的 长期临床结果。组织再生不完全，新形成的软骨质量 （纤维软骨/透明），并且缺乏带状结构形成导致宿主组织整合不良。目前的 组织工程知识阐明了生物材料的作用及其表面形式的线索 化学、形貌和基质硬度在二维培养物中调节干细胞命运和谱系定向。 然而，在 3D 支架中纳入材料和结构线索以诱导 干细胞谱系承诺。该提案的主要目标是开发一个脚手架平台 注入结构和材料线索来驱动间充质干细胞 (MSC) 谱系定型、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工作表明 体外和体内受控培养的 MSC 在支架结构内形成分层 OC 组织 体内条件。当前的支架技术是创新的，因为它使用单一材料来创建孔隙 区域配置中的梯度以避免材料兼容性问题和分层。此外， 文献缺乏表征区域组织（如本文中介绍的 OC 和支架）的方法 应用。我们建议开发和验证热图方法作为新的分析工具来衡量 材料硬度并通过体外和体内再生组织的组织学结果进行定量验证 体内样本。我们假设支架结构充满了不同的基质刚度和生长因子 将促进植入的成体干细胞分化，实现带状组织的完全再生 结构。该项目的具体目标是： 目标 1：优化嵌入 3D 支架平台 界面工程的结构和物理线索。目标 2：阐明生物材料与细胞的相互作用以及 局部基质刚度和结构在影响体外 MSC 谱系定向中的机械作用。目标 3： 利用兔模型中 OC 界面形成的生物物理线索评估工程支架系统。这 该项目的成果可能会导致（i）开发出一种用于工程干细胞的支架技术， (ii) 开发 OC 试验台支架平台，促进区域结构形成，从而导致宿主 组织整合。通过该项目开发的支架技术、工具和方法将 适用于构建界面工程的支架驱动的再生策略。