Jaime Castillo, Maria Dimaki and Winnie E. Svendsen at the Technical University of Denmark explain how micro and nano manipulation techniques are helping researchers understand biological systems

Understanding the biochemical background of diseases at their deepest levels is a challenging task. It has motivated researchers from a range of disciplines - from biology to physics to robotics - to combine their efforts to improve patients' quality of life.

Researchers can move, image and characterise chromosomes using micro and nano manipulation methods

Much of this research is focused on developing techniques and tools to handle biological material without damaging it or altering its natural state. In this way, the study of biological systems will be as close to the real, in vivo situation that we can get in a research lab.

Several manipulation techniques have emerged in recent decades thanks to advances in micro- and nanofabrication. For instance, the atomic force microscope (AFM) uses a probe to image, push, pull, cut and indent biological material in air, liquid or vacuum.

Scanning electron microscopes offer improved magnification over AFMs but samples have to be fixed, dehydrated and coated with metal, which alters their size and shape. However, metal coating is not needed for environmental scanning electron microscopes, allowing scientists to image and manipulate samples in their natural state.

Using these techniques, scientists can make manipulation tools, such as microgrippers and nanotweezers, on the same length scale as the biological samples.

And so researchers can now move, position, image, stimulate and characterise biological samples, including cells, DNA and bacteria, in a controlled way. The choice of manipulation technique depends on the size and shape of the sample, in addition to the medium in which it is found.

Unfortunately, manipulation tools can affect the structure of biological samples. In these cases, techniques such as dielectrophoresis, acoustophoresis or microfluidics, which use physical phenomena rather than direct contact to manipulate the samples, are good options. Combining these techniques increases the possibilities for handling samples. For example, scientists combine micromanipulators with precise fluidic and motion control in assisted in vitro fertilisation techniques.

Researchers need to consider the consequences of scaling down their studies. Effects that are dominant at the macroscale become negligible when moving to the micro- and nanoscale. For example, in a microfluidic microchannel, gravity no longer plays a role but surface tension, which is insignificant on the macroscale, is crucial. Understanding these scaling laws is critical for a successful transition from the macroscopic to the micro- and nanoscopic dimensions.

Although great progress has been made, challenges are still present. To understand the complex interactions between and inside biological samples, scientists will always have to manipulate, transport, sort and integrate samples in different environments. For this, we need to improve manipulation techniques and make new tools so we can continue to explore biological entities in their natural environments.

Read more in "Manipulation of biological samples using micro and nano techniques" in the first issue of  Integrative Biology

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