基于微流控芯片的浓度梯度实现新方法及其应用研究
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摘要
生物体能够感受周围环境中多种化学分子信号，并根据其浓度梯度改变自身的生理活动。传统的研究生物体对于外界环境反应的方法操作繁琐、耗时较长、难以定量分析、并且不具有通用性。微流控芯片技术能够将不同的操作整合在一块芯片内，从而实现分析设备的微型化、集成化、自动化，将可以解决传统方法难以解决的生物学问题。因此，利用微流控芯片模拟外界环境，建立化学物质浓度梯度，并在细胞以及个体水平上研究生物体对于外界环境的反应无疑具有重要的意义。
本文建立了一种新型浓度梯度微流控芯片。不同于已报道的常见的“圣诞树”的浓度梯度形成结构，该芯片利用阶梯状微通道网络，采用了逐步分流再混流的方式逐步稀释样品溶液，从而产生液体浓度梯度。
我们首先对该微流控芯片进行理论分析与优化。采用数学建模的方法对这种通过液体串行稀释而产生化学物质浓度梯度的微流控新方法进行了原理阐述。通过流体力学计算方法，对微流控芯片内微通道结构进行了数学建模，并模拟分析不同的结构对于浓度梯度的影响。结果表明采用微通道宽度为100μm、下层主通道液体分流的分叉口处于右位、入口流量为0.5μL/min时的阶梯状网络结构最有利于形成液体浓度梯度。
为了验证数学模拟的结果，我们在芯片入口分别通入水和荧光素，并通过荧光显微镜进行成像分析。结果表明在芯片内混流的区域，水和荧光素实现了完全混合，并在出口的六条微通道处形成了线性浓度梯度。在出口主通道中，六路溶液呈现层流特性，形成了明显的稳定的浓度梯度，保持了较长距离。实验结果与流体动力学计算得到的模拟结果非常吻合。
之后，我们利用该微流控芯片进行了细胞水平上的应用。表达有可以检测细胞凋亡的CD2探针的HeLa细胞通过正压从芯片出口处进入主通道内，并贴附其通道壁生长。通过该芯片微通道网络在主通道中形成稳定的抗癌药物—顺铂浓度梯度，从而实现不同浓度的顺铂药物对细胞的处理。利用荧光能量共振转移成像系统对顺铂诱导细胞凋亡的进行实时在体监测。实验表明：顺铂可以诱导HeLa细胞凋亡，且顺铂的浓度与细胞凋亡率呈正相关，其中蛋白酶Caspase-2介导了顺铂诱导的细胞凋亡。这些结果说明该微流控浓度梯度产生芯片可以用于细胞凋亡的研究。
最后，我们利用该微流控芯片形成了传统方法难以实现的含有浓度梯度的线虫培养环境，并分析了线虫对于NaCl的趋向性以及趋向学习行为。通过正压，我们将线虫直接注入芯片内出口主通道中，并通过芯片内阶梯状微通道网络在主通道中形成NaCl浓度梯度。为定量分析芯片内线虫的化学物质趋向性行为，我们通过成像，分析了在出口主通道中不同NaCl浓度区域内的线虫分布。结果表明野生型线虫主要趋向于浓度大于20mM的NaCl溶液，对于50-100mM之间的NaCl溶液没有偏好性，对高于300mM的NaCl溶液则表现出明显的厌恶性行为。此外，我们在该芯片内直接实现了NaCl与饥饿共处理线虫，从而将线虫的学习训练与训练后趋向性分析同在一块芯片内进行。结果表明：类似于平板上的学习行为，NaCl与饥饿共处理的线虫表现出厌恶原来喜欢的低浓度的NaCl的行为。这种芯片内学习方式可以让线虫通过学习建立低浓度NaCl与厌恶行为的联系。因此，该芯片可以为研究线虫的化学物质趋向以及学习行为提供良好的研究平台，并能够提高分析效率，降低分析时间，可以分析记忆时间很短的线虫可塑性学习行为。
上述实验结果表明该微流控新技术平台具有设计新颖、结构简单以及实现效果明显的特点，能够实现可控的化学物质浓度梯度，并能够应用于不同的生物体系中。除了形成浓度梯度，该方法还可以形成温度梯度，为将来研究细胞和多细胞生物体在不同温度条件下的反应提供一种新的途径。该芯片在药物筛选、生物检测以及环境检测等方面也具有潜在的应用价值。
Organisms can sense a variety of chemical signals surrounding them, and changetheir physiological activities in accordance with the signals’ concentration gradient.Traditional methods for investigating the responses of organisms to the externalenvironment are complicated, time-consuming, and difficult to realize quantitativeanalysis. Microfluidic chip technology allows different operations on a single chip,showing advantages such as miniaturization, integration and automation. Therefore, it isof great significance to use microfluidic-based method to simulate external environment,and establish chemical concentration gradient for studying the responses of organisms tothe external environment at the single-cell level.
In this paper, a new concentration gradient microfluidic chip is developed. Differentfrom preveiously reported "Christmas tree" structure, the new microfluidic chip make useof stepped microchannel network to dilute the sample solution, and to generateconcentration gradients.
We first used numerical simulations to optimize the design of the microfluidic chipfor generating chemical concentration gradient by serial dilution. The influence ofdifferent microchannel structures on the concentration gradient was investigated. Resultsshowed that the best concentration gradient generating structure was the ladder networkwith the right bifurcation in the lower main channel and the microchannel width of100μm at quantity of flow of0.5μL/min in inlets.
In order to verify the results of mathematical modeling, we loaded water andfluorescein into the chip, and studied the generation of concentration gradient byfluorescence imaging. Results showed that water and fluorescein were mixed completely,and a linear concentration gradient was generated at the outlet of the six microchannels. Inthe main channel of the outlet, the six-way concentrations of the solution are broughttogether. The solutions are layered, and last a long distance for keeping stableconcentration gradients apparently. These results were consistent to those obtained fromnumerical simulations.
Subsequently, we applied the microfluidic chip to cell analysis. HeLa cells,expressing CD2probes for detecting apoptosis, were loaded into the main channel throughthe outlet of the chip, and attached to the bottom of the microchannel for cell culture. Astable concentration gradient of the anti-cancer drug, cisplatin was established in the main channel. Thus adherent cells could be treated with different concentrations of cisplatinsimultaneously. Fluorescence resonance energy transfer imaging system was used tomonitor the cisplatin-induced apoptosis in real time. Experimental results showed thatcisplatin could induce the apoptosis of HeLa cells, and the apoptosis rate was positivelycorrelated with the cisplatin concentrations. The protease caspase-2mediated theapoptosis induced by cisplatin. All these results suggested that the microfluidicconcentration gradient chip could be used for studying apoptosis.
Finally, we used the microfluidic chip to establish concentration gradient forculturing Caenorhabditis elegans (C. elegans), which was difficult to achieve throughtraditional methods. The chemotaxis of C. elegans to NaCl was investigated. We loaded C.elegans to the main channel from the outlet of the microchannel, and the NaClconcentration gradient was generated simultaneously. The distribution of C. elegans in themain channel was investigated to quantify the chemotaxis C. elegans to NaCl. Resultsshowed that the wild-type C. elegans responded to NaCl with a concentration more than20mM. C. elegans showed no chemotaxis to50-100mM NaCl, and hated NaClconcentration higher than300mM. In addition, we have implemented directly the C.elegans with Nacl and with hungry on the same chip. Therefore, the learning training andthe chemotaxis analysis after training were conducted on the same chip. Results showedthat C. elegans could change its chemotaxis to low concentration of NaCl through leaning.Thus, the microfluidic chip provided a useful platform for investigating the chemotaxisand learning behaviors of C. elegans with reduced analysis time and enhanced analyticalefficiency.
Above experimental results showed that the novel, simple and efficient microfluidicmethod was able to generate controllable chemical concentration gradients, and it could beapplied to study different model organisms. Except forming concentration gradient, thischip can also form a temperature gradient, which provides a new way for the future studyof reaction of cells and multicellular organisms in different temperature. This new methodwould have potential applications in drug screening, biological examination andenvironmental testing.
本文建立了一种新型浓度梯度微流控芯片。不同于已报道的常见的“圣诞树”的浓度梯度形成结构，该芯片利用阶梯状微通道网络，采用了逐步分流再混流的方式逐步稀释样品溶液，从而产生液体浓度梯度。
我们首先对该微流控芯片进行理论分析与优化。采用数学建模的方法对这种通过液体串行稀释而产生化学物质浓度梯度的微流控新方法进行了原理阐述。通过流体力学计算方法，对微流控芯片内微通道结构进行了数学建模，并模拟分析不同的结构对于浓度梯度的影响。结果表明采用微通道宽度为100μm、下层主通道液体分流的分叉口处于右位、入口流量为0.5μL/min时的阶梯状网络结构最有利于形成液体浓度梯度。
为了验证数学模拟的结果，我们在芯片入口分别通入水和荧光素，并通过荧光显微镜进行成像分析。结果表明在芯片内混流的区域，水和荧光素实现了完全混合，并在出口的六条微通道处形成了线性浓度梯度。在出口主通道中，六路溶液呈现层流特性，形成了明显的稳定的浓度梯度，保持了较长距离。实验结果与流体动力学计算得到的模拟结果非常吻合。
之后，我们利用该微流控芯片进行了细胞水平上的应用。表达有可以检测细胞凋亡的CD2探针的HeLa细胞通过正压从芯片出口处进入主通道内，并贴附其通道壁生长。通过该芯片微通道网络在主通道中形成稳定的抗癌药物—顺铂浓度梯度，从而实现不同浓度的顺铂药物对细胞的处理。利用荧光能量共振转移成像系统对顺铂诱导细胞凋亡的进行实时在体监测。实验表明：顺铂可以诱导HeLa细胞凋亡，且顺铂的浓度与细胞凋亡率呈正相关，其中蛋白酶Caspase-2介导了顺铂诱导的细胞凋亡。这些结果说明该微流控浓度梯度产生芯片可以用于细胞凋亡的研究。
最后，我们利用该微流控芯片形成了传统方法难以实现的含有浓度梯度的线虫培养环境，并分析了线虫对于NaCl的趋向性以及趋向学习行为。通过正压，我们将线虫直接注入芯片内出口主通道中，并通过芯片内阶梯状微通道网络在主通道中形成NaCl浓度梯度。为定量分析芯片内线虫的化学物质趋向性行为，我们通过成像，分析了在出口主通道中不同NaCl浓度区域内的线虫分布。结果表明野生型线虫主要趋向于浓度大于20mM的NaCl溶液，对于50-100mM之间的NaCl溶液没有偏好性，对高于300mM的NaCl溶液则表现出明显的厌恶性行为。此外，我们在该芯片内直接实现了NaCl与饥饿共处理线虫，从而将线虫的学习训练与训练后趋向性分析同在一块芯片内进行。结果表明：类似于平板上的学习行为，NaCl与饥饿共处理的线虫表现出厌恶原来喜欢的低浓度的NaCl的行为。这种芯片内学习方式可以让线虫通过学习建立低浓度NaCl与厌恶行为的联系。因此，该芯片可以为研究线虫的化学物质趋向以及学习行为提供良好的研究平台，并能够提高分析效率，降低分析时间，可以分析记忆时间很短的线虫可塑性学习行为。
上述实验结果表明该微流控新技术平台具有设计新颖、结构简单以及实现效果明显的特点，能够实现可控的化学物质浓度梯度，并能够应用于不同的生物体系中。除了形成浓度梯度，该方法还可以形成温度梯度，为将来研究细胞和多细胞生物体在不同温度条件下的反应提供一种新的途径。该芯片在药物筛选、生物检测以及环境检测等方面也具有潜在的应用价值。
Organisms can sense a variety of chemical signals surrounding them, and changetheir physiological activities in accordance with the signals’ concentration gradient.Traditional methods for investigating the responses of organisms to the externalenvironment are complicated, time-consuming, and difficult to realize quantitativeanalysis. Microfluidic chip technology allows different operations on a single chip,showing advantages such as miniaturization, integration and automation. Therefore, it isof great significance to use microfluidic-based method to simulate external environment,and establish chemical concentration gradient for studying the responses of organisms tothe external environment at the single-cell level.
In this paper, a new concentration gradient microfluidic chip is developed. Differentfrom preveiously reported "Christmas tree" structure, the new microfluidic chip make useof stepped microchannel network to dilute the sample solution, and to generateconcentration gradients.
We first used numerical simulations to optimize the design of the microfluidic chipfor generating chemical concentration gradient by serial dilution. The influence ofdifferent microchannel structures on the concentration gradient was investigated. Resultsshowed that the best concentration gradient generating structure was the ladder networkwith the right bifurcation in the lower main channel and the microchannel width of100μm at quantity of flow of0.5μL/min in inlets.
In order to verify the results of mathematical modeling, we loaded water andfluorescein into the chip, and studied the generation of concentration gradient byfluorescence imaging. Results showed that water and fluorescein were mixed completely,and a linear concentration gradient was generated at the outlet of the six microchannels. Inthe main channel of the outlet, the six-way concentrations of the solution are broughttogether. The solutions are layered, and last a long distance for keeping stableconcentration gradients apparently. These results were consistent to those obtained fromnumerical simulations.
Subsequently, we applied the microfluidic chip to cell analysis. HeLa cells,expressing CD2probes for detecting apoptosis, were loaded into the main channel throughthe outlet of the chip, and attached to the bottom of the microchannel for cell culture. Astable concentration gradient of the anti-cancer drug, cisplatin was established in the main channel. Thus adherent cells could be treated with different concentrations of cisplatinsimultaneously. Fluorescence resonance energy transfer imaging system was used tomonitor the cisplatin-induced apoptosis in real time. Experimental results showed thatcisplatin could induce the apoptosis of HeLa cells, and the apoptosis rate was positivelycorrelated with the cisplatin concentrations. The protease caspase-2mediated theapoptosis induced by cisplatin. All these results suggested that the microfluidicconcentration gradient chip could be used for studying apoptosis.
Finally, we used the microfluidic chip to establish concentration gradient forculturing Caenorhabditis elegans (C. elegans), which was difficult to achieve throughtraditional methods. The chemotaxis of C. elegans to NaCl was investigated. We loaded C.elegans to the main channel from the outlet of the microchannel, and the NaClconcentration gradient was generated simultaneously. The distribution of C. elegans in themain channel was investigated to quantify the chemotaxis C. elegans to NaCl. Resultsshowed that the wild-type C. elegans responded to NaCl with a concentration more than20mM. C. elegans showed no chemotaxis to50-100mM NaCl, and hated NaClconcentration higher than300mM. In addition, we have implemented directly the C.elegans with Nacl and with hungry on the same chip. Therefore, the learning training andthe chemotaxis analysis after training were conducted on the same chip. Results showedthat C. elegans could change its chemotaxis to low concentration of NaCl through leaning.Thus, the microfluidic chip provided a useful platform for investigating the chemotaxisand learning behaviors of C. elegans with reduced analysis time and enhanced analyticalefficiency.
Above experimental results showed that the novel, simple and efficient microfluidicmethod was able to generate controllable chemical concentration gradients, and it could beapplied to study different model organisms. Except forming concentration gradient, thischip can also form a temperature gradient, which provides a new way for the future studyof reaction of cells and multicellular organisms in different temperature. This new methodwould have potential applications in drug screening, biological examination andenvironmental testing.
引文
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