Microfluidic Platforms for Biological Investigations

微制造的芯片实验室（Lab-On-a-Chip，简称MEMS）设备正被广泛应用于细胞、组织、器官和整个生物系统的生物学研究，例如蠕虫（C. elegans）和果蝇（Drosophila）。由于其许多优点，整个生物系统提供了成本效益和相关的手段来研究感知和响应各种刺激信号的神经行为机制。然而，它们的小尺寸（微米至毫米）对它们在细胞和行为测定中的操纵提出了挑战。因此，目前的手工工作不仅缓慢和费力，而且有时在研究整个生物系统时不准确和不一致。这项研究计划提出开发创新的生物技术，将改善生物有机体的分析方法，以回答基本和复杂的神经行为问题。该研究计划的总体目标是开发各种生物学技术（通过进行两个创新的研究主题），以准确地操纵和测量生物标本在神经元和行为水平上对相关刺激（例如化学和电）的反应。这些LOCs将使筛选果蝇和C. elegans在自动化，高通量，定量和可重复的方式。*在研究主题1中，我们将开发LOCs，使不同化学品对果蝇幼虫的毒性作用的自动测量成为可能。为了能够做到这一点，我们将发展的表面特性刺激空间偏好的成年果蝇产卵的影响的基本理解。我们将利用所获得的知识和专业知识来开发分选和分区模块，将鸡蛋平行放入微室，在那里它们将可控地暴露于化学品。研究水流特性对卵存活和发育的影响具有重要意义。然后将研究刺激和参数化研究幼虫运动和神经元活动的技术。在研究主题2中，我们将开发独特的操作（例如固定和定向）和手术（例如解剖）微型工具，并将其集成到芯片中，即使是非专业研究人员也可以及时自动化地访问小型生物物质（例如蠕虫和果蝇）的内部环境。我们需要从根本上研究这些生物体的外体架的机械特性，以及使用各种力（例如介电泳和声学）来操纵它们，以便能够设计和开发上述工具。有待开发的知识和技术可直接应用于许多研究，如器官/卵子提取和/或生物标本中神经肌肉活动的体内记录。* 六名研究生和五名本科生将在本研究计划中接受培训，并将获得技术，科学，跨学科和软技能。所开发的知识和技术可应用于药物发现、毒理学、神经科学和系统生物学。通过自动化，与现有技术相比，可以以简单的方式以更高的通量从这些样品获得定量数据。从长远来看，该研究将通过加速和降低毒性测试、临床前药物发现、神经元映射和生物过程基础研究的成本而使加拿大受益。

Microfabricated Lab-On-a-Chip (LOC) devices are being applied to a wide range of biological studies on cells, tissues, organs and whole biological systems, e.g. the worm (C. elegans) and the fruit fly (Drosophila). Due to their many advantages, whole biological systems offer cost-effective and relevant means to study the neurobehavioral mechanisms of sensing and responding to various stimulating signals. However, their small sizes (micrometers to millimeters) impose challenges for their manipulation in cellular and behavioral assays. Hence, current manual efforts are not only slow and laborious, but also sometimes inaccurate and inconsistent in studying whole biological systems. This research program proposes developing innovative LOC techniques that will improve the ways bio-organisms are assayed to answer fundamental and complex neurobehavioral questions.****The overall goal of this research program is to develop various LOC techniques (by conducting two innovative research themes) to accurately manipulate and measure the response of biological specimens to relevant stimuli (e.g. chemical and electrical) at neuronal and behavioural levels. These LOCs will make it possible to screen chemicals on Drosophila and C. elegans in automated, high-throughput, quantitative and repeatable manners.****In research theme 1, we will develop LOCs that enable automated measurements of the toxic effects of different chemicals on Drosophila larvae. To be able to accomplish this, we will develop fundamental understanding of the effects of surface properties on stimulating spatial preference of egg-laying in adult Drosophila. We will use the knowledge and expertise acquired to develop sorting and compartmentalization modules to parallelize eggs into microchambers where they will be exposed controllably to chemicals. It is important to investigate the effects of flow characteristics on the survival and development of eggs into larvae. Techniques to stimulate and parametrically study the movement and neuronal activities of larvae will then be investigated.****In research theme 2, we will develop unique manipulation (e.g. immobilization and orientation) and surgical (e.g. dissection) micro-tools and integrate them inside chips that can enable even non-expert researchers access the internal environment of small biological substances (e.g. worm and fruit fly) in a timely automated manner. We need to fundamentally investigate the mechanical properties of the outer body shelves of these organisms and the use of various forces (e.g. dielectrophoretic and acoustic) to manipulate them in order to be able to design and develop the abovementioned tools. Knowledge and techniques to be developed are directly applicable to many studies such as organ/egg extraction and/or inner-body recording of neuromuscular activities in bio-specimens. ****Six graduate and five undergraduate students will be trained in this research program and will gain technical, scientific, interdisciplinary and soft skills. The developed knowledge and techniques can be applied in drug discovery, toxicology, neurosciences and systems biology. By automation, quantitative data from these specimens in higher throughputs can be obtained in easy manners as compared to existing techniques. In the long term, the research will benefit Canada by accelerating and lowering the cost of toxicity tests, preclinical drug discovery, neuronal mapping and fundamental investigation of bio-processes.