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sex; standard care; stem cell differentiation; stem cell fate; stem cells; tissue regeneration; tissue repair; tool; unpublished works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.

响应生物材料线索的干细胞谱系承诺为复杂疾病提供了有吸引力的替代手段 组织再生。该项目的目标是设计、开发和评估一个能够 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 评估这一支架技术以研究骨软骨(OC)组织发育，并将界面作为潜在的 复杂组织修复的解决方案，是唯一的临床需要。卵巢癌组织的再生仍然是主要的 临床障碍，尽管有许多优点，但目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。不完全组织再生，新形成的软骨的质量 (纤维软骨/透明质)，缺乏带状结构形成，导致宿主组织整合不良。海流 组织工程学知识阐明了生物材料的作用及其表面形式的线索 在2D培养中，化学、地形和基质硬度在调节干细胞命运和谱系承诺中的作用。 然而，在3D支架中融入材料和结构线索以诱导 干细胞谱系承诺。这项提议的主要目标是开发一个脚手架平台， 灌输结构和材料线索以驱动间充质干细胞(MSC)谱系承诺，分化， 以及形成带状结构以再生OC组织。我们最近的出版物和未发表的工作表明 体外和体外控制培养的MSCs在支架结构内形成层状OC组织 活体条件。目前的支架技术是创新的，因为它使用单一材料来制造毛孔 分区配置中的渐变，以避免材料兼容性问题和分层。此外， 文献缺乏描述带状组织的方法学，例如OC和本论文中提出的支架 申请。我们建议开发和验证热图方法作为一种新的分析工具来测量 材料的硬度，并与组织学结果进行定量验证 活体样本。我们假设支架结构具有不同的基质硬度和生长因子。 将促进植入的成体干细胞分化为完全的OC组织再生 结构。该项目的具体目标是：目标1：优化嵌入了 界面工程的结构和物理线索。目的2：阐明生物材料与细胞之间的相互作用 局部基质硬度和结构在影响骨髓间充质干细胞体外定向分化中的作用。目标3： 在兔模型中，用生物物理线索评估构建的支架系统中OC界面的形成。这个 该项目的结果可能导致(I)开发使能支架技术来设计干细胞， 以及(Ii)开发促进通向宿主的带状结构形成的OC试验台脚手架平台 组织整合。通过该项目开发的脚手架技术、工具和方法将是 适用于构建脚手架驱动的界面工程再生策略。