EAGER: (ST2) Engineering Biomaterials that Integrate in the Native ECM of Cells.

非技术摘要：生物材料是与生物系统相互作用的材料，因此是基础生物学研究、医学应用和工程组织的重要组成部分。然而，目前的生物材料被设计为与细胞和组织接口和相互作用，细胞不能主动重塑生物材料并将其整合到最终细胞生成的组织中。受2号方桌会议的启发，该项目建议设计综合合成材料(ISMS)，作为一种新型的生物材料，细胞循环并整合到新构建的组织中。研究人员假设，ISM可以导致具有新特性的工程化组织。为了验证这一假说，研究小组旨在应用最近开发的合成生物学方法，将非标准氨基酸整合到细胞外基质蛋白中，作为合成生物材料的连接物分子，从而将新的化学引入工程组织。该项目的成功带来了一个范式的转变，从“与组织结合的材料”到“整合到组织中的材料”，并为研究体内自然组织环境中细胞-细胞外基质的相互作用、设计组织和器官以及输送药物提供了一个新的平台。这项由波士顿大学生物设计中心进行的研究与一个强有力的教育计划紧密相连。该项目培训研究生和本科生，涵盖合成生物学、组织工程和材料科学领域，为21世纪的科学劳动力提供富有成效的职业生涯。学生将有充分的机会学习最先进的技术，出席国际会议，并与大波士顿地区的研究社区建立联系。技术摘要：聚丙烯酰胺和聚乙二醇等生物软材料具有高度可调的生物物理性质、可控的降解特性和生化信号的释放动力学，为细胞机械转导和细胞信号传递提供了前所未有的见解。尽管取得了这些重大进展，但所有生物材料都有一个共同的局限性，那就是细胞不能主动重塑材料，并将其整合到最终细胞生成的组织中。事实上，当细胞附着在材料表面时，细胞会降解材料，同时在细胞-材料界面上沉积新的细胞外基质(ECM)，但生物材料本身并不包含在新生组织基质中。因此，随着细胞重塑细胞-材料界面，材料传递的控制细胞行为的生物物理或生化线索逐渐丢失。这一限制限制了可实现的工程化组织的功能。为了克服生物材料的这一根本局限性，该项目提出开发综合合成材料(ISMS)作为一种新型的生物材料，细胞可以回收和使用这些材料来组装它们的细胞外基质。利用对纤维连接蛋白重塑的新见解，这是一种普遍存在的ECM蛋白，在胚胎发育期间和损伤后的组织组装中至关重要，以及重新编码的大肠杆菌菌株的发展，在蛋白质中加入非标准氨基酸，该项目旨在设计合成修饰的纤维连接蛋白片段，这些片段标记有叠氮残基，为与葡聚糖等聚合物材料的交联提供反应位点。使用合成修饰的纤维连接蛋白片段作为ISM的构建块，该项目追求的假设是，当ISMS在从头组装的ECM中并入时，对ISM的合成控制，如调节硬度，保持不变。如果成功，这个项目将带来一个范式的转变，从“与细胞接触的生物材料”转变为“整合到细胞本身的细胞外基质中的生物材料”。材料研究部(DMR)的这项拨款支持开发综合合成材料(ISMS)的研究，这是一种新型的生物材料，细胞可以循环使用，以组装其细胞外基质(ECM)，由数学和物理科学(MPS)主管DMR的凝聚态物质物理(CMP)计划管理。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Non-technical abstract:Biomaterials are materials that interact with biological systems, and are therefore an essential component for fundamental biology studies, medical applications, and engineering tissues. However, current biomaterials are designed to interface and interact with cells and tissues, and cells cannot actively remodel and incorporate biomaterials into the final cell generated tissue. Inspired by the Square-Table-2 meeting, this project proposes to design Integrative Synbio-Materials (ISMs) as a novel class of biomaterials that cells recycle and integrate into newly built tissue. The researchers hypothesize that ISMs can lead to engineered tissues with novel properties. To test this hypothesis, the research team aims to apply recently developed synthetic biology approaches to incorporate non-standard amino acids in extracellular matrix proteins, which serve as linker molecules to synthetic biomaterials and as such introduce novel chemistry into engineered tissue. Success from this project brings about a paradigm shift from ‘materials that interface with tissues’ to ‘materials that integrate into tissues’ and provides a new platform to study cell-extracellular matrix interactions in their native tissue environment in vivo, to engineer tissues and organs, and to deliver drugs. This research, conducted at the Biological Design Center at Boston University, is tightly coupled to a strong education plan. The project trains students at graduate and undergraduate levels, across the fields of synthetic biology, tissue engineering, and material science, for productive careers in the 21st century scientific workforce. Students will have ample opportunities to learn state-of-the-art technologies, present at international conferences, and connect with research communities in the greater Boston area. Technical abstract:Recent advances in soft biomaterials such as polyacrylamide and polyethylene glycol with highly tunable biophysical properties, controllable degradation characteristics, and release kinetics of biochemical signals have provided unprecedented insights in cellular mechano-transduction and cell signaling. Despite these major advances, all biomaterials share one common limitation; that is cells cannot actively remodel and incorporate that material into the final cell generated tissue. Indeed, when adherent to a material surface, cells degrade the material while depositing new extracellular matrix (ECM) on the cell-material interface, but the biomaterial itself is not incorporated in the de novo tissue matrix. Thus, as cells remodel the cell-material interface, the biophysical or biochemical cues delivered by the material to control cell behavior are progressively lost. This limitation constrains the function of the engineered tissue that can be achieved. To overcome this fundamental limitation of biomaterials, this project proposes to develop Integrative Synbio-Materials (ISMs) as a novel class of biomaterials that cells recycle and use to assemble their ECM. Taking advantage of new insights in fibronectin remodeling, a ubiquitous ECM protein that is critical for the assembly of tissues during embryonic development and after injury, and the development of recoded E. coli strains that incorporate non-standard amino acids in proteins, this project aims to engineer synthetically modified fibronectin fragments that are tagged with azido residues, which provide reactive sites for crosslinking with polymeric materials such as dextran. Using synthetically modified fibronectin fragments as building blocks for ISMs, this project pursues the hypothesis that synthetic control of ISMs, such as tuning stiffness, is retained upon the incorporation of ISMs in de novo assembled ECMs. When successful, this project brings about a paradigm shift from ‘biomaterials that interface with cells’ to ‘biomaterials that integrate into the native ECM of cells’. This Division of Materials Research (DMR) grant supports research to develop Integrative Synbio-Materials (ISMs) as a novel class of biomaterials that cells recycle and use to assemble their extra-cellular matrix (ECM) managed by the Condensed Matter Physics (CMP) Program in DMR of the Mathematical and Physical Sciences (MPS) Directorate.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.