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

职业：用户可编程水凝胶生物材料来探测和指导 4D 干细胞命运

• 批准号: 1652141
• 负责人: Cole DeForest
• 金额: $ 49.75万
• 依托单位: University of Washington
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1652141&HistoricalAwards=false
• 关键词: CAREER; User; Programmable; Hydrogel; Biomaterials

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.

非技术性：人体组织不断发生变化。虽然这些改变在对抗疾病，促进愈合，让我们过上幸福，健康的生活方面至关重要，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可以用生物活性信号蛋白可逆和按需修饰的生物材料来解决这一知识不足，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，并为复杂的3D组织工程提供清晰的道路。此外，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。将与当地外展计划合作开发基于开源生物材料的模块，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，并有助于鼓励未来对生物材料充满热情的工程师的多元化社区。与生物材料学会合作，为年轻科学家建立一个包容性的支持网络，进一步确保他们的终身兴趣和生物材料领域的蓬勃发展。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，其中生物功能可以响应用户定义的物理化学信号。虽然凝胶已被用于控制工程化简单同质组织所需的基本细胞行为（例如，粘附，增殖），控制更复杂的细胞过程的策略（例如，迁移、分化）仍然很难预测。更困难的是获得时空和动态控制这些功能的能力，这是创造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种合成策略来解决，以实现具有位点特异性修饰的生长因子的3D细胞培养平台的可逆模式化。这些材料将用于通过BMP-2和TGF-β的时空模式化呈递来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，以探测和指导4D细胞的命运，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。

项目成果

Photopatterned biomolecule immobilization to guide three-dimensional cell fate in natural protein-based hydrogels

• DOI: 10.1073/pnas.2014194118
• 发表时间: 2021-01-26
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Batalov, Ivan;Stevens, Kelly R.;DeForest, Cole A.
• 通讯作者: DeForest, Cole A.

Boolean Biomaterials: Logic‐Based Delivery of Site‐Specifically Modified Proteins from Environmentally Responsive Hydrogel Biomaterials (Adv. Mater. 33/2019)

• DOI: 10.1002/adma.201970237
• 发表时间: 2019-08
• 期刊: Advanced Materials
• 影响因子: 29.4
• 作者: Prathamesh Milind Gawade;Jared A. Shadish;Barry A. Badeau;Cole A. DeForest

Dynamic Biomaterials: Cyclic Stiffness Modulation of Cell‐Laden Protein–Polymer Hydrogels in Response to User‐Specified Stimuli Including Light (Adv. Biosys. 12/2018)

动态生物材料：细胞负载蛋白质聚合物水凝胶响应用户指定刺激（包括光）的循环刚度调节（Adv. Biosys. 12/2018）

• DOI: 10.1002/adbi.201870111
• 发表时间: 2018
• 期刊: Advanced Biosystems
• 影响因子: 4.1
• 作者: Liu, Luman;Shadish, Jared A.;Arakawa, Christopher K.;Shi, Kevin;Davis, Jennifer;DeForest, Cole A.
• 通讯作者: DeForest, Cole A.

Multicellular Vascularized Engineered Tissues through User-Programmable Biomaterial Photodegradation.

• DOI: 10.1002/adma.201703156
• 发表时间: 2017-10
• 期刊: Advanced materials (Deerfield Beach, Fla.)
• 作者: Arakawa CK;Badeau BA;Zheng Y;DeForest CA
• 通讯作者: DeForest CA

Bioactive site-specifically modified proteins for 4D patterning of gel biomaterials

• DOI: 10.1038/s41563-019-0367-7
• 发表时间: 2019-09-01
• 期刊: NATURE MATERIALS
• 影响因子: 41.2
• 作者: Shadish, Jared A.;Benuska, Gabrielle M.;DeForest, Cole A.
• 通讯作者: DeForest, Cole A.