In the recent issue of Nature·Communication, we, a team composed of Professor Lu Tao from the University of Victoria in Canada and Professor Lin Qiang from the University of Rochester, USA, and their PhD students, Yu Wenyan and Jiang Wei, reported a An optical sensor that detects a single biomolecule in a liquid environment.
Professor Lu Tao (second from right) takes a group photo.
Inspired by the whispering effect of the Temple of Heaven, we have combined the optical and mechanical properties of a glass sphere of the diameter of a single hair filament to create a super-sensitive single-molecule biosensor using the "photon spring effect". . What is the use of this little thing? It may revolutionize the state of cancer screening and make cancer screening a part of your daily routine.
Unconsciously, the biological detection on the taller gradually entered the daily life of thousands of households. Today, there are routine tests such as pregnancy tests and blood glucose meters that no longer rely on complex laboratory instruments and expertise, but become routine operations that the general public can do. You don't have to go to the hospital to check in, avoiding the need to wait in line to save time, save money in your purse, and better protect your privacy.
But for now, most of the inspections still need to go to the hospital. If you pay great attention to your health and have enough time and money, an annual physical check is a good choice. But is this really enough?
As a deadly disease that has not yet been fully overcome, cancer is also one of the main screening programs for medical examinations. Although current medical technology cannot find a way to completely eradicate cancer, the earlier the timing of cancerous cells is detected, the more likely the patient will survive. The difference in time of one year is likely to determine a person's life and death.
Some people who are afraid of trouble may only have a physical examination in two or three years or simply do not experience it. However, there is no obvious discomfort in the early stage of cancer. It is often too late to go to the hospital when it feels that the body is abnormal. So, isn't it better if we can develop a technique that simply measures cancer cells every day like blood glucose? We have developed a single-molecule biosensor using the "photon spring effect" that may solve this problem.
We have developed a glass sphere with a diameter of only about 100 microns, called the optical whispering wall microcavity.
What is our optical microcavity?
Just as sound waves can travel a long distance along the whispering wall of the Temple of Heaven, photons also travel along the equator at the surface of the microcavity. Interestingly, when the optical equivalent distance (optical path) of a light wave running along a glass ball is exactly an integer multiple of the photon wavelength, the light will resonate in the microcavity. At this time, even if only 10 milliwatts of laser light is used to input light into the microcavity, the cavity can produce a light field with a intensity of up to 5 megawatts per square meter - or as many as fifty in each second. The trillions of photons pass through the cross section of the microcavity.
Photon is an elementary particle that is a quantum of electromagnetic radiation. In quantum field theory, it is the force carrier responsible for transmitting electromagnetic force. The picture above shows photons emitted from the coherent beam of the laser. Image source: wikimedia
Another interesting phenomenon in which light travels in a microcavity is caused by light pressure.
As we all know, a high-speed car will have a huge impact when it hits the wall (warm reminder, drive safely, don't hit the wall, otherwise this may be the last time you feel the power). This force is due to the change in momentum of the car. When the sun shines on our windows, the reflection and absorption of the glass also changes the momentum of the photons to produce force. This force is usually expressed in terms of the density per unit area, called light pressure.
In daily life, the light pressure is too small, only a few microPascals (μPa), it is impossible to make even a slight deformation of your home glass window. However, in a microcavity, the situation can be quite different. Since the photon moves in a circular motion along the equator of the glass sphere, its momentum direction changes moment by moment. Therefore, it will produce a continuous push-out force on the ball.
Of course, the light pressure produced by a single photon is minimal, but when the light propagates resonantly within the microcavity, all of the fifty trillion photons can produce a light pressure of 60,000 Newtons per square meter.
What is the concept? It is said that Bruce Lee's kicking force reaches 200 pounds (890 Newtons). Assuming his foot is 100 square centimeters, the pressure on the person is only about 890,000 Newtons per square meter. The force generated by the light in the ball can be compared with the leg of Bruce Lee.
In fact, this force can easily push the glass ball outwards. At the same time, the path of the light traveling along the equator of the small ball is also getting longer and longer because of the expansion of the small ball, and the condition of resonance can no longer be satisfied. Therefore, the light pressure will gradually decrease as the ball expands until the ball is pushed. At this point, the strong elastic force of the ball begins to compress the expanded ball back until the light pressure is large enough to resume expansion due to the reduced optical path. In this way, the ball is like the spring's periodic expansion and contraction, so we call it the "photon spring."
Speaking of springs, you must remember the famous Hook theorem, that is, if an object of mass m is hung on a spring with a spring constant of k, then the vibration angular frequency of the spring is
As Liu Yang, the first female astronaut in China, mentioned in space lectures, even in the outer space with almost no gravity, by measuring the vibration frequency of the spring, we can know the quality of the object hanging on it. Similarly, a protein molecule sticking to a glass sphere can also increase the mass of the pellet, causing a change in the vibration frequency of the photon spring.
Protein molecules attached to the glass spheres increase the mass of the micro-cavity pellets, causing changes in the vibration frequency of the micro-cavity.
Twists and turns of experiment
In theory, we can also detect a single protein molecule by observing the change in the frequency of the photon spring. Only with respect to a 100 micron diameter pellet, the mass of a molecule that is only a few ten nanometers in length is too small, so that it only reduces the frequency of the photon spring by 0.01 Hz. Such small changes will be completely submerged in the background noise and cannot be detected. Although we had successfully observed the photon spring effect for the first time in a liquid environment as early as 2014 and published it in the Optical Express, we did not think it would be a sensitive detector at the time. The reason is that the quality of the glass microcavity is too large relative to a single molecule.
However, our preliminary experimental results are surprising. When a suspension containing glass particles having a diameter of about 100 nm was injected around the microcavity, we observed a change in the vibration frequency of several kilohertz. This is orders of magnitude larger than the quality-induced changes we estimate. The team carefully examined the experimental steps and found no flaws. After some scratching, Professor Lu of our team decided to shoot the work, because at the time, the results of the experiment were too unreliable. Fortunately, the team of Professor Lin Qiang of the University of Rochester did not give up. After half a year of exploration, Professor Lin Qiang and Dr. Jiang Wei finally realized that the frequency change of the resonance is caused by the change of the spring constant.
Of course, no experiment is done overnight. In order to achieve the best results, the experiment was basically carried out in the dead of night. Therefore, for Yu Wenyan of the Victoria team, it is almost a part of his daily life to finish the experiment at 4 or 5 in the morning. In order to make the experiment more efficient and try to avoid human error, Professor Lu personally used labview to write almost every instrument used in the software automatic control experiment, and then wrote a shell script to automatically extract the original data from the instrument. Save in a different document. Finally, using Matlab and script mixed data processing software to automatically process the data, find the jump point of the vibration frequency and automatically generate an experimental report.
Yu Wenyan needs to do experiments in the middle of the night because the interference is smaller.
Although all of this is highly automated, it still takes a lot of time and effort to complete. Finally, after spending nearly a year, after accumulating and processing about 20TB of data, the brilliant results are presented to us, and the repeatability of the experiment is also very high.
What can a micro-cavity do?
It can be said now that our research team has found that if a single molecule sticks to the surface of a small ball, it can make the photon go a little more, thus changing the resonance wavelength of the ball by about one hundred meters (100 memi = 10- 16 meters, 1 Ami is the smallest variable that can be detected by the laser interference gravitational wave observatory). This little change can change the spring constant of the photon spring, which in turn causes the spring frequency to change by as much as several hundred hertz. Such large frequency changes are enough to be easily captured by scientists. In fact, we have estimated that using this unique property of photon springs and integrating other existing technologies, we will be able to detect molecules much smaller than protein molecules, even when single atoms are detected.
In the future, this small device can be used to detect cancer cell biomarkers in blood or urine samples. Because its accuracy is capable of measuring single-molecule signals, it is theoretically possible to capture only one biomarker in a sample. This means that when the first few cells become cancerous, they can be found by timely inspection and gain a lot of valuable time for further examination and treatment. After the technology matures, its operation is as difficult as the blood glucose meter, and the low cost of the device can completely change the status of cancer screening. You don't have to wait for an annual medical checkup, you can test at home.
Finally, it should be emphasized that this technology is based entirely on the physical properties of the micro-cavity and "photon spring" and does not involve any chemical reactions. If the surface of the device is chemically treated to achieve functionalization, that is, only for a specific biomarker, it can be used to screen for various diseases without being confined to cancer. At that time, its application may be broader.
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