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.

(Left) Schematic cartoon of electron beam nanochemistry. (center) LCEM video of silver nanocrystal nucleation and growth. (right) Nanometric spatial map of nucleation kinetics on a chemically heterogeneous surface.

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. Of particular concern is the presence of sub-micron protein aggregates in biologics, as this class of aggregates is not currently quantified with conventional analytical techniques. 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 an optical based microscopy method capable of visualizing and quantifying protein aggregates with sizes as small as 100 nm. These techniques will allow us to answer several fundamental questions about protein aggregation. What is the particle size distribution of sub-micron sized aggregates in biologic solutions? How does aggregate size and formation mechanisms affect its interaction with the targeted antigen and the immune system? 

(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.

(Left) Free energy diagram showing the out-of-equilibrium nature of dissipative assemblies formed by addition of chemical fuels. (Right) Colloidal stability based model of dissipative assembly.