Single Molecule Sensing Beyond Fluorescence (Nanostructure Science and Technology)

Preface
Contents
Editors and Contributors
Part I Optical Sensing
1 Interferometric Biosensing
	1.1 Introduction
	1.2 Single Molecule Sensing
		1.2.1 Interferometric Scattering Microscopy (iSCAT)
		1.2.2 Dark-Field Heterodyne Biosensing
	1.3 Signal to Noise
		1.3.1 Signal Strength
		1.3.2 Noise Sources
		1.3.3 Shot Noise Limit to Signal-to-Noise
	1.4 Applications
	1.5 Conclusion and Outlook
	References
2 Optoplasmonic Whispering Gallery Mode Sensors for Single Molecule Characterization: A Practical Guide
	2.1 Introduction
	2.2 Background Information
	2.3 Why Optoplasmonic Sensing?
		2.3.1 Optoplasmonic Sensing Theory
	2.4 Sensing Single-Molecule Reactions and Interactions
		2.4.1 Sensing Ligand Surface Reactions
		2.4.2 DNA Sensing by Hybridization
		2.4.3 Sensing Enzyme Conformational Dynamics
	2.5 Fabrication of Optical Microcavities
	2.6 Plasmonic Gold Nanoparticles: Synthesis and Functionalization
		2.6.1 Single Phase Ligand Exchange
		2.6.2 Bi-Phasic Ligand Exchange
	2.7 Optoplasmonic Sensor Assembly: Combining Plasmonic Nanoparticles with Optical Micro Cavities
		2.7.1 Bottom-Up Approaches
		2.7.2 Top-Down Approaches
	2.8 Sensitivity, Signal-to-Noise and Detection Limits
	2.9 Time Resolution
		2.9.1 Cavity Ring-Up Spectroscopy
	2.10 Optoplasmonic Sensor Instrumentation
	2.11 Signal Acquisition and Analysis
	2.12 Outlook
	References
3 Nonlinear Optical Microcavities Towards Single-Molecule Sensing
	3.1 Introduction
	3.2 Nonlinear Optical Processes in Microcavities
		3.2.1 Raman and Brillouin Scattering
		3.2.2 Sum Frequency and Harmonic Generation
		3.2.3 Four-Wave Mixing (FWM) and Optical Frequency Combs
	3.3 Molecular Sensing Based on WGM Raman Spectroscopy
		3.3.1 Surface Enhanced Raman Spectroscopy
		3.3.2 Stimulated Raman and Stimulated Anti-Stokes Raman spectroscopy
		3.3.3 Stimulated Scattering Based Sensitivity Enhancement
	3.4 Surface Enhanced Harmonic and Sum Frequency Generation for Molecular Sensing
	3.5 High Precision Molecular Spectroscopy Based on Microcavity Frequency Combs
	3.6 Emerging Sensing Methods via Other Nonlinear Processes
	3.7 Conclusion and Outlook
	References
Part II Optomechanical Sensing
4 Optomechanical Sensing
	4.1 Introduction
	4.2 Cavity Optomechanics
		4.2.1 Optical Spring Effect
		4.2.2 Principles of Optical Spring Sensing
		4.2.3 Mechanical Frequency Shift Induced by Particle Binding
		4.2.4 Distinction from Conventional Mass Sensing
	4.3 Experiment Demonstration of Optomechanical Oscillation in Heavy Water
		4.3.1 Experiment Results and Discussions
	4.4 Single Nanoparticle and Biomolecule Detection
		4.4.1 Device Characterisation
		4.4.2 OMO Frequency Versus Laser-Cavity Detuning
		4.4.3 Silica Nanoparticles Detection
		4.4.4 Single Protein Molecules Sensing
	References
5 Quantum Optical Theories of Molecular Optomechanics
	5.1 Introduction
	5.2 Quantum Optics Model of Single Molecule SERS Using a System-Bath Master Equation Approach
		5.2.1 System Hamiltonian, Photonic Green Function and Interaction Hamiltonian for the Raman Induced Dipole
		5.2.2 Pump Field Enhancement Simplified Interaction Hamiltonian
		5.2.3 General Quantum Master Equation Using a Photonic Bath Approximation
		5.2.4 Analytical Expression for the SERS Spectrum
		5.2.5 Coupled Mode Quantum Optomechanical Model with Simple Lindblad Decay Processes
		5.2.6 Quasinormal Modes, Green Function Expansions, and Purcell Factors for Two Example Resonators
		5.2.7 Numerical Results for the Cavity-Emitted SERS Spectrum from Single Molecules
	5.3 Molecular Optomechanics in the Sideband-Resolved Strong Coupling Regime Using Hybrid Metal-Dielectric Cavity Modes
		5.3.1 Optomechanical System Hamiltonian and the Dressed States
		5.3.2 Quantum Master Equations for Exploring Molecular Optomechanics in the Sideband-Resolved Regime
		5.3.3 Plasmonic Quasinormal Modes with High Quality Factors and Large Optomechanical Coupling Rates
		5.3.4 Cavity Emitted Spectrum and Population Dynamics in the Sideband-Resolved Regime
	5.4 Resonant Raman Scattering in the Strong Coupling Regime of Cavity-QED
		5.4.1 Polaronic Picture and Connection Between Off-Resonant SERS and Resonant SERS
		5.4.2 Standard and Generalized Master Equations for Resonant SERS
		5.4.3 Numerical Results for Resonant SERS in the Strong Coupling Regime
	5.5 Conclusions and Outlook
	References
Part III Biomolecular Manipulation
6 Dielectrophoresis of Single Molecules
	6.1 Introduction
	6.2 Theory
		6.2.1 Conceptual Description
		6.2.2 Polarizability and Clausius-Mossotti Factor (CMF)
		6.2.3 Dielectrophoresis (DEP) Force Derivation
		6.2.4 DEP Trapping Volume
	6.3 DEP Design and Fabrication for Single Molecule Manipulation
	6.4 Dielectrophoretic Manipulation of Single Molecules
		6.4.1 Dielectrophoretic Manipulation of DNA and RNA
		6.4.2 Dielectrophoretic Manipulation of Protein
	6.5 Discussion
		6.5.1 Electrolysis
		6.5.2 RC Roll-Off
		6.5.3 Joule Heating
	6.6 Future Outlook
	References
7 Optical Trapping of Single Molecules
	7.1 Introduction
		7.1.1 Theory
		7.1.2 Single-Molecule Trapping
	7.2 Single-Molecule Trapping Techniques
		7.2.1 Plasmonic Nanostructure-Based Traps
		7.2.2 Self-Induced Back-Action Traps
		7.2.3 Waveguide-Based Traps
		7.2.4 Whispering Gallery Mode Based Traps
	7.3 Fabrication and Instrumentation
		7.3.1 Fabrication of Plasmonic and Resonant Nanostructures
		7.3.2 Instrumentation
	7.4 Outlook
	References
8 Applications of Trapping to Protein Analysis and Interactions
	8.1 Introduction
	8.2 Optical Tweezers and Proteins
		8.2.1 Stable Trapping Against Thermal Motion
		8.2.2 Elongation and Orientation
		8.2.3 SIBA
	8.3 Optical Tweezer Studies of Proteins with Tethering and/or Labelling
	8.4 Protein Analysis with Nanoapertures
		8.4.1 Protein Mass and Mixtures
		8.4.2 Conformational Changes
		8.4.3 Vibrational Resonances of Proteins
	8.5 Analysis of Protein Interactions at Single Molecule Level
		8.5.1 Protein–Small Molecule Interactions
		8.5.2 Protein–Protein Interactions
		8.5.3 Protein–DNA Interactions
	8.6 Challenges to Trapping with Nanostructures
		8.6.1 Surface Interactions
		8.6.2 Thermal Effects
	8.7 Technological Advances
		8.7.1 Trapping Characterization
		8.7.2 Aperture Fabrication
		8.7.3 Microfluidic Integration
		8.7.4 Fiber Based Methods
		8.7.5 Potential for Complementary Analysis
	8.8 Conclusions and Outlook
	References
9 Towards Single-Molecule Chiral Sensing and Separation
	9.1 Introduction
	9.2 Chromatographic and Related Methods
	9.3 Optical Foundations for Chiral Selection
	9.4 Harnessing Enantiospecific Magnetic Forces for Chiral Sorting
	9.5 Using Achiral Nanoparticles to Increase Chiro-Optical Signaling
	9.6 Chiral Sensing with Inherently Chiral Metasurfaces
	9.7 Cavity-Based Nanophotonic Platforms for Chiral Sensing and Sorting
	9.8 Conclusion
	References
Part IV Nanopores
10 Experimental Approaches to Solid-State Nanopores
	10.1 Introduction
	10.2 Transport Phenomena in Nanopores
		10.2.1 Analyte Capture
		10.2.2 Electrokinetic Flows in Nanopores
	10.3 Planning a Nanopore Experiment
		10.3.1 Chemical Conditions
		10.3.2 Electronics
		10.3.3 Membrane Properties
	10.4 Nanopore Characterization
		10.4.1 Size and Shape Characterization
		10.4.2 Surface Characterization
		10.4.3 Analyte Responsiveness/Sensitivity (Δanalyte)
		10.4.4 Pore Quality and Resilience
	10.5 Features Defining a Resistive Pulse
		10.5.1 Translocation Time (td)
		10.5.2 Current Drop (ΔIB)
		10.5.3 Multi-Level Events
		10.5.4 Event Analysis
		10.5.5 Analysis of ΔIB
		10.5.6 Volume Exclusion Models for ΔIB
		10.5.7 Other Models for ΔIB
		10.5.8 Analysis of td
		10.5.9 Other Models for td
		10.5.10 Machine Learning
	10.6 Noise in Solid-State Nanopores
		10.6.1 1/f Noise
		10.6.2 Effect of Solution pH
		10.6.3 Effect of Applied Voltage
		10.6.4 Effect of Electrolyte Concentration
		10.6.5 Effect of Pore Diameter
		10.6.6 Reducing Noise
	10.7 Improving Measurements
		10.7.1 Slowing Down td
		10.7.2 Increasing ΔIB
		10.7.3 Increasing Analyte Detection Sensitivity/Throughput
		10.7.4 Multiple Recapturing
		10.7.5 Electrode Maintenance
		10.7.6 Analyte Concentration
		10.7.7 Optimizing Lowpass Filter Settings
	10.8 Conclusions
	10.9 Acronym Glossary
	References
11 Challenges in Protein Sequencing Using 2-D MoS2 Nanopores
	11.1 Introduction
	11.2 Methods
		11.2.1 Modeling of MoS2 Nanopore Device and Molecular Dynamics
		11.2.2 Ionic Conductance of MoS2 Nanopores
		11.2.3 Ionic Current Measurements from Translocation Experiments
	11.3 Threading of Proteins Through MoS2 Nanopores (Challenge One)
	11.4 Slowing down Protein Translocation by Tuning Pore Dimensions (Challenge Two)
	11.5 Identifying Protein Sequence Motifs from Ionic Current Measurements (Challenge Three)
	11.6 Concluding Remarks
	References
12 Single-Molecule Ionic and Optical Sensing with Nanoapertures
	12.1 Introduction
	12.2 Principle of Ionic Current Sensing with Nanopores
	12.3 Application of Ionic Sensing in Nanopore Experiments
	12.4 Limitations and Challenges of Ionic Sensing
	12.5 Optical Sensing in Plasmonic Apertures
	12.6 Application of Optical Sensing in Nanopores
	12.7 Limitations and Challenges in Optical Sensing
	12.8 Simultaneous Ionic and Optical Sensing
	12.9 Summary and Outlook
	References
13 Self-induced Back-Action Actuated Nanopore Electrophoresis (SANE) Sensing
	13.1 Introduction
		13.1.1 The SIBA Effect
		13.1.2 Concurrent Optical and Electrical Data Capture with the SANE Sensor
	13.2 Sensor Chip Fabrication and Experimental Setup
		13.2.1 Sensor Chip Fabrication
		13.2.2 Optical Measurement Setup
		13.2.3 Flow Cell and Electrical Measurement Setup
	13.3 Experiments
		13.3.1 Nanoparticle Sensing with the SANE Sensor
		13.3.2 High-Affinity (Nanomolar) Interaction Sensing with the SANE Sensor
		13.3.3 Low-Affinity (Micromolar) Interaction Sensing with the SANE Sensor
	13.4 Conclusions
		13.4.1 Identification of Analytes and Complexes They Form in Simple Mixtures
		13.4.2 Enhancement of Protein-Ligand Bound Fractions
		13.4.3 Limitations in Sensor Throughput
	13.5 Acronym Glossary
	References
Index