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Liquid Phase Transmission Electron Microscopy

Liquid phase transmission electron microscopy (LP-TEM) is a technique for imaging hydrated nanoscale samples in their native environment with transmission electron microscopy (top).  The technique utilizes a unique microfluidic sample holder that contains a thin (100 nm - 1 micron) liquid layer between two microfabricated chips (bottom). An etched area in the center of each window is spanned by a thin solid membrane to create an electron transparent imaging window. The strength of LP-TEM is its ability to unambiguously reveal nanoscale mechanisms for dynamic processes for nearly any type of nanosized hydrated material, including nanomaterials, live cells, biomolecules, and energy-storage materials. Electrochemical capabilities enable investigation of battery electrode materials and electrocatalysis. Spatial resolution varies with the sample but ranges atomic resolution (for very thin liquid layers) to tens of nanometers for larger samples such as living cells.  The technique is capable of up to video-rate imaging to form in situ movies of nanoscale dynamics (e.g. see movies below).

Liquid cell electron microscopy collaborations are welcome, interested parties should contact Prof. Woehl.


Nanochemistry of nanocrystal formation

In this project, we are investigating the nucleation and growth mechanisms of transition metal and catalyst nanoparticles using LP-TEM in situ electron beam induced nucleation and growth. We are applying concepts from radiation chemistry and chemical kinetics to systematically vary reaction parameters and determine the resulting effects on nucleation and growth kinetics. The main question we aim to answer is: How do molecular reaction kinetics, such as precursor reduction and ligand complexation, affect the nucleation and growth kinetics of nanocrystals? What is the role of nucleation in determining the final composition and structure of complex nanocrystals, such as bimetallics? This project has broad applications in rational design of metal nanocrystals for catalysis and advanced optical materials. This work is currently supported by ACS PRF (Award #61111-DNI10).

(Left) LCEM video of silver nanocrystal nucleation and growth. (right) 2020 MRS presentation on LCEM visualization of ligand mediated AuCu alloyed nanocrystal formation mechanisms.

Protein aggregation in biologics

Biopharmaceuticals, or biologics, are biologically derived therapeutics and include monoclonal antibodies, vaccines, recombinant proteins, and blood components. Biologics are inherently unstable and aggregation prone under non-physiological conditions, which they are often exposed to during manufacturing, packaging, shipping, and storage. Protein aggregates pose significant risk of adverse health effects, such as decreased drug efficacy, capillary blockage, and immunogenicity.  Our current interest in this area is developing new high-throughput and correlative microscopy methods for detecting sub-micron protein aggregates in biologics. One technique we have developed is interferometric scattering microscopy (IFS), which is capable of visualizing and quantifying protein aggregates with sizes as small as 50 nm. With this technique we are currently exploring question such as, how does aggregate size and formation mechanisms affect the surface structure of protein aggregates? How does aggregate surface structure impact its interactions with the targeted antigen and the immune system? This work is funded by the FDA Center for Drug Evaluation and Research.

(Left) Interferometric scattering microscopy (IFS) for detection and sizing of sub-micron protein aggregates. (Right) Correlative IFS and fluorescence microscopy enables probing the surface concentration of immunogenicity induced Fc domains (right).

Dissipative assembly of colloids and nanoparticles

Biological cells utilize far-from-equilibrium assembly processes driven by chemical reactions to facilitate cell division and transport of nutrients. Discovery of synthetic systems that behavior similarly is of current interest due to their ability to autonomously change their physical properties (e.g. mechanical and optical properties) and perform functions like sensing and catalysis in response to addition of a chemical fuel. These systems are broadly referred to as dissipative assembly systems, indicating that energy is added to the system to induce assembly and then energy is dissipated to return the system to its initial state. The overall goal of the project is to establish the mechanisms for how chemical reactions drive the assembly of nanoparticle and nanoscale objects. Specifically, we are working to (1) develop design rules for dissipative assembly of colloidal systems based on quantitative colloid stability models, (2) directly visualize dissipative assembly of nanoparticles using LP-TEM, and (3) design new dissipative assembly strategies that enable multiresponsive nanomaterials. This work is currently supported by the Army Research Office (Contract #W911NF2010169).

(Left) Free energy diagram showing the out-of-equilibrium nature of dissipative assemblies formed by addition of chemical fuels. (Right) AICHE 2020 presentation on dissipative assembly of colloids.

Single particle characterization of organic aerosols

This project focuses on the impact of organic vapors on the CCN activity of water-insoluble aerosols and the nanoscale dynamic processes that occur during droplet condensation. The project directly visualizes nanoscale dynamic processes that occur during CCN activation. These observations are used to derive new mechanistic understanding of the CCN behavior of this important class of aerosols. The team utilizes a novel single particle technique, liquid cell transmission electron microscopy, to visualize particle dissolution kinetics and droplet growth kinetics in real time with nanometer scale spatial resolution. The electron microscopy data are directly correlated with quantitative measurements of CCN activation using controlled aerosol characterization techniques. Together these data are expected to reveal the series of chemical and physical processes occurring during CCN activation of water insoluble aerosols. These insights will contribute to a broader theoretical framework for cloud-aerosol interactions. This work is funded by the National Science Foundation (NSF-CHE Award #2003927)

Electrokinetics of colloids in pH gradients

This project studies the behavior of micron scale colloids in pH gradients and low frequency (< 1 kHz) oscillatory electric fields. Microscopic pH gradients are electrochemically generated near the electrode surface by redox reactions of electroactive quinone molecules, which consume or generate protons at the electrode-electrolyte interface. The behavior of the colloids in a parallel plate electrochemical cell is directly observed with optical and confocal microscopy. Colloids experience various competitive and synergistic phoretic and advective forces, including electrophoresis, electroosmosis, electrohydrodynamic fluid flow, and sedimentation, which together determine the assembly state and levitation height of colloids above the electrode surface. Dynamic coupling of colloid surface charge and dipole field as the particles move through the pH gradient lead to interesting behavior, including explosive disassembly of colloidal crystals, particle levitation, and separation of particles based on their size, shape, density, and surface chemistry. We are currently exploring research questions including, What is the effect of dynamic colloid surface charge on AC and DC electrokinetic phenomena (e.g. electrophoresis, electrohydrodynamic flow)? How do multiple electrokinetic phenomena work competitively and synergistically to manipulate colloids in pH gradients? New electrokinetic phenomena discovered in this project will have applications in separating mixtures of similarly sized particles based on shape (e.g. mixtures of colloidal oligomers) and surface chemistry.

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