EAGER: (ST2) Peptide-Functionalized Hydrogels that Communicate with Preprogrammed Cells

非技术摘要：一些组织，如软骨，在受损时修复或再生其基质材料的能力有限。具有检测和替换受损基质能力的自我修复材料将使治疗更有效、更持久。这个早期概念的探索性研究资助(AGER)项目调查了水凝胶中编程细胞的使用，作为一种能够检测和取代基质丢失的新型材料。这项研究旨在通过根据需要生产新的基质材料，对水凝胶中的细胞进行编程，以检测和应对基质丢失。细胞产生的基质被标记为“OFF”信号，细胞使用该信号来检测何时产生了足够的基质。随着“关闭”信号的积累，细胞减少，最终停止生产，直到由于进一步损坏或降解而需要更多的基质。该项目旨在促进对生物反馈机制的基本理解，并通过支持顶峰项目团队中两名研究生和本科生的博士培训，为研究生和本科生提供多学科研究机会。这个渴望的项目的灵感来自于方桌2(ST2)可编程接口研讨会上提出的想法。技术摘要：尽管细胞具有刺激性合成受体，产生物质(例如抗体、细胞因子等)。一旦肽被激活，这些预先编程的细胞就失去了一旦制造出足够的材料就停止生产的能力。这个迫切的项目的目标是研究作为一种新的生物反馈机制的刺激性和抑制性受体-配体通信，并利用这些见解开发具有自我修复特性的适应性材料。这种新型材料由预先编程的细胞组成，细胞内包裹着可酶降解的水凝胶，其中含有刺激性和抑制性合成受体。当被空间拴系的刺激肽激活后，细胞产生绿色荧光蛋白(GFP，可测量的荧光)和标记有抑制配体的基质蛋白。然后，受刺激的细胞用细胞分泌的基质取代周围的水凝胶，直到在相互竞争的刺激和抑制信号之间达到平衡。为了确认这些材料的自我修复能力，细胞产生的基质被局部移除，通过细胞绿色荧光蛋白和荧光标记的新生基质的3D成像来测量细胞的反应和材料的产生。材料研究(DMR)分部的这项拨款支持研究，以了解和开发刺激性和抑制性受体-配基通信作为一种新的生物反馈机制，并利用这些见解开发具有自我修复特性的适应性材料，由数学和物理科学(MPS)总监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:Some tissues, such as cartilage, have limited capacity to repair or regenerate their matrix material when damaged. Self-healing materials with the ability to detect and replace damaged matrix would enable more effective and longer lasting therapies. This EArly-concept Grant for Exploratory Research (EAGER) project investigates the use of programmed cells within hydrogels as a new class of materials able to detect and replace matrix loss. This research aims to program cells within hydrogels to detect and respond to matrix loss by producing new matrix material as needed. The matrix produced by cells is tagged with an “OFF” signal that is used by the cells to detect when enough of matrix has been produced. As the “OFF” signal accumulates, the cells decrease and eventually stop production until more matrix is needed due to further damage or degradation. This project is designed to advance the fundamental understanding of biological feedback mechanisms and to provide multidisciplinary research opportunities for graduate and undergraduate students by supporting the Ph.D. training of two graduate students and undergraduate students in capstone project teams. This EAGER project is inspired by ideas developed at the Square Table 2 (ST2) workshop on Programmable Interfaces.Technical abstract:Although cells with stimulatory synthetic receptors that produce materials (e.g., antibodies, cytokines, etc.) upon peptide activation exist, these preprogrammed cells lack the ability to stop production once enough material is made. The goal of this EAGER project is to investigate stimulatory and inhibitory receptor-ligand communication as a novel biological feedback mechanism and to use these insights to develop adaptive materials with self-healing properties. This new class of materials consists of cells preprogrammed with stimulatory and inhibitory synthetic receptors encapsulated in enzymatically degradable hydrogels. Upon activation with spatially tethered stimulatory peptides, cells produce green fluorescent protein (GFP, measurable fluorescence) and a matrix protein tagged with inhibitory ligand. Stimulated cells then replace their surrounding hydrogel with cell-secreted matrix until a balance is reached between competing stimulatory and inhibitory signals. To confirm the self-healing capabilities of these materials, cell-produced matrix is removed locally, and cellular responses and material production are measured via 3D imaging of cellular GFP and fluorescently labeled nascent matrix.This Division of Materials Research (DMR) grant supports research to understand and develop stimulatory and inhibitory receptor-ligand communication as a novel biological feedback mechanism and to use these insights to develop adaptive materials with self-healing properties 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.