CAREER: DYNAMIC LIVING HYDROGEL NETWORKS FOR SPATIO-TEMPORAL CONTROL OF CELL SIGNALING

技术摘要基于生物材料的三维水凝胶能够更好地反映天然组织的细胞外微环境，对于组织修复和再生以及细胞-基质相互作用的研究非常重要。重要的是，细胞和周围基质之间的生化信号在多个时间（秒-周）和长度（nm-cm）尺度上是动态的，并且取决于组织硬度。因此，被工程化以调节细胞反应的材料在其生物配体和材料刚度的时空呈现中必须是类似动态的。虽然已经实现了通过使用外部触发剂控制生物配体的空间和时间呈现的水凝胶，但是这些水凝胶尚未提供3个关键性质：a）细胞信号传导的空间控制，B）生物粘附性的同时时间呈现，以及c）生物粘附性和材料刚度的独立控制以解析对细胞调节的个体贡献。该NSF CAREER奖由材料研究部的生物材料项目资助，将能够开发一类新的纳米复合水凝胶，并在单一水凝胶中控制上述三个关键特性。这项工作将推进目前的理解的作用，生物材料的性能控制人类干细胞的命运，通过用户导向的时空控制细胞基质的相互作用。这项工作将通过培训教师和学生，使互动探究式学习渗透到贫困的初中和高中。该CAREER奖将通过教学和前沿研究，发展美国工程师的基础设施，特别是那些来自代表性不足的少数民族的工程师，在生物材料方面具有强大的学科能力。非技术摘要基于生物材料的3D水凝胶，更好地反映了天然组织的生态位，并捕捉动态微环境的关键方面，对于培养哺乳动物细胞，包括干细胞，在生物医学中有着广泛的应用。细胞及其周围生态位之间的信息流在空间和时间上取决于生化信号和细胞-细胞相互作用。尽管在生物材料领域取得了进展，但使用单一水凝胶系统不能有效地研究材料的时空生物化学信号和生物物理性质的独立作用。这项NSF CAREER奖将通过开发一类新的水凝胶来克服目前生物材料研究中的瓶颈，这种水凝胶可以动态地与细胞通信以控制它们的命运。这项研究将通过开发用于再生医学的先进生物功能组织来造福社会。特别是，我们希望这项工作能够产生动态生物材料，以便更好地了解干细胞及其与局部环境的相互作用，这将有助于治疗神经系统疾病，并使神经移植物再生用于短和长的神经间隙。这项研究的结果将催化多个学科的潜在研究途径，包括细胞培养，组织制造，血管生成，药物输送，肿瘤工程和植入物。这项工作将通过培训教师和学生，使互动探究式学习渗透到贫困的初中和高中。这项职业建议将增加美国工程师的基础设施，特别是本科生和研究生，包括那些来自代表性不足的少数民族，通过教学法和尖端研究在生物材料方面具有较强的学科能力。

Technical AbstractBiomaterials-based three-dimensional hydrogels that better reflect the extracellular microenvironment of native tissues are important for tissue repair and regeneration as well as cell-matrix interaction studies. Importantly, the biochemical signals between cell and surrounding matrix are dynamic over multiple time (seconds-weeks) and length (nm-cm) scales, and are dependent on tissue stiffness. Therefore, materials engineered to modulate cell response must be similarly dynamic in their spatio-temporal presentation of bio-ligands and material stiffness. Although hydrogels that control spatial and temporal presentation of bio-ligands by use of external triggers have been realized, these hydrogels have not yet provided 3 key properties: a) spatial control of cell signaling, b) simultaneous temporal presentation of bio-adhesivity, and c) independent control of bio-adhesivity and material stiffness to parse individual contributions to cell modulation. This NSF CAREER award, funded by the Biomaterials program in the Division of Materials Research, will enable development of a new class of nanocomposite hydrogels with control over the above mentioned three key properties within a single hydrogel. This work will advance current understanding of the role of biomaterial properties in controlling human stem cell fate through user-directed spatio-temporal control of cell-matrix interactions. This work will make interactive inquiry based learning permeate the underprivileged middle and high schools by training teachers and students. This CAREER award will grow the infrastructure of US engineers, in particular those from underrepresented minorities, with strong disciplinary competence in biomaterials through pedagogy and cutting-edge research.Non-Technical AbstractBiomaterials-based 3D hydrogels that better reflect the niche of native tissues and capture critical aspects of the dynamic microenvironment are of increasing importance for culturing of mammalian cells, including stem cells, for a wide range of applications in biomedicine. The flow of information between cells and their surrounding niche is spatially and temporally dependent on biochemical signals and cell-cell interactions. Despite advancement in the field of biomaterials, independent role of spatio-temporal biochemical signaling and biophysical properties of materials cannot be effectively studied using a single hydrogel system. This NSF CAREER award will overcome the current bottlenecks in biomaterials research by enabling the development of a new class of hydrogel that dynamically communicates with cells to control their fates. The proposed research will benefit society by developing advanced bio-functional tissues for regenerative medicine. In particular we expect this work to generate dynamic biomaterials for better understanding of stem cells and their interactions with local surroundings that will help treatment of neurological disorders and enable regeneration of neural grafts for short and long nerve gaps. The outcomes of this research will catalyze potential avenues of investigation in multiple disciplines, including cell culture, tissue fabrication, blood vessel generation, drug delivery, tumor engineering, and implants. This work will make interactive inquiry based learning permeate the underprivileged middle and high schools by training teachers and students. This CAREER proposal will grow the infrastructure of US engineers, in particular undergraduate and graduate students including those from underrepresented minorities, with strong disciplinary competence in biomaterials through pedagogy and cutting-edge research.