Engineering Complex, Spatially-patterned Tissue Structures from Stem Cells

ROY/1159326在过去十年中，干细胞分化在创造工程化组织方面取得了重大进展。然而，到目前为止，大多数努力都集中在再生一种同质的组织结构，其体积特性与天然组织相似。但是，大多数人体组织在结构和功能上都是复杂的，并且具有空间变化的组成和机械性能。将干细胞定向到这种成熟的、三维组织的、复杂的组织中还没有实现。一个典型的例子是关节软骨，它在组织工程中已经被广泛研究了几十年。从解剖学和功能上讲，关节软骨由四个空间上不同的区域组成：浅层、移行区、深层和钙化区。每个区域都具有独特的细胞外基质组成、机械性能和细胞组织。为关节软骨创造同质组织替代物的经典组织工程方法未能取得广泛的临床效果，因为工程化的整体特性不能模拟自然的组织功能。根据最近的发现，独特的材料成分可以将干细胞定向到特定类型的软骨细胞中，这些细胞对应于关节软骨的不同区域，该项目将探索一种独特的多层水凝胶结构，具有空间变化的生物材料-利基环境，用于同时将单个干细胞群体分化为复杂的关节软骨。收集到的知识将为设计复杂的、功能相关的组织的可行性提供新的见解，这些组织的机械性能和成分可以在空间上变化。

Roy/ 1159326 In the past decade significant advances have been made in stem cell differentiation to create engineered tissues. However, most efforts to date have focused on regenerating a homogenous tissue structure whose bulk properties are similar to that of native tissues. But, most human tissues are complex, both structurally and functionally, and possess spatially-varying compositions and mechanical properties. Directing stem cells into such mature, three-dimensionally organized, complex tissues has not yet been achieved. A model example is articular cartilage, which has been widely studied in tissue engineering for several decades. Anatomically and functionally, articular cartilage consists of four, spatially distinct regions; the superficial, transitional, deep, and calcified zones. Each zone is characterized by unique extra-cellular matrix compositions, mechanical properties and cellular organization. Classical tissue engineering approaches for creating homogenous tissue replacements for articular cartilage has failed to achieve widespread clinical effectiveness because the engineered bulk properties do not mimic native tissue function. Based on recent findings that unique material compositions can be used to direct stem cells into specific types of chondrocytes that correspond to those from the various zones of articular cartilage, this project will explore a unique multi-layered hydrogel constructs with spatially varying biomaterial-niches for simultaneously differentiating a single stem cell population into a complex articular cartilage. The knowledge gathered would provide new insights on the feasibility of engineering complex, functionally-relevant tissues whose mechanical properties and composition can vary spatially.