The Beihang University team develops an ultra-resolution photonic force microsco

Recently, a team from Beihang University has developed an ultra-resolution photonic force microscope.

For the first time, they achieved sub-femtocow sensitivity in mechanical sensing near the nano-thermodynamic limit in an aqueous solution, detecting the smallest electric field force at 108.2aN, with a sensitivity of 1.8fN/√Hz.

According to the introduction, to develop this microscope, researchers combined ion resonance nano-probes, optical three-dimensional ultra-resolution positioning methods, and machine learning technologies.

Through this, they solved the problem of weak force measurement sensitivity in aqueous solutions, greatly improving the resolution of weak force measurement in aqueous solutions.

Speaking of the application prospects, the team gave an example.It indicates that for complementary DNA strands, they will pair up in an aqueous solution.

Traditional theory holds that base pairs only produce an interactive force at a very close distance, or only when they actually come into contact, which pulls them together.

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It is very interesting that the aforementioned pairing efficiency is extremely high, and does not seem to be completed by single-stranded DNA randomly colliding and then pairing up.

Therefore, some researchers predict that there may be long-range forces between complementary base pairs. However, due to the extremely weak nature of this force, it cannot be observed using conventional methods.

This achievement provides an effective tool for measuring the extremely weak interactions between DNA molecules.By this means, the optical tweezers probe and the surface under test can be bound with different biomolecules, thereby enabling the detection of interaction forces.

This not only allows for the study of the interaction forces between DNAs but also the interactions of molecules such as CRISPR proteins.

In other words, this achievement provides an effective tool for studying the long-range interactions of biomolecules in physiological environments.

Why is the detection of extremely weak forces in aqueous solutions important?

It is reported that the detection of extremely weak forces in aqueous solutions is crucial for exploring the operation of biomolecules.However, due to the limitations of measurement techniques, the highest sensitivity currently achievable in aqueous solutions for force measurement is around 10fN/√Hz, which means that to achieve a resolution below 1fN, it would take approximately 100 seconds.

Previously, the smallest weak force detected in aqueous solutions was about 2.4fN. However, to measure the intermolecular forces of individual molecules in aqueous solutions, as well as the long-range dynamic forces between molecules, it is necessary to rapidly achieve sub-femtometer Newton level force measurements.

In fact, before this work, they discovered and proposed the principle of resonant optical force enhancement of rare earth ions.

Their discovery showed that compared to the optical force of traditional nano-probes, when using lanthanide-doped nanoparticles (Ln-NPs) as optical force probes, the detection capability is improved by about 30 times.

Based on this, they began to use stronger probes to develop methods for measuring weak forces.In the study, theoretical exploration and experimental research were carried out concurrently. On one hand, this was to determine the minimum force that could be measured. On the other hand, it aimed to theoretically establish the limits of measurement sensitivity and to clarify the parameters required to achieve the sensitivity limit.

Subsequently, they theoretically discovered that the current method could achieve the highest force measurement sensitivity in aqueous solutions at this stage.

However, the challenge lies in the fact that, in aqueous solutions, optical tweezers must capture the high-speed three-dimensional super-resolution positioning of particles.

Therefore, they introduced super-resolution imaging and machine learning into nano-fluorescence optical tweezers, developing a super-resolution optical tweezers that achieved the smallest weak force measurement in aqueous solutions.Achieving a Breakthrough in Force Measurement Precision at the Level of Flying Cattle

Furthermore, the team discovered through theoretical analysis that: by utilizing lower potential well stiffness, higher positioning accuracy, and a large amount of positioning data, the force measurement precision can be improved.

The probability distribution center of the fluorescent center of mass can be used to determine the positioning in the radial plane.

At the same time, they also introduced the column lens positioning method from super-resolution imaging, thereby obtaining more axial information.

This allows for the precise positioning in the z-direction to be achieved through neural network training, thereby completing the final step of three-dimensional force measurement.Using this high-precision positioning method, the research group carried out the detection of weak electric field forces of upconversion nanoparticles in an electric field.

In the experiment, under the action of parallel plate electrostatic fields of 0.1V and 0.2V, they measured the average electric field force experienced by nanoparticles with a surface potential of 35mV: 591aN and 1182aN, respectively.

At the same time, the minimum electric field force they detected was 108.2aN. This also means that by using the photon force microscope, the team achieved a breakthrough in the measurement accuracy of the order of flying cows in the aqueous solution for the first time.

Figure | Schematic diagram of measuring the electric field force of a captured single nanoparticle in a uniform electric field (source: Nature Photonics)

On this basis, they further explored the interaction force between a single nanoparticle and a gold film.This discovery reveals that when optical tweezers manipulate nanoparticles to approach a gold film, they experience a resisting force in the opposite direction.

As the nanoparticles get closer, this tiny pushing force also intensifies. The research group speculates that the reason is due to laser scattering.

Furthermore, after the gold film is modified with DNA, the average reverse pushing force experienced by the nanoparticles will decrease from 80 femtonewtons to about 40 femtonewtons.

Experiments also show that in an aqueous solution, there are long-range interactions between nanoparticles and DNA molecules.

In the submission, based on the reviewers' suggestions, they more rigorously measured this method and presented more precise result measurements and comparative results in the paper.In addition, they also introduced some preliminary applications of weak force measurement, measuring the long-range interaction forces between a single nanoparticle and a gold surface, as well as the metal surface with bound DNA.

When the researchers saw that the surfaces with DNA and without DNA would produce different forces, everyone was very excited.

Thus, this not only represents that the surface potential has a considerable long-range effect on a single nanoparticle, but also indicates that it is feasible to measure the interaction forces between DNA chains.

Ultimately, the related paper was published in Nature Photonics with the title "Sub-femtonewton force sensing in solution by super-resolved photonic force microscopy" [1].

Assistant Professor Shan Xuchen from Beihang University, Dr. Ding Lei from RMIT University in Australia, and doctoral student Wang Dajing from Beihang University are co-first authors, Professor Wang Fan, Professor Zhong Xiaolan, and Professor Chang Lingqian from Beihang University serve as co-corresponding authors.In addition to studying the interactions between DNA molecules, it is also possible to investigate the interactions between DNA and molecules such as CRISPR proteins, which will be the direction of the research group's subsequent efforts.

Moreover, by utilizing super-resolution localization and the sensing capabilities of particles, super-resolution sensing imaging can be achieved.

"This is also one of the projects we are working on, and it is particularly interesting, capable of doing things that existing technologies cannot do," said the researchers.

It is also reported that Wang Fan graduated from Beihang University with a bachelor's degree, and then obtained a master's degree and a doctorate at the University of New South Wales in Australia. He also engaged in postdoctoral research at the Australian National University, Macquarie University, and the University of Technology Sydney.

In 2020, he obtained a lecturer position at the University of Technology Sydney and began to establish his own research group independently. In 2022, he returned to his alma mater, Beihang University, as an overseas outstanding young scholar, and has now established a nanophotonics team.At present, the team is recruiting postdoctoral, doctoral, and master's candidates with a background in photonics. Interested parties can send an email to fanwang@buaa.edu.cn.