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制的关键因素。来控制功能和行为 通过调节pH微环境来调节细胞的pH对于促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应用。然而，基于pH值的细胞 控制仍然是一个挑战，由于缺乏手段，以实时，空间选择性调制的 虽然细胞系统中的pH微环境在时间上是高度异质的， 在空间上，已知pH调节方法是通过CO2/HCO 3 −缓冲和H+扩散，这是缓慢的， 各向同性和非特异性。因此，迫切需要在时空上调节pH微环境， 具体方式。不这样做意味着pH值，决定细胞命运和功能的重要因素， 控制得很好PI的长期目标是基于微环境pH值的细胞功能闭环调节， 代谢和形态发生。该项目的总体目标是实现长期目标的关键一步， 通过实时、空间选择性调节pH微环境来控制细胞。假设细胞 功能和行为可以通过超高时空分辨率（10-100 µm，<50 s）进行调节， 传统的基于扩散的方法（>103 µm，>103 s），在pH调节的微环境中 通过基于石墨烯的微电极进行纳米电化学，石墨烯是一种具有独特 出色的生物转导特性，解决了芯片上pH调节的主要挑战， 典型微电极材料的电池系统。测试这一假设的方法是量化实时 模型细胞系统对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是光学透明的，以允许微观表征， 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调节本项目将达到以下里程碑目标：（1）创建 通过开发双向石墨烯微电极阵列， 换能器和（2）控制模型细胞系统（心肌细胞和肿瘤细胞）的功能和行为 通过使用石墨烯换能器阵列的时空微环境pH调节。PI是独一无二的 由于PI的实验室能够创建可集成的石墨烯微电极， 在用于介接细胞系统、询问电/化学细胞信号和控制的流体装置中， 细胞行为通过产生微尺度pH梯度。为了利用和联合收割机， 用于选择性实时pH微环境的双向石墨烯换能器阵列的开发 调制和细胞控制。该项目的预期成果是基于pH值的细胞控制工具， 数量级增强的时空分辨率相比，传统的方法。这一结果 对生物工程发展、再生医学和合成形态学产生积极影响。