Hydrogel Scaffolds with Engineered Dynamically Tunable Topographies for hMSC Diff

描述（由申请人提供）：临床外科医生在重建先天性异常、创伤、感染和/或肿瘤切除导致的骨缺损时选择有限。目前的骨移植植入技术和材料都有局限性。出于这个原因，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善骨移植材料，这些材料将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。已显示地形线索影响hMSCs的细胞粘附、运动、增殖、蛋白质表达、基因调控和分化。Bowman-Anseth实验室开发的基于硫醇-烯的光聚合方案将用于创建包含细胞粘附模拟物和酶促和光降解连接的生物材料，这些生物材料允许使用精确的空间侵蚀来创建形貌。拟议的研究旨在通过研究如何将地形线索纳入含有细胞粘附模拟物和酶促可降解连接的聚合物支架中来设计改进的骨移植材料，从而影响成骨分化。我假设，分化将取决于动态变化，在他们的微环境，将通过光不稳定的化学实现。概述了两个具体目标：目标1：确定巯基-烯聚合物支架中促进hMSCs成骨分化的地形特征和空间排列。目的2：研究实时改变地形特征的空间排列对成骨分化的影响。 这些目标的完成将显着推进我们的地形如何诱导MSC分化的机制的理解。这种聚合物系统和方法的多功能性使我们能够进行独特的hMSC培养实验，并提高我们对材料系统的理解，这些材料系统可以很容易地针对基于干细胞递送或归巢的组织再生应用进行定制。 公共卫生相关性：该提案的目的是设计一种改进的生物活性骨移植材料，用于修复由先天性异常、创伤、感染和癌症引起的骨缺损。我的方法是研究细胞如何对动态生物物理线索（如地形）做出反应的机制。拟议研究的结果将导致创建改进的三维合成基质，这些基质将作为支架从周围组织中招募细胞并促进自然骨再生。

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. PUBLIC HEALTH RELEVANCE: The aim of this proposal is to engineer an improved, bioactive bone graft material for repairing bone defects resulting from congenital anomalies, trauma, infection and cancer. My approach is to investigate the mechanisms for how cells respond to dynamic biophysical cues, such as topography. The results of the proposed research will lead to the creation of improved 3-dimensional synthetic matrices that will act as scaffolds to recruit cells from surrounding tissues and promote natural bone regeneration.