CAREER: User-Programmable Hydrogel Biomaterials to Probe and Direct 4D Stem Cell Fate

非技术：人体组织经历着不断的变化。尽管这些改变对于对抗疾病、促进康复、让我们过上幸福健康的生活至关重要，但这些变化如何影响细胞行为的细节在很大程度上仍然未知。拟议的研究旨在通过开发生物材料来解决这一知识缺陷，这些生物材料可以用生物活性信号蛋白进行可逆和按需修饰，从而模仿天然组织的动态生化特性。这些先进的材料将用于研究和指导干细胞功能，以响应局部信号的变化，为疾病/愈合过程提供新的见解，并为复杂3D组织的工程提供明确的途径。此外，一个多学科的教育计划，包括新的实验课程和研究机会，让学生学习高分子化学，反应工程和生物材料科学的基础知识。开源的基于生物材料的模块将与当地的推广项目合作开发，以鼓励代表性不足的群体从事工程职业。模块将在网上免费提供给其他人使用，并有助于鼓励对生物材料充满热情的未来工程师的多元化社区。与生物材料学会合作，为青年科学家建立一个包容性的支持网络，进一步确保他们的终身兴趣和生物材料领域的繁荣未来。技术：合成水凝胶已经成为强大的体外细胞培养平台，提供简化的，接近生理的，3D环境，其中生物功能可以根据用户定义的物理化学信号进行指导。虽然凝胶已经被用来控制设计简单的同质组织所需的基本细胞行为（例如，粘附，增殖），但控制更复杂的细胞过程（例如，迁移，分化）的策略在很大程度上仍然难以捉摸。更困难的是获得通过时空和动态控制来指导这些功能的能力，这是创建异质多细胞组织所必需的。在拟议的研究中，这一缺陷将通过开发第一个合成策略来解决，以实现具有特定位点修饰的生长因子的3D细胞培养平台的可逆模式。这些材料将通过BMP-2和tgf - β的时空模式呈现，用于指导水凝胶基质内的人间充质干细胞分化。在合成化学，蛋白质工程和干细胞生物学的界面操作，学生学员将开发独特的强大的生物材料来探测和指导4D细胞命运，以响应动态和异质微环境信号。这项研究将通过创建一个开源的教育和推广平台来补充，通过以生物材料为中心的编程来激发人们对工程的兴趣。

Non-Technical:Human tissue undergoes constant change. Though such alterations are critical in combating disease, promoting healing, and allowing us to live happy, healthy lives, the specifics of how these changes affect cell behavior remain largely unknown. The proposed research seeks to address this knowledge deficiency through the development of biomaterials that can be modified reversibly and on demand with bioactive signaling proteins, thereby mimicking the dynamic biochemical properties of native tissue. These advanced materials will be used to study and direct stem cell function in response to changes in local signaling, providing new insight into disease/healing processes and a clear path towards the engineering of complex 3D tissues. Furthermore, a multidisciplinary education program involving new laboratory classes and research opportunities for students to learn the fundamentals of polymer chemistry, reaction engineering, and biomaterial science will be created. Open-source biomaterial-based modules will be developed in collaboration with local outreach programs that encourage under-represented groups to pursue careers in engineering. Modules will be made freely available online for others to use and help encourage a diverse community of future engineers with a passion for biomaterials. In partnership with the Society for Biomaterials, an inclusive support network will be built for young scientists, further ensuring their lifelong interest and a thriving future for the field of biomaterials.Technical:Synthetic hydrogels have emerged as powerful in vitro cell culture platforms, providing simplified, near-physiological, 3D environments in which biological function can be directed in response to user-defined physicochemical signals. While gels have been exploited to control basic cell behaviors required to engineer simple homogenous tissues (e.g., adhesion, proliferation), strategies to govern more complex cellular processes (e.g., migration, differentiation) remain largely elusive. Even more difficult has been gaining the ability to direct such functions with spatiotemporal and dynamic control, required to create heterogeneous multicellular tissues. In the proposed research, this deficiency will be addressed by developing the first synthetic strategy to enable reversible patterning of 3D cell culture platforms with site-specifically-modified growth factors. These materials will be utilized to direct human mesenchymal stem cell differentiation within hydrogel matrices via the spatiotemporally patterned presentation of BMP-2 and TGF-beta. Operating at the interface of synthetic chemistry, protein engineering, and stem cell biology, student trainees will develop uniquely powerful biomaterials to probe and direct 4D cell fate in response to dynamic and heterogeneous microenvironmental signals. This research will be complemented by the creation of an open-source educational and outreach platform that inspires interest in engineering through biomaterial-centered programming.