Cell Control via Spatiotemporal Microenvironmental pH Modulation

通过时空微环境 pH 调节进行细胞控制

• 批准号: 10713388
• 负责人: Jinglei Ping
• 金额: $ 37.92万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713388
• 关键词: Address; Advanced Development; Behavior; Bicarbonates; Biomedical Engineering; Buffers; Carbon Dioxide; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell model; Cell physiology; Cells; Cellular biology; Chemicals; Communication; Development; Devices; Diffusion; Drug Delivery Systems; Failure; Goals; Malignant Neoplasms; Metabolism; Methods; Microelectrodes; Microscopic; Mission; Morphogenesis; Morphology; Optics; Outcome; Pathogenesis; Positioning Attribute; Property; Public Health; Reaction Time; Regenerative Medicine; Regulation; Resolution; Signal Transduction; System; Techniques; Testing; Therapeutic; Time; Tissue Engineering; Transducers; United States National Institutes of Health; anti-cancer; cell behavior; disability; graphene; improved; meter; nanomaterials; neoplastic cell; pH gradient; spatiotemporal; tool; two-dimensional

Microenvironmental pH is a key factor in cell functioning and pathogenesis. To control the function and behavior of cells by modulating pH microenvironments is critical to advancing the development of cell biology and tissue engineering and enabling applications in drug delivery and regenerative medicine. However, pH-based cell control remains a challenge due to the lack of means to real-time, spatioselective modulation of microenvironmental pH. While pH microenvironments in cell systems are highly heterogeneous in time and space, known pH-modulation methods are through CO2/HCO3− buffering and H+ diffusion, which are slow, isotropic, and nonspecific. An urgent need, therefore, is to modulate pH microenvironments in a spatiotemporally specific manner. Failure to do so means that pH, an essential factor that determines cell fate and function, is not in good control. The PI’s long-term goal is microenvironmental pH–based closed-loop regulation of cell function, metabolism, and morphogenesis. The overall goal of this project, a critical step towards the long-term goal, is to control cells by real-time, spatioselective modulation of pH microenvironments. The hypothesis is that cell function and behavior can be regulated with ultra-high spatiotemporal resolutions (10–100 µm, <50 s), compared to conventional, diffusion-based methods (>103 µm, >103 s), in pH microenvironments that are modulated nanoelectrochemically by microelectrodes based on graphene, a two-dimensional nanomaterial with unique outstanding bio-transduction properties that address the primary challenge of on-chip pH modulation of living cell systems for typical microelectrode materials. The approach to test this hypothesis is to quantify real-time responses of model cell systems to arrayed pH microenvironment generated by an array of bidirectional graphene-microelectrode transducers that are optically transparent to allow microscopic characterization and communicate with cellular systems through electrical signal interrogation and rapid nanoelectrochemical microenvironmental-pH modulation. The following milestone goals will be reached in this project: (1) to create densely arrayed pH microenvironment by developing an array of bidirectional graphene-microelectrode transducers and (2) to control the function and behavior of model cell systems (cardiomyocytes and tumor cells) via spatiotemporal microenvironmental pH modulation using the graphene transducer array. The PI is uniquely positioned to conduct the project due to the ability of the PI’s lab to create graphene microelectrodes integrable in a fluidic device for interfacing cellular systems, interrogating electrical/chemical cell signals, and controlling cell behavior by generating microscale pH gradients. To harness and combine these techniques allows the development of arrays of bidirectional graphene transducers for selective, real-time pH-microenvironment modulation and cell control. The expected outcome of the project is pH-based cell-control tools with over two- orders-of-magnitude enhanced spatiotemporal resolutions compared to conventional methods. This outcome is to generate positive impact on bioengineering development, regenerative medicine, and synthetic morphology.

微环境pH是细胞功能和发病机理的关键因素。控制功能和行为 通过调节pH微环境调节细胞对于推进细胞生物学和组织的发展至关重要 在药物输送和再生医学中的工程和启用。但是，基于pH的细胞 由于缺乏实时的，时空选择的调制，控制仍然是一个挑战 微环境PH。而细胞系统中的pH微环境在时间上是高度异质的，而 空间，已知的pH调节方法通过CO2/HCO3-缓冲和H+扩散，它们很慢 各向同性和非特异性。因此，迫切需要是在空间上调节pH微环境 具体方式。不这样做意味着pH是决定细胞命运和功能的重要因素，不是 很好地控制。 PI的长期目标是基于细胞功能的基于微环境的闭环调节， 代谢和形态发生。该项目的总体目标是朝着长期目标迈出的关键一步，是 通过实时的，pH微环境的时空选择性调节来控制细胞。假设是细胞 比较了超高时空分辨率（10-100 µm，<50 s），功能和行为可以调节 在调制的pH微环境中，传统的基于扩散的方法（> 103 µm，> 103 s） 基于石墨烯的微电极在纳米电子化学上，这是一种二维纳米材料，独特 出色的生物转变特性，该特性应对生活芯片pH调制的主要挑战 典型微电极材料的细胞系统。检验该假设的方法是量化实时 模型细胞系统对由双向阵列产生的阵列pH微环境的响应 石墨烯 - 微电极换能器在光学上透明以允许微观表征和 通过电信号询问和快速纳米电化学与细胞系统通信 微环境-PH调制。该项目将实现以下里程碑目标：（1）创建 通过开发一系列双向石墨烯 - 微电极，呈不良阵列的pH微环境 传感器和（2）控制模型细胞系统的功能和行为（心肌细胞和肿瘤细胞） 通过使用石墨烯传感器阵列的时空微环境pH调制。 PI是独特的 由于PI实验室能够创建石墨烯微电极可集成的能力，因此可以进行项目 在用于接口细胞系统的流体设备中，询问电气/化学细胞信号并控制 通过产生微观pH梯度来通过细胞行为。利用和结合这些技术允许 开发用于选择性的实时pH-微环境的双向石墨烯传感器的阵列 调节和细胞控制。该项目的预期结果是基于pH的细胞控制工具，具有超过两种的工具 与常规方法相比，稳定阶的时空分辨率增强了。这个结果是 对生物工程开发，再生医学和合成形态产生积极影响。