Role of spatial heterogeneous matrix stifness in development of craniofacial tissue interfaces

空间异质基质刚度在颅面组织界面发育中的作用

• 批准号: 9569268
• 负责人: Sam Carsten-Puisis Norris
• 金额: $ 4.53万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-07 至 2019-09-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9569268
• 关键词: Arthritis; Behavior; Biocompatible Materials; California; Cartilage; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Cellular Assay; Chemicals; Complex; Cues; Degenerative Disorder; Development; Developmental Biology; Differentiation Antigens; Dimensions; Encapsulated; Engineering; Environment; Extracellular Matrix; Heterogeneity; Human; Hydrogels; Investigation; Length; Location; Los Angeles; Mandibular Condyle; Mechanics; Mesenchymal Differentiation; Mesenchymal Stem Cells; Modulus; Morphology; Nature; Pattern; Phenotype; Physiological; Polymers; Positioning Attribute; Property; Reconstructive Surgical Procedures; Regenerative Medicine; Research; Research Personnel; Research Proposals; Resolution; Role; Sampling; Scientist; Seeds; Stem Cell Research; Stem cells; Structure; Surface; System; Techniques; Testing; Time; Tissue Engineering; Tissues; Tooth structure; Universities; Variant; base; bone; cell behavior; cell motility; craniofacial development; craniofacial structure; craniofacial tissue; crosslink; density; dental structure; design; high throughput analysis; human stem cells; in vivo; insight; interest; light intensity; mechanical properties; novel; response; stem cell fate; submicron; three dimensional cell culture; tool

Project Summary/Abstract Research demonstrates that extracellular matrix (ECM) stiffness dictates the differentiation of the mesenchymal stem cells (MSCs) attached to it. Stiffer substrates promote the differentiation of stiffer cell lineages [1]. Photodegradable hydrogels are a novel class of polymeric biomaterials that have been developed by our group at University of California, Los Angeles. They are uniquely suited to replicate the ECM[2, 3] and are physically and chemically similar to the ECM, having a wide range of elastic moduli (~1-500 kPa). Distinctive of photodegradable hydrogels is that their cross-link density can be altered externally, where stiffness is a function of the light intensity and exposure time. This biomaterial can replicate complex, anisotropic, and heterogeneous microenvironments that mimic the structural heterogeneities of native tissue with sub-micron resolutions. This project proposes to advance tissue engineering through the design and use of this photodegradable hydrogel as a high-precision advanced biomaterial, with five degrees of control (three spatial dimensions, time and intrinsic property gradation). I intend to mimic patterns and stiffness gradations found in native tissue interfaces in order to analyze MSC behavior and advance the understanding of stem cell fate in vivo. The mechanical patterns I intend to create will ultimately replicate the inherently complex environments found in nature, such as the developing tooth and the bone-cartilage interface of the mandibular condyle. To date, ECM-based stem cell research has not replicated the body's polarized structures to a degree that allows for an understanding of cell fate in such environments. This research proposal intends to establish how heterogeneous mechanical environments impact MSCs in 2D and 3D culture to subsequently answer the following: Are microenvironments that contain polarized structures dictating stem cell fate? If we engineer an environment to mimic native conditions, will stem cells follow suit? Hypothesis: Photo-tunable polymer networks can be used to structure heterogeneities similar to those found native tissue by inducing a cellular response to mechanical cues. Since it has been established that cell differentiation can be triggered mechanically in static isotropic materials, a system with spatial differences in mechanical properties should trigger multiple cell lineages within a continuous material across a multitude of length and time scales. I also expect that beyond controlling cell phenotype, intermediate behavior, as found in native tissue interfaces, will be observed.

项目总结/摘要 研究表明，细胞外基质（ECM）的硬度决定了间充质细胞的分化， 更硬的基质促进更硬细胞谱系的分化[1]。 光降解水凝胶是一类新型的聚合物生物材料， 加州大学，洛杉矶。他们是唯一适合复制ECM[2，3]，并在物理上和 化学上类似于ECM，具有宽范围的弹性模量（~1-500 kPa）。特有 可光降解水凝胶的另一个优点是它们的交联密度可以在外部改变，其中刚度是一个函数， 光强度和曝光时间的关系。这种生物材料可以复制复杂的、各向异性的和异质的 模拟具有亚微米分辨率的天然组织的结构异质性的微环境。这 该项目提出通过设计和使用这种可光降解的水凝胶来推进组织工程， 一种高精度的先进生物材料，具有五个控制度（三个空间维度，时间和内在维度）， 属性分级）。我打算模仿天然组织界面中发现的模式和刚度梯度， 分析MSC的行为，促进对干细胞体内命运的理解。 我打算创造的机械模式将最终复制所发现的内在复杂环境 在自然界中，如发育中的牙齿和下颌骨髁突的骨-软骨界面。到目前为止， 基于ECM的干细胞研究还没有复制身体的极化结构到一定程度， 了解细胞在这种环境中的命运。这项研究提案旨在确定如何异质化 机械环境影响2D和3D培养中的MSC，随后回答以下问题： 包含决定干细胞命运的极化结构的微环境？如果我们设计一个环境， 模仿自然条件，干细胞会效仿吗？假设：可以使用光可调聚合物网络 通过诱导细胞对机械刺激的反应， 线索由于已经确定，细胞分化可以在静态各向同性环境中机械地触发， 材料，一个在机械性能上具有空间差异的系统应该在内部触发多个细胞谱系， 一种跨越多种长度和时间尺度的连续材料。我还希望除了控制细胞 将观察天然组织界面中发现的表型、中间行为。