Science of Singles

Living at the age of energy and healthcare crises, ICeNd crafts technologies on 'the shoulders of the giants' who gifted us seminal fundamental science to make life on earth sustainable.

Why singles are important? 

Understanding the dynamics of individual molecules will allow us to solve lots of problems, such as discerning a protein’s real-time structural biophysics, drug discovery, clean-energy production, and unconventional computing. 

At ICeNd, we harness quantum mechanics and nanoengineering to convert seminal science of single systems into accessible technologies for everyone's use.

Stakeholders of nanotechnology need advanced tools for 'singles'.

Prof Jom Luiten and coworkers from the Eindhoven University of Technology  works on ultrafast electron microscopy and LINAC. 

Prof Luiten mentioned that combining ICeNd's novel nanotechnology and their sub-Poissonian detection at ultrfast timescale is a fundamental breakthrough which can be applied to study materials at extreme condition.

With Prof Luiten, ICeNd is working on single molecule dynamics at ultrafast timescale.

Prof Raimond Ravelli and coworkers from the Maastricht University have recently spent a lot of time creating this partial understanding of the SARS-CoV-2. 

Prof Ravelli mentioned to ICeNd that the understanding is still quite theoretical, 'We do not have any means to observe these complex biological activities in real-time. We need a solution to observe these at single-molecule level in liquid-phase'. 

Andy Felton, Vice President of Platform, Research & Applied from Thermo Fisher Scientific.

'What we need to capture in these surveillance efforts is how these viruses are changing and how quickly they are changing.'

With Prof Ravelli, ICeNd is pushing the boundary towards real-time structural biology.

Prof Sonia Contera from the Oxford University told 'We need solid-state nanodevices. These are really important since the soft-nanodevices bring a set of unavoidable noises.' 

Due to this, Prof Contera collaborates with ICeNd in a consortium called SemiNanoLife.

Prof Ramin Golestanian from the Max Planck Institute for Dynamics and Self Organisation told 'The field of active nanomachines is an unconventional field and made of diverse range of backgrounds. We need to work together to make these devices work.' 

We are working with Prof Golestanian to make theoretical sense of the nanomotions.

Prof Nicole Pamme from the Stockholm University finds ICeNd's R&D 'really cool, a lot of cutting edge stuff in there.' 

With Prof Pamme, we are developing scalable nanodevices for single molecules.

In the Inaugural Symposium of Centre for Multiscale Electron Microscopy, Prof Jan van Hest from the Eindhoven University of Technology mentioned said 'It is a dream to see how quickly nanoparticles move in solution and can we measure them.' and Prof Paula da Vonseca from Glasgow University highlighted, 'requirement of biological structural determination closer to native condition, district native functional state can be resolved from a single samples, time resolved molecular reaction, on the fly data analysis, and faster data requirement.

Prof Somnath Dutta from the Indian Institute of Science said, 'multi-component biology of anti-microbial resistance is really difficult problem, the high quality data of ICeNd is important in this aspect.' 

With Prof Dutta, we are developing decomposition of multi-component biological problems with single molecule nanofluidics.

Prof Ravelli and coworkers came up with their scientific prediction of viruses impact on our molecular health. It still needs experimental validation. ICeNd comes there.

Prof Contera, the author of the 'Nano Comes Life' discusses about the basics of nanotechnology for biology. ICeNd aims to make 'nano comes to life' a reality.

35 years of single-molecule detection have passed and three Nobel prizes for super-resolution microscopy [2014], cryo-electron microscopy [2017], and optical tweezers [2018] were awarded. 

At present, it is still not possible to study a single molecule for a prolonged duration that is free to move in a fluidic environment. 

ICeNd uniquely bridges this gap. Let us understand how.

Although we human could not engineer it yet, biological cells are able to interact with single molecules - process information and extract energy from their motions. 

To achieve engineering wonder, we require a smooth integration of nanofluidics, light-optics, electron-optics, quantum fluids, and non-dissipative coherent detection schemes. 

On the way to approach this, ICeNd's research has reached the stage where it coincides with emerging fields of single-molecule nanofluidics and quantum fluids. Together, we call them ‘quantum nanofluidics’ where quantum fluids interface nanometric fluidic environment with single molecules. 

At ICeNd, we bring a disruptive breakthrough beyond the state-of-the-art single molecule and nanoparticle measurements towards engineering a universal tool to transport them individually and interpret their dynamics without any loss of information at the limit of the uncertainty principle.

Let's revisit a bit of science to appreciate this proposition.

Single Quantum Systems

In 2001, Orly Alter and Yoshihisa Yamamoto published a book called 'Quantum Measurement of a Single Systems'. It has a beautiful cover page that will attract many young physicists.  

"In this book we establish the quantum theoretical  limits to the information that  can be obtained in the measurement of a single system. We show that information about the unknown quantum wavefunction of the system is  limited to estimates of the expectation values of the  measured  observables, where the estimate errors satisfy the uncertainty  principle. This is due to the reduction in the quantum state of the measured  system: In a series of measurements of a single system, each measurement changes the wavefunction of the measured system in accordance with the measurement result, and therefore the statistics of each measurement result depend on the results of all previous  measurements. Any quantum measurement that does not change the wavefunction of the measured  system at all  requires full a priori knowledge of this wavefunction. We show that this  impossi- bility of determining the quantum wavefunction of a  single  system and the quantum Zeno effect of a  single system are equivalent, and impose a  fundamental quantum limit to external force detection. In the monitoring of a single harmonic  oscillator, this  limit  requires an exchange of at least one quantum of energy  between the force and the oscillator."

Paths of Singles

Prof Richard Feynman developed a genius approach called 'path-integral formulation'.  In a BBC interview, Prof Brian Cox explained quantum mechanics by defining the path integral and how it generlises the action principle of classical mechanics.

At ICeNd, we use path-integral approach always to locate and predict single molecule motions.

Single-molecule motions in the nanofluidic domain are extremely difficult to characterise because of various complex physical and physicochemical interactions. 

ICeNd's cofounder, Dr Sid Ghosh presented a method for quasi-one-dimensional sub-diffraction-limited nanofluidic motions of fluorescent single molecules using the Feynman-Enderlein path integral approach. This theory was validated using the Monte Carlo simulation to provide fundamental understandings of single-molecule nanofluidic flow and diffusion in liquid. 

The distribution of single-molecule burst size can be precise enough to detect molecular interaction. The realisation of this theoretical study considers several fundamental aspects of single molecule nanofluidics, such as electrodynamics, photophysics, and multi-molecular events/molecular shot noise. 

Dr Ghosh studied realistic length scale for organic molecules, biomolecules, and nanoparticles where 1.127 nm and 11.27 nm hydrodynamic radii of molecules were driven by a wide range of flow velocities ranging from 0.01 µm/s to 10 µm/s. It is the first study to report distinctly different velocity-dependent nanofluidic regimes.

Single-molecule and multi-molecule events inside a nanofludic channel that is narrower than the diffraction limit. 

(a) Nanofluidic channels placed inside two confocal foci – green and purple colour represents orthogally polarised light from each other. The black dots represent single fluorophore molecules; in the detection volume photon, emission is represented with magenta circle. 

(b) Multi-molecule (MM) event with more than one single molecules or crawling/dragging single-molecules may result in photobleached/photo-inactive molecules – white dot. 

(c) FEPI-MC simulated two-foci SM events (i and ii) and MM events (iii and iv) of 1.127 nm molecules in 50 nm nanofluidic channel (ratio of these diameters is 0.022 at zero velocity, exemplary SM events are shown using the arrows. 

(d) Experimental two-foci single-molecule fluorescence intensities of Atto-488 in 50 nm nanochannel (molecule:nanochannel ≈ 0.024 approximately zero velocities) and 48bp DNAs flowing through a 30 nm nanochannel (molecule:nanochannel ≈ 0.36 at approximately zero velocities); details of grey regions are shown in the left panel.

Electrodynamic Precision for Singles

To date, we could not engineer Nature's ability to dynamically handle diffusing single molecules in the liquid-phase as it takes place in pore-forming proteins and tunnelling nanotubes. 

We can consistently resolve the dynamics of diffusing single molecules if they are confined within a uniform dielectric environment at nanometre length-scales. 

A uniform dielectric environment is the key characteristic since intrinsic electronic properties of molecules are modified while interacting with surfaces, and the effect is not the same from one dielectric surface to another. 

ICeNd's cofounder, Dr Sid Ghosh and coworkers showed dynamic nanofluidic detection of optically active single molecules in a liquid. They engineered an all-silica nanofluidic environment for electrokinetic handling of individual single-molecules where they also resolved the molecular shot noise. These study was done by recording the single-molecule motion of small fragments of DNA, carbon-nanodots, and organic fluorophores in water. The electrokinetic 1D molecular mass transport under two-focus fluorescence correlation spectroscopy (2fFCS) showed confinement-induced modified molecular interactions (due to various inter-molecular repulsive and attractive forces), which have been theoretically interpreted as molecular shot noise. This demonstration of high-throughput nanochannel fabrication, 2fFCS-based 1D confined detection of fast-moving single molecules and fundamental understanding of molecular shot noise opens an avenue for single-molecule experiments where physical manipulation of dynamics is necessary.

Superfluidity in Nanoconfinement

Self-driven nanofluidic flow at the liquid-air interface is a non-intuitive phenomenon. This flow behaviour was not driven by classical pressure difference or evaporation only. Depending on the position of the nanofluidic pore, we can observe flow and no-flow with chaotic behaviour. ICeNd is the first to observe nonlinear dynamics of a confined nanopore system at the liquid-air interface. The finite-range interactions between the interacting species are quantified with a corresponding critical velocity of the system. This is visualised using the finite element method and analysed mathematically with the Landau criterion. 

We found formation of Bose-Einstein-like condensates due to the transport through nanofluidic pores. 

We show that systems with more than one nanofluidic pore with a sub-100 nm diameter create a highly nonlinear and complex. We also found oscillating condensate within the system in the liquid phase. We came across a transition of classical fluid mechanics with the outlook of quantum fluid mechanics, which leaves several open questions for further investigation in the field of quantum nanofluidics.

Singles with electrons, photons and phonons

Electrons, photons, and phonons are widely studied quantum particles. They are also used widely to study singles but rarely used together. 

Single photon emission with defect engineering

Quantifying and characterising atomic defects in nanocrystals is difficult and low-throughput using the existing methods such as high resolution transmission electron microscopy (HRTEM). In this article, using a defocused wide-field optical imaging technique, we demonstrate that a single ultrahigh-piezoelectric ZnO nanorod contains a single defect site. We model the observed dipole-emission patterns from optical imaging with a multi-dimensional dipole and find that the experimentally observed dipole pattern and model-calculated patterns are in excellent agreement. This agreement suggests the presence of vertically oriented degenerate-transition-dipoles in vertically aligned ZnO nanorods. The HRTEM of the ZnO nanorod shows the presence of a stacking fault, which generates a localised quantum well induced degenerate-transition-dipole. Finally, we elucidate that defocused wide-field imaging can be widely used to characterise defects in nanomaterials to answer many difficult questions concerning the performance of low-dimensional devices, such as in energy harvesting, advanced metal-oxide-semiconductor storage, and nanoelectromechanical and nanophotonic devices.

We found single photon emitting quantum well from electromechanical response at atoms

Vertically aligned ZnO nanorods with stacking defects. 

(a) Tilted scanning electron microscopic image of vertically aligned ZnO nanorods with 200 nm scale bar. (b) Focused wide-field photoluminescence intensity image. 

(c) High Resolution Transmission Electron Microscopic (HRTEM) image of nanorod showing high crystallinity and growth direction along the c-axis. The stacking fault region is highlighted with a green rectangle. This region is magnified in d (along with a defect free region) and f for defect analysis. The scale bar represents 5 nm. 

(d) The electron intensity plot comparing a wurtzite region and a stacking fault initiating region. The magnified HRTEM is angle-corrected (φ) for +1.4°. The black line profiles the ababa… stacking of ZnO. The intensity peaks of the atomic positions of ababa… stacking correspond to the simulated atomic arrangements. The light-yellow red bordered line profiles the initiation of the stacking fault. The plot shows distinct disordered periodicity from 1.86 to 2.65 nm (δ = 0.79 nm). The grey arrow indicates this region in the intensity plot. At this region, perfect overlapping of two plots is missing. The black plot maintains the periodicity of ababa. crystallinity. 

(e) Presence of the stacking fault which has created a localised quantum well at the wurtzite/zinc-blend/ wurtzite interface with an energy difference of ΔE from the energy of wurtzite (E_{wz}) to the energy of zinc blend (E_{zb}) and resulted in an excitation energy of Eex. 24 The transition energy of this kind of QW is dependent on the thickness of the stacking fault region, explained using di as the effective electronic thickness or the thickness of the BSF. Here d2 > d1, which shifts the transition energy from NBE to DLE. 

(f) Line profile of the BSF region with the corresponding HRTEM in the background. Here, the stacking fault continued for 5.5 nm (with a lattice parameter of more than 5.22 Å as shown with white arrows), which is considered as the effective electronic thickness d2.

Quantum statistics of electron-phonon interaction

Inorganic carbon nanomaterials, also called carbon nanodots, exhibit a strong photoluminescence with unusual properties and, thus, have been the focus of intense research. Nonetheless, the origin of their photoluminescence is still unclear and the subject of scientific debates. Here, we present a single particle comprehensive study of carbon nanodot photoluminescence, which combines emission and lifetime spectroscopy, defocused emission dipole imaging, azimuthally polarized excitation dipole scanning, nanocavity-based quantum yield measurements, high resolution transmission electron microscopy, and atomic force microscopy. We find that photoluminescent carbon nanodots behave as electric dipoles, both in absorption and emission, and that their emission originates from the recombination of photogenerated charges on defect centers involving a strong coupling between the electronic transition and collective vibrations of the lattice structure.

We played with quantum statistics of electron-phonon by imaging single-photon emissions and their single step bleaching.

Recent application science

At ICeNd, our vision stands to unify everything

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Please reach out to us with challenging problems.