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，当前的生物材料被设计为与细胞和组织交互并相互作用，并且细胞不能主动重塑生物材料并将其整合到最终的细胞生成的组织中。受 Square-Table-2 会议的启发，该项目提议将综合合成材料 (ISM) 设计为一类新型生物材料，细胞可回收并整合到新建组织中。研究人员假设 ISM 可以产生具有新特性的工程组织。为了检验这一假设，研究小组旨在应用最近开发的合成生物学方法，将非标准氨基酸纳入细胞外基质蛋白中，作为合成生物材料的连接分子，从而将新颖的化学物质引入工程组织中。该项目的成功带来了从“与组织相互作用的材料”到“融入组织的材料”的范式转变，并提供了一个新的平台来研究体内天然组织环境中的细胞与细胞外基质的相互作用、设计组织和器官以及输送药物。这项研究在波士顿大学生物设计中心进行，与强有力的教育计划紧密结合。该项目为合成生物学、组织工程和材料科学领域的研究生和本科生提供培训，帮助他们在 21 世纪的科学劳动力中实现富有成效的职业生涯。学生将有充足的机会学习最先进的技术、出席国际会议以及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软生物材料的最新进展，具有高度可调的生物物理特性、可控的降解特性和生化信号的释放动力学，为细胞力传导和细胞信号传导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：也就是说，细胞无法主动重塑该材料并将其整合到最终的细胞生成的组织中。事实上，当粘附到材料表面时，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），但生物材料本身并未并入从头组织基质中。因此，当细胞重塑细胞-材料界面时，材料传递的用于控制细胞行为的生物物理或生化线索逐渐丢失。这种限制限制了工程组织所能实现的功能。为了克服生物材料的这一基本限制，该项目建议开发综合合成材料（ISM）作为一类新型生物材料，细胞可以回收并使用它来组装其 ECM。利用纤连蛋白重塑（一种普遍存在的 ECM 蛋白，对胚胎发育期间和损伤后的组织组装至关重要）的新见解，以及在蛋白质中掺入非标准氨基酸的重新编码大肠杆菌菌株的开发，该项目旨在工程化带有叠氮残基标记的合成修饰纤连蛋白片段，为与葡聚糖等聚合材料交联提供反应位点。该项目使用合成修饰的纤连蛋白片段作为 ISM 的构建模块，提出了这样的假设：将 ISM 纳入从头组装的 ECM 中后，保留了 ISM 的合成控制（例如调节刚度）。一旦成功，该项目将带来从“与细胞交互的生物材料”到“融入细胞天然 ECM 的生物材料”的范式转变。材料研究部 (DMR) 拨款支持开发综合合成材料 (ISM) 作为一类新型生物材料的研究，细胞回收并使用这种生物材料来组装细胞外基质 (ECM)，由数学和物理科学 (MPS) 理事会 DMR 凝聚态物理 (CMP) 项目管理。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查进行评估，被认为值得支持标准。

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.