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Nanomechanical resonators and their applications in biological/chemical detection: Nanomechanics principles

Abstract Recent advances in nanotechnology have led to the development of nano-electro-mechanical systems (NEMS) such as nanomechanical resonators, which have recently received significant attention from the scientific community. This is not only due to their capability of label-free detection of bio/chemical molecules at single-molecule (or atomic) resolution for future applications such as the early diagnosis of diseases like cancer, but also due to their unprecedented ability to detect physical quantities such as molecular weight, elastic stiffness, surface stress, and surface elastic stiffness for adsorbed molecules on the surface. Most experimental works on resonator-based molecular detection have been based on the principle that molecular adsorption onto a resonator surface increases the effective mass, and consequently decreases the resonant frequencies of the nanomechanical resonator. However, this principle is insufficient to provide fundamental insights into resonator-based molecular detection at the nanoscale; this is due to recently proposed novel nanoscale detection principles including various effects such as surface effects, nonlinear oscillations, coupled resonance, and stiffness effects. Furthermore, these effects have only recently been incorporated into existing physical models for resonators, and therefore the universal physical principles governing nanoresonator-based detection have not been completely described. Therefore, our objective in this review is to overview the current attempts to understand the underlying mechanisms in nanoresonator-based detection using physical models coupled to computational simulations and/or experiments. Specifically, we will focus on issues of special relevance to the dynamic behavior of nanoresonators and their applications in biological/chemical detection: the resonance behavior of micro/nanoresonators; resonator-based chemical/biological detection; physical models of various nanoresonators such as nanowires, carbon nanotubes, and graphene. We pay particular attention to experimental and computational approaches that have been useful in elucidating the mechanisms underlying the dynamic behavior of resonators across multiple and disparate spatial/length scales, and the resulting insight into resonator-based detection that has been obtained. We additionally provide extensive discussion regarding potentially fruitful future research directions coupling experiments and simulations in order to develop a fundamental understanding of the basic physical principles that govern NEMS and NEMS-based sensing and detection applications.

Dominant surface stress driven by biomolecular interactions in the dynamical response of nanomechanical microcantilevers

Nanomechanical microcantilevers have played a vital role in detecting biomolecular interactions. The ability of microcantilevers to detect biomolecular interactions is ascribed to the principle that the surface stress, caused by biomolecular interactions, dominates the dynamical response of the microcantilever. Here we have experimentally studied the correlation between biomolecular interactions and the dynamical response of microcantilevers. Moreover, the authors employed a mechanical beam model to calculate the surface stress, representing the biomolecular interactions, through measuring the resonant frequency shift. The quantitative analysis of surface stress, driven by the specific protein-protein interactions, demonstrated that microcantilevers enable the quantitative study of biomolecular interactions.

Mechanical Properties of Silicon Nanowires

Nanowires have been taken much attention as a nanoscale building block, which can perform the excellent mechanical function as an electromechanical device. Here, we have performed atomic force microscope (AFM)-based nanoindentation experiments of silicon nanowires in order to investigate the mechanical properties of silicon nanowires. It is shown that stiffness of nanowires is well described by Hertz theory and that elastic modulus of silicon nanowires with various diameters from ~100 to ~600 nm is close to that of bulk silicon. This implies that the elastic modulus of silicon nanowires is independent of their diameters if the diameter is larger than 100 nm. This supports that finite size effect (due to surface effect) does not play a role on elastic behavior of silicon nanowires with diameter of >100 nm.

In situ real-time monitoring of biomolecular interactions based on resonating microcantilevers immersed in a viscous fluid

The authors report the precise (noise-free) in situ real-time monitoring of a specific protein antigen-antibody interaction by using a resonating microcantilever immersed in a viscous fluid. In this work, they utilized a resonating piezoelectric thick film microcantilever, which exhibits the high quality factor (e.g., Q=15) in a viscous liquid at a viscosity comparable to that of human blood serum. This implies a great potential of the resonating microcantilever to in situ biosensor applications. It is shown that the microcantilever enables them to monitor the C reactive protein antigen-antibody interactions in real time, providing an insight into the protein binding kinetics.

Nanomechanical mass detection using nonlinear oscillations

Nanomechanical resonators have allowed the in vitro molecular recognition. Most of detection is implemented in harmonic oscillation regime, albeit nanomechanical resonators can easily reach the nonlinear oscillation regime. In this letter, we have studied the nanomechanical mass detection using nonlinear oscillators based on continuum elastic model. It is shown that nonlinear oscillation leads to the unique resonant frequency shift due to mass adsorption, quite different from that in harmonic oscillation. Moreover, the effect of mechanical tension on the mass detection in nonlinear oscillation is also discussed. This study highlights the nonlinear oscillation for label-free detection.

In Situ Detection of Live Cancer Cells by Using Bioprobes Based on Au Nanoparticles

We fabricate the high-performance probes based on Au nanoparticles (AuNP) for detection of live cancer cell. AuNP were synthesized with narrow sized distribution (ca. 10 nm) by Au salt reduction method and deposited onto the aminated substrate as a cross-linker and hot spot. Herein, AuNP has enabled the easy and efficient immobilization of the antibody (Cetuximab), which can selectively interact with epidermal growth factor receptor (EGFR) on the surface of epidermal cancer, as detecting moiety onto the AuNP-deposited substrate without nanolithography process. After conjugation of Cetuximab with AuNP-deposited substrate, Cetuximab-conjugated probe as a live cancer cell detector (LCCD) could detect EGFR-highexpressed A431 cells related to epithelial cancer with 54-times larger specificity and sensitivity in comparison with EGFR-deficient MCF7 cells. This implies that AuNP-based probes demonstrate abundant potentials for detection and separation of small biomolecules, cells and other chemicals.

Role of Sequence and Structural Polymorphism on the Mechanical Properties of Amyloid Fibrils

Amyloid fibrils playing a critical role in disease expression, have recently been found to exhibit the excellent mechanical properties such as elastic modulus in the order of 10 GPa, which is comparable to that of other mechanical proteins such as microtubule, actin filament, and spider silk. These remarkable mechanical properties of amyloid fibrils are correlated with their functional role in disease expression. This suggests the importance in understanding how these excellent mechanical properties are originated through self-assembly process that may depend on the amino acid sequence. However, the sequence-structure-property relationship of amyloid fibrils has not been fully understood yet. In this work, we characterize the mechanical properties of human islet amyloid polypeptide (hIAPP) fibrils with respect to their molecular structures as well as their amino acid sequence by using all-atom explicit water molecular dynamics (MD) simulation. The simulation result suggests that the remarkable bending rigidity of amyloid fibrils can be achieved through a specific self-aggregation pattern such as antiparallel stacking of β strands (peptide chain). Moreover, we have shown that a single point mutation of hIAPP chain constituting a hIAPP fibril significantly affects the thermodynamic stability of hIAPP fibril formed by parallel stacking of peptide chain, and that a single point mutation results in a significant change in the bending rigidity of hIAPP fibrils formed by antiparallel stacking of β strands. This clearly elucidates the role of amino acid sequence on not only the equilibrium conformations of amyloid fibrils but also their mechanical properties. Our study sheds light on sequence-structure-property relationships of amyloid fibrils, which suggests that the mechanical properties of amyloid fibrils are encoded in their sequence-dependent molecular architecture.

Micromechanical observation of the kinetics of biomolecular interactions

Resonant microcantilevers have recently enabled the label-free detection of biomolecules. Here, we observed the kinetics of biomolecular interactions such as antigen-antibody interactions and/or DNA hybridization based on a resonant frequency shift, obeying Langmuir kinetics, measured in a buffer solution. It is shown that the kinetics of DNA adsorptions on the surface is governed by intermolecular interactions between adsorbed DNA molecules. It is also shown that the kinetics of DNA hybridization is determined by the intermolecular interaction. It is implied that resonant microcantilever in buffer solution may allow for gaining insights into the kinetics of various molecular interactions.

Mapping the surface charge distribution of amyloid fibril

It is of high importance to measure and map the surface charge distribution of amyloids, since electrostatic interaction between amyloidogenic proteins and biomolecules plays a vital role in amyloidogenesis. In this work, we have measured and mapped the surface charge distributions of amyloids (i.e., β-lactoglobulin fibril) using Kelvin probe force microscopy. It is shown that the surface charge distribution is highly dependent on the conformation of amyloids (e.g., the helical pitch of amyloid fibrils) as well as the pH of a solvent.

Nonlinear vibration behavior of graphene resonators and their applications in sensitive mass detection.

Graphene has received significant attention due to its excellent mechanical properties, which has resulted in the emergence of graphene-based nano-electro-mechanical system such as nanoresonators. The nonlinear vibration of a graphene resonator and its application to mass sensing (based on nonlinear oscillation) have been poorly studied, although a graphene resonator is able to easily reach the nonlinear vibration. In this work, we have studied the nonlinear vibration of a graphene resonator driven by a geometric nonlinear effect due to an edge-clamped boundary condition using a continuum elastic model such as a plate model. We have shown that an in-plane tension can play a role in modulating the nonlinearity of a resonance for a graphene. It has been found that the detection sensitivity of a graphene resonator can be improved by using nonlinear vibration induced by an actuation force-driven geometric nonlinear effect. It is also shown that an in-plane tension can control the detection sensitivity of a graphene resonator that operates both harmonic and nonlinear oscillation regimes. Our study suggests the design principles of a graphene resonator as a mass sensor for developing a novel detection scheme using graphene-based nonlinear oscillators.