Fluidic Force Microscopy (FluidFM): Combining Nanoscale Imaging and Manipulation

Overview of Fluidic Force Microscopy

Fluidic force microscopy (FluidFM) is a cutting-edge technique that integrates atomic force microscopy (AFM) with nanofluidics, enabling simultaneous imaging and manipulation of biological samples at the nanoscale. By combining the high-resolution imaging capabilities of AFM with the precise fluid delivery and force measurements provided by nanofluidics, FluidFM offers unique opportunities for studying living cells, single molecules, and nanoscale interactions.

Key Components of FluidFM

The FluidFM system integrates several key components:
  • Hollow AFM Cantilever: The core of the FluidFM system is a specially designed hollow AFM cantilever with a microfluidic channel running through it. The cantilever acts as a nanopipette, allowing for the precise delivery of fluids to the sample surface.
  • Nanofluidic System: The microfluidic channel in the cantilever is connected to a nanofluidic system that precisely controls the fluid flow. This system enables the delivery of femtoliter to microliter volumes of fluids with high accuracy and repeatability.
  • Pressure Control: The fluid flow in the FluidFM system is regulated by a pressure controller, which allows for the application of both positive and negative pressures. This pressure control enables the aspiration and dispensing of fluids, as well as the manipulation of biological samples.
  • Force Feedback: The FluidFM system incorporates a force feedback mechanism that measures the interaction forces between the cantilever tip and the sample surface. This force feedback allows for the precise control of the applied forces during imaging and manipulation.

Applications of FluidFM

FluidFM has found diverse applications in the fields of biology, materials science, and nanotechnology:

Single-Cell Analysis and Manipulation

FluidFM has revolutionized single-cell analysis by enabling the precise manipulation and interrogation of individual living cells. With FluidFM, researchers can perform single-cell isolation, drug delivery, and intracellular measurements with unprecedented accuracy. This has opened up new avenues for studying cellular heterogeneity, drug response, and cell-to-cell interactions.

Single-Molecule Force Spectroscopy

FluidFM has extended the capabilities of single-molecule force spectroscopy by combining it with precise fluid control. By delivering specific molecules or buffers to the sample surface, FluidFM enables the study of molecular interactions under different chemical environments. This has led to new insights into protein folding, receptor-ligand binding, and enzymatic reactions at the single-molecule level.

Nanoscale 3D Printing and Patterning

FluidFM has emerged as a powerful tool for nanoscale 3D printing and patterning. By dispensing tiny volumes of materials through the cantilever aperture, FluidFM enables the fabrication of complex 3D structures with nanometer precision. This has applications in tissue engineering, drug delivery systems, and nanoelectronics.

Advantages and Limitations

FluidFM offers several advantages over traditional AFM and nanofluidic techniques:
  • High-Resolution Imaging and Manipulation: FluidFM combines the high-resolution imaging capabilities of AFM with the precise fluid delivery and force measurements of nanofluidics. This allows for the simultaneous imaging and manipulation of biological samples at the nanoscale.
  • Versatility: FluidFM is compatible with a wide range of fluids, including aqueous solutions, organic solvents, and biological media. This versatility enables the study of diverse biological systems and materials under native-like conditions.
  • Non-Destructive Analysis: FluidFM allows for the gentle manipulation of delicate biological samples, such as living cells and single molecules, without causing damage. This non-destructive nature of FluidFM is particularly advantageous for studying live-cell processes and fragile biomolecules.
However, FluidFM also has some limitations:
  • Complex System Setup: The integration of AFM with nanofluidics in FluidFM requires a complex system setup, including specialized cantilevers, microfluidic components, and pressure controllers. This complexity may limit the accessibility and widespread adoption of FluidFM.
  • Limited Throughput: FluidFM is primarily designed for single-cell and single-molecule analysis, which can be time-consuming and low-throughput compared to bulk measurements. While advances in automation and parallelization are being developed, FluidFM currently remains a specialized technique for targeted studies.

Future Perspectives

The field of FluidFM is rapidly evolving, with ongoing research aimed at expanding its capabilities and applications. Future developments in FluidFM technology may include:
  • Integration with Advanced Imaging Techniques: Combining FluidFM with other advanced imaging techniques, such as super-resolution microscopy and correlative light-electron microscopy, could provide unprecedented insights into the structure and function of biological systems at the nanoscale.
  • High-Throughput Screening: The development of parallel FluidFM arrays and automated fluid delivery systems could enable high-throughput screening of single cells and molecules, accelerating drug discovery and functional genomics studies.
  • In Vivo Applications: Miniaturization of FluidFM probes and integration with minimally invasive surgical techniques could open up possibilities for in vivo single-cell analysis and targeted drug delivery in animal models and clinical settings.
As FluidFM continues to evolve, it is expected to play an increasingly important role in advancing our understanding of biological systems at the nanoscale and enabling novel applications in personalized medicine, drug development, and materials science.

Further Reading