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Cilia Are Minuscule Wonders, and Scientists Are Finally Figuring Out How to Mimic Them

2022-07-15
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One tiny flick of a microscopic cellular hair, known as a cilium, can’t do much on its own. But together, these structures routinely pull off biological marvels within the body. Cilia remove inhaled pathogens from the respiratory tract, carry cerebrospinal fluid across brain cavities, transport eggs from the ovary to the uterus, and drain mucus from the middle ear to the nasal cavity. These tiny, extracellular organelles exert precise microfluidic control over life-sustaining liquids in the body. To better understand how these crucial wonders of nature work, scientists have been trying for years to mimic them.

Now researchers have come close to doing so, creating a chip covered with artificial cilia that can precisely control the minuscule flow patterns of fluids. The developers hope this technology will become the basis of new portable diagnostic devices. Currently, many diagnostic lab tests are time-consuming, resource-intensive and demand close human support. A cilia-covered chip, the researchers say, could enable field testing that would be easier, cheaper and more efficient than lab-based tests—as well as using much smaller samples of blood, urine or other testing material.

Humans have achieved spectacular large-scale engineering feats, but “we are still kind of stuck when it comes to engineering miniaturized machines,” says Itai Cohen, a Cornell University physicist and senior author of a new Nature study describing his team’s cilia chip. Researchers had previously tried to make artificial cilia that worked by means of pressure, light, electricity and even magnets. But a major hurdle remained: designing extremely tiny actuators—the motion-triggering parts of a machine—that can be controlled individually or in small clusters rather than all at once.

The Cornell researchers vaulted that hurdle by taking inspiration from some things they learned in their earlier work. In August 2020 Guinness World Records recognized Cohen and his team for designing the world’s smallest walking robot, a machine that was just a fraction of a millimeter wide and could walk on four bendable legs. Much like those legs, the new artificial cilia are made of bendable, nanometer-thin film that can respond to electrical control. Each cilium is one-twentieth of a millimeter long (less than half the length of a dust mite) and 10 nanometers thick—slimmer than the smallest cell organelle—with a strip of platinum on one side and a coating of titanium film on the other.

The key to electrically controlling these artificial cilia comes from their metal makeup. Running a low positive voltage through a cilium triggers a chemical reaction: as a droplet of test fluid flows past, the electrified platinum breaks apart the water molecules within the droplet. This frees up oxygen atoms, which are absorbed into the platinum’s surface. The added oxygen stretches the strip, making it bend in one direction. Once the voltage is reversed, the oxygen is driven out of the platinum—and the cilium returns to its original shape. “So by oscillating the voltage back and forth, you can bend and unbend the strip, which will generate waves to drive the movement,” Cohen says. Meanwhile the electrically inert titanium film stabilizes the structure.

Next, the researchers had to figure out how to pattern a surface with thousands of their artificial cilia. By simply bending and unbending one after the other, these fine strips can drive a microscopic amount of fluid in a set direction. But to direct a droplet to flow in a more complex pattern, the researchers had to divide their chip’s surface into “ciliary units” of a few dozen cilia each—with each unit individually controllable. The Cornell team first planned a control system virtually, collaborating with University of Cambridge researchers to digitally simulate in three dimensions how a droplet would move over a cilia-covered chip.

Once the researchers had used these computer simulations to check out the theoretical aspects of what they were doing, they went on to produce a physical device. Their centimeter-wide chip is carpeted with about a thousand tiny platinum-titanium strips, divided into 16 ciliary units of 64 cilia each. Because each unit is independently connected to a computer control system, individual units can be separately programmed and then coordinated to move the test fluid in any given direction. Working together, the 16 units could thus create near-endless combinations of flow patterns.

The team’s first device can drive droplets in specific patterns, but it is not as efficient as the researchers would like. They are now already planning next-generation chips with cilia that have more than one “hinge.” This will give them more bending ability, “which can allow you to have much more efficient flow of the fluid,” Cohen says.

The study “elegantly enlightened us about how independent, addressable control of artificial cilia arrays could be realized via electronic signals to generate complex programmable microfluidic operations,” says Zuankai Wang, a microfluidics researcher at the City University of Hong Kong, who was not involved in the new study. “Hopefully, the mass production of untethered low-cost diagnostic devices could be within reach in the years to come.”

Because the new technology imitates biological structures, it makes sense to use it in medical applications. The researchers envision a cilia-covered chip as the basis of a diagnostic device that could test any sample of water, blood or urine to find contaminants or markers of disease. A user would place a drop of blood or urine on the chip, and the artificial cilia would carry the sample—along with any chemicals or pathogens within it—from one spot to another, allowing it to mix and react with various testing agents as it moves. Biosensors built into the chip would measure the products of these chemical reactions and then direct the cilia to further manipulate the liquid’s flow, allowing the chip to perform additional tests to confirm the results. “This way, you can do all of the chemistry experiments, in a centimeter-size chip, that would normally happen in a chemistry lab,” Cohen explains. “The chip could also be made to function on its own, as it can use little solar panels fitted on the chip itself.” Such a self-powered device would be ideal for use in the field.

“It’s superb how they have combined microelectronics with fluid mechanics,” says Manoj Chaudhury, a materials scientist at Lehigh University, who was not involved in the new study. The researchers have solved an essential problem, but bringing the resulting product to fruition will require further work, Chaudhury says. “When they design a reactor system to analyze a drop of blood, there have to be local stations where they may even have to heat or cool the sample,” he says. “So it would be interesting to see how they may integrate all these aspects in a micro reactor.”

参考译文
纤毛是微小的奇迹,科学家们终于找到了模仿它们的方法
一根微小的微细胞毛,被称为纤毛,不能自己做太多事情。但这些结构结合在一起,通常会在体内创造出生物奇迹。纤毛从呼吸道清除吸入的病原体,携带脑脊液穿过脑腔,将卵子从卵巢运输到子宫,并将黏液从中耳引流到鼻腔。这些微小的细胞外细胞器对体内维持生命的液体施加精确的微流体控制。为了更好地理解这些重要的自然奇迹是如何运作的,科学家们多年来一直试图模仿它们。现在,研究人员已经接近于做到这一点,他们创造了一种覆盖着人工纤毛的芯片,可以精确控制流体的微小流动模式。开发人员希望这项技术将成为新型便携式诊断设备的基础。目前,许多诊断实验室测试耗时、资源密集,并需要密切的人力支持。研究人员说,一种覆盖纤毛的芯片可以使现场测试比实验室测试更容易、更便宜、更有效,而且使用更小的血液、尿液或其他测试材料样本。人类已经取得了壮观的大规模工程壮举,但“在工程小型化机器方面,我们仍然有点停滞不前,”康奈尔大学物理学家伊泰·科恩(Itai Cohen)说,他是《自然》杂志一项新研究的资深作者,描述了他的团队的纤毛芯片。研究人员此前曾试图制造通过压力、光、电甚至磁铁工作的人工纤毛。但是一个主要的障碍仍然存在:设计极其微小的驱动器——机器的运动触发部件——可以单独或小范围控制,而不是一次性控制所有驱动器。康奈尔大学的研究人员从他们早期工作中学到的一些东西中获得了灵感,从而跨越了这一障碍。2020年8月,吉尼斯世界纪录承认科恩和他的团队设计了世界上最小的步行机器人,这台机器只有一毫米宽,可以用四条可弯曲的腿行走。和这些腿很像,新的人造纤毛是由可弯曲的纳米薄膜制成的,可以对电气控制做出反应。每根纤毛只有二十分之一毫米长(不到尘螨长度的一半),10纳米厚——比最小的细胞器还要细——一面有一条白金条,另一面有一层钛膜。电控这些人造纤毛的关键在于它们的金属结构。在纤毛上运行低正电压会引发化学反应:当测试液液滴流过时,带电的铂会将液滴内的水分子分解。这会释放氧原子,氧原子被铂的表面吸收。添加的氧气会拉伸金属带,使其向一个方向弯曲。一旦电压逆转,氧气就会被逐出铂,纤毛就会恢复到原来的形状。科恩说:“因此,通过来回振荡电压,你可以弯曲或伸直金属带,这将产生波来驱动运动。”同时,电惰性钛膜稳定了结构。接下来,研究人员必须弄清楚如何用数千根人工纤毛来设计一个表面。通过简单地一个接一个地弯曲和不弯曲,这些细条可以驱动微小数量的流体朝设定的方向流动。但为了引导液滴以更复杂的模式流动,研究人员必须将芯片表面分成几十个纤毛组成的“纤毛单元”,每个单元都是独立可控的。康奈尔大学的研究团队首先计划了一个虚拟控制系统,与剑桥大学的研究人员合作,在三维数字模拟液滴如何在覆盖着纤毛的芯片上移动。 一旦研究人员使用这些计算机模拟来检验他们正在做的事情的理论方面,他们继续生产一个物理设备。它们厘米宽的芯片上覆盖着大约1000条细小的铂钛条,分成16个纤毛单元,每个纤毛有64根。由于每个单元都独立地连接到计算机控制系统,因此每个单元都可以单独编程,然后进行协调,使测试流体向任何给定的方向移动。这16个单元一起工作,可以创造出几乎无穷无尽的流动模式组合。该团队的第一个设备可以驱动特定模式的液滴,但它的效率不如研究人员希望的那样。他们现在已经在计划下一代具有不止一个“铰链”纤毛的芯片。这将赋予它们更强的弯曲能力,“这可以让流体更有效地流动,”科恩说。这项研究“优雅地启发了我们,如何通过电子信号来产生复杂的可编程微流控操作来实现对人工纤毛阵列的独立、可处理的控制,”香港城市大学的微流控研究员王祖凯(音译)说,他没有参与这项新研究。“希望在未来几年内,可以实现无栓低成本诊断设备的大规模生产。”由于这项新技术模仿了生物结构,因此将其用于医疗应用是有意义的。研究人员设想,一种覆盖有纤毛的芯片作为诊断设备的基础,可以测试任何水、血液或尿液样本,以发现污染物或疾病的标志。用户只需在芯片上滴一滴血或尿,人工纤毛就会携带样本——连同其中的任何化学物质或病原体——从一个点到另一个点,使其在移动过程中与各种测试剂混合并发生反应。芯片内置的生物传感器将测量这些化学反应的产物,然后引导纤毛进一步操纵液体的流动,允许芯片进行额外的测试来确认结果。科恩解释说:“通过这种方式,你可以在一个厘米大小的芯片中完成所有化学实验,而这通常会在化学实验室中发生。”“这种芯片还可以自行工作,因为它可以使用安装在芯片上的小型太阳能电池板。”这种自供电设备将是在现场使用的理想设备。“他们把微电子学和流体力学结合起来的方式太棒了,”利哈伊大学(Lehigh University)的材料科学家Manoj Chaudhury说,他没有参与这项新研究。乔杜里说,研究人员已经解决了一个基本问题,但要让最终的产品结出果实还需要进一步的工作。他说:“当他们设计一个分析一滴血的反应堆系统时,必须有当地的工作站,他们甚至可能需要加热或冷却样本。”“所以,看看他们如何将所有这些方面集成到一个微型反应堆中,将是一件有趣的事情。”
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