Research

We develop tools and platforms for single-molecule analysis, resolving cell–cell communication at the single-cell level and identifying DNA and proteins down to their individual building blocks.

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Nanopore sensors are emerging tools for DNA and protein analysis; we introduce interfacial nanopores with dynamically tunable pore sizes. Read more about nanopores here: What is a Nanopore ?

Interfacial Nanopore - formed at the contact point between two surfaces, enables dynamic, real-time reconfigurability, allowing the pore size and sensing regime to be tuned on demand down to the sub-nm scale. This provides precise control over molecular transport, translocation speed, selectivity, and sensitivity to molecular configuration. Using these features, we study nanoscale biophysical processes, including protein unfolding as they translocate through nm-scale pores of varying sizes, resolving sub-molecular protein features toward single molecule sequencing, and systematic characterization of complex analytes such as protein mixtures.

Dynamic Interfacial Nanopores — Interfacial Nanopores - Conceptual Illustration

So far we have developed three configurations for creating interfacial nanopores, including a micropipette–elastomer interface controlled by micromanipulators, a piezo-actuated FluidFM system, and an on-chip platform enabling the formation of multiple dynamic nanopores within a microfluidic device.

Pippette-Elastomer Interfacial Nanopores: A nanopore is created at the interface of an elastomer (PDMS) and a rigid micropipette (glass) using a micromanipulatore. Dynamically selecting and modifying aperture size with high resolution allows for size-specific sensing and probing of biomolecules.

On-chip Interfacial Nanopore (schematic illustration)

On-Chip Interfacial Nanopores: Microfabricated interfaces are integrated into microfluidic chips to enable versatile, high-throughput applications. The geometry and operation are optimized for stable ionic current measurements in deformable systems.

FluidFM-based interfacial nanopore — FluidFM-based Interfacial Nanopore

Piezo-actuated FluidFM Interfacial Nanopores: The nanoscale gap between a FluidFM opening and a substrate is controlled via force regulation by a piezo actuator (external page Nat. Nano. 2019, external page ACS Nano 2020).

external page FluidFM is based on hollow AFM cantilevers and is used for localized surface modification and single-cell manipulation in liquid environments. The technology was developed at the Laboratory of Biosensors and Bioelectronics, ETH Zurich.

Projects

Single-molecule studies reveal molecular features and behaviors hidden in bulk measurements, uncovering dynamics and heterogeneity that provide critical insights for biology and diagnostics. We are developing tools to probe increasingly small and nuanced features of biomolecules.

Protein Unfolding — Unfolding by spatial confinement under electric field - Schematic Illustration

Protein Unfolding: By adjusting the nanopore diameter, we can apply geometric confinement to proteins. If the pore becomes comparable to or smaller than the protein’s folded size, the protein may partially or fully unfold to pass through. Ionic current signals provide insight into unfolding dynamics, as well as protein structure & stability.

DNA Sequencing with Oxford Nanopore — Illustration of DNA sequencing with biological nanopores - Oxford Nanopore Technology

Single-Molecule Sequencing requires precision and sensitivity, demanding sub-nm control over pore size and the ability to resolve subtle differences between nucleotides or amino acids. Interfacial nanopores, with their dynamic, real-time tunability, enables adjustable dwell times and selective sensing for sub-molecular discrimination.

We collaborate with external page UNOMR (ETH spin-off) in advancing interfacial nanopores for single-molecule sequencing applications.

Projects

Real-time profiling of single neurons can reveal key insights into neural computation, communication, and brain function. Although computation arises from large networks, its core signaling occurs at the nanoscale, requiring tools with matching precision and sensitivity.

Measuring Neural Activity with Nanopore — Measuring Neural Activity - Nanopore vs Microelectrode

Nanopores enable real-time measurements of ion fluxes, bridging the gap between network-level activity and nanoscale signaling.(external page Nat. Nano. 2019).
Interfacial Nanopores
positioned in the proximity of single neurons can record neural secretions continuously over several hours.(external page ACS Nano 2020)

Axons in micochannels — Axons of Single-Neuron Cells Patterned in Micochannels

Axons branching and nanoscale geometry shape spike propagation for information transfer. Soma recordings capture only integrated output, missing key modulations for neural coding and timing. Can nanopores enable direct intracellular access to single-axons?

Projects

Amelie Viol

Cell–Cell Communication drives decision-making in living systems; examples range from fate determination during development, to immune responses, to neuronal signaling. Secretion of ions and proteins is a key channel for this communication, occurring over vastly different patterns.

Protein Secretion from Cells — Protein secretion profiles obtained by nanopore measurements.

Dynamic interfacial nanopores are used to monitor single-cell secretions in real time (external page Nat. Nano. 2019 , external page ACS Nano 2020). By tuning pore size and voltage in situ, we now aim toward discriminating secretion patterns, classify products, and ultimately achieve time-resolved secretomics.

Projects

Instrumentation for Dynamic Interfacial Nanopores

Interfacial nanopores integrate actuators, patch-clamp amplifiers, and high-speed digitizers with FPGA-based feedback. With nanosecond resolution, the system monitors signals and adapts in real time for single-molecule measurements, enabling:

Respond dynamically to structural differences along a single molecule – for example, detecting folds, kinks, or different nucleotide/amino acid sequences as the molecule passes through the pore.
Perform multiple reads of the same molecule – so that measurements can be repeated on the same molecule to improve accuracy and generate statistical data, reducing errors or uncertainty in the analysis.

Projects

Lorenzo Petrella

Keywords:

Nanopores: Interfacial Nanopores; Instrumentation
Single-Molecules: Single-Molecule Sequencing; Protein Unfolding
Single-Cells: Neurons & Axons; Cell-Cell Communication