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

非技术：人体组织经历不断的变化。虽然这种改变在抗击疾病、促进愈合以及让我们过上快乐、健康的生活方面至关重要，但这些改变如何影响细胞行为的细节在很大程度上仍不清楚。这项拟议的研究试图通过开发生物材料来解决这一知识不足的问题，这种生物材料可以根据需要使用生物活性信号蛋白进行可逆修改，从而模拟自然组织的动态生化特性。这些先进材料将用于研究和指导干细胞功能，以应对局部信号的变化，为疾病/愈合过程提供新的见解，并为复杂3D组织的工程提供一条明确的途径。此外，还将创建一个多学科教育计划，包括新的实验室课程和研究机会，让学生学习聚合物化学、反应工程和生物材料科学的基础知识。基于开源生物材料的模块将与当地推广计划合作开发，这些计划鼓励代表性不足的群体在工程领域追求职业生涯。模块将在网上免费提供，供其他人使用，并有助于鼓励对生物材料充满热情的未来工程师的多样化社区。与生物材料学会合作，将为年轻科学家建立一个包容性的支持网络，进一步确保他们在生物材料领域的终身兴趣和蓬勃发展的未来。技术：合成水凝胶已成为强大的体外细胞培养平台，提供简化的、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，黏附、增殖)，但管理更复杂的细胞过程(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，这一不足将通过开发第一个合成策略来解决，以实现具有特定部位修饰的生长因子的3D细胞培养平台的可逆图案。这些材料将被用来通过BMP-2和转化生长因子-β的时空图案化呈现，在水凝胶基质中指导人类间充质干细胞分化。学生将在合成化学、蛋白质工程和干细胞生物学的界面上操作，开发独特的强大生物材料来探测和指导4D细胞的命运，以响应动态和不同种类的微环境信号。这项研究将通过创建一个开源教育和推广平台来补充，该平台通过以生物材料为中心的编程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.