Hydrogel Scaffolds with Engineered Dynamically Tunable Topographies for hMSC Diff

描述(申请人提供)：临床外科医生在重建因先天畸形、创伤、感染和/或肿瘤切除引起的骨缺损时，选择有限。目前的植骨技术和材料都有局限性。为此，我的目标是通过研究人类间充质干细胞(HMSCs)如何从其微环境中接收信息来改进骨移植材料，使其能够从周围组织中招募细胞，并促进成骨分化，这是自然骨再生过程的一部分。地形图提示对hMSCs的细胞黏附、运动、增殖、蛋白表达、基因调控和分化均有影响。在Bowman-Anseth实验室开发的一种基于硫醇-烯的光聚合方案将被用来创建包含细胞黏附模拟以及酶和光可降解连接的生物材料，这些连接允许使用精确的空间侵蚀来创建地形。这项拟议的研究旨在通过研究将地形线索结合到含有细胞黏附模拟物和可酶降解连接的聚合物支架中如何影响成骨分化来设计改进的骨移植材料。我推测，分化将取决于它们微环境的动态变化，这将通过耐光化学实现。两个具体的目标被概述：目标1：确定促进hMSCs成骨分化的硫醇-烯聚合物支架的形态特征和空间排列。目的2：研究实时改变地形地物的空间排列对成骨分化的影响。这些目标的完成将极大地促进我们对地形诱导MSC分化机制的理解。这种聚合物系统和方法的多功能性使我们能够为hMSC培养进行独特的实验，并提高我们对材料系统的理解，这些材料系统可以轻松地为基于干细胞输送或归巢的组织再生应用量身定做。

DESCRIPTION (provided by applicant): Clinical surgeons have a limited number of options when reconstructing bone defects that result from congenital anomalies, trauma, infection and/or oncologic resection. Current bone-graft implantation techniques and materials each have limitations. For this reason, I aim to improve bone grafting materials that will recruit cells from the surrounding tissue and promote osteogenic differentiation, part of the natural bone regeneration process, by investigating how human mesenchymal stem cells (hMSCs) receive information from their microenvironments. Topographic cues have been shown to influence cell adhesion, motility, proliferation, protein expression, gene regulation and differentiation of hMSCs. A thiol-ene based photopolymerization scheme developed in the Bowman-Anseth laboratories will be used to create biomaterials containing cell adhesion mimics and enzymatically and photo-degradable linkages that allow for the creation of topographies using precise spatial erosion. The proposed research aims to engineer improved bone grafting materials by investigating how incorporating topographic cues into a polymer scaffold that contains cell adhesion mimics and enzymatically degradable linkages influences osteogenic differentiation. I hypothesize that differentiation will depend on dynamic changes in their microenvironment that will be achieved through the photolabile chemistry. Two specific aims are outlined: Aim 1: Identify topographic features and spatial arrangements in thiol-ene polymer scaffolds that promote osteogenic differentiation of hMSCs. Aim 2: Examine the effects of changing the spatial arrangement of topographic features in real-time on osteogenic differentiation. Completion of these aims will significantly advance our understanding of the mechanisms for how topography induces MSC differentiation. The versatility of this polymer system and approach allows us to conduct unique experiments for hMSC culture and improve our understanding of material systems that can be easily tailored for tissue regeneration applications based on stem cell delivery or homing.