Bionanotechnology: arrays in the future prospects of the field

Nanotechnology's prominence in modern medicine is indisputable, but establishing exactly how biological systems will interact with nanostructures can be far from clean cut. Biological systems can seem messy and difficult to reproduce with precision, so that different reports of similar studies seem to contradict each other. Arrays of one-dimensional nanostructures serve as a case in point. The nanostructure dimensions—roughly the size of a cell in length but 100–1000 times smaller in diameter—can allow access deep into the cell without causing excessive damage making them potentially very useful. However, studies of these systems have highlighted how sensitive they can be to apparently insignificant differences in the experimental details. In this issue Karen Martinez and colleagues at the University of Copenhagen describe some of the advances that have been made in cellular applications of arrays of one-dimensional nanostructures [1]. The review highlights the progress in the field so far and trends that are emerging from the literature.

In fact although the attention of the early microscopists was largely absorbed by biological species, when nanoscale imaging first arrived it was largely motivated by electronics. As co-inventor of the atomic force microscope Christophe Gerber highlights in our Nanotechnology discussion podcast [2] looking back over the first 25 years of the journal, 'In the early 1980s the semiconductor industry was approaching the nanoscale but there were no instruments that could measure at that scale.' The scanning tunnelling microscope [3] and subsequently the atomic force microscope [4] provided the tools the industry lacked at the time, but it was not long before the potential to apply the same cantilever systems for detecting interactions with molecular scale biological substances became apparent.

Molecular recognition based on atomic force microscopy technology detects the presence of molecules by the change in mass of the cantilever system when molecules bind to it either by a change in the deflection (static mode) or the change in the resonance frequency of the cantilever oscillations (dynamic mode). The surface of the cantilever can be treated to encourage interactions with the chemical of interest. As with the original work to create high-resolution images with tips and cantilevers, applying these systems to biosensing posed significant challenges at first, such as misleading readings from the cantilever deflection. This issue was resolved by integrating a sensor cantilever and at least one reference cantilever into an array. Further details of the technique are explained in a tutorial by Christophe Gerber and colleagues from IBM Research and the University of Basel in Switzerland [5].

Another aspect of nanostructures that can be invaluable for detecting trace substances is the enhancements to electromagnetic fields that occur nearby when light of a well-tuned wavelength excites a plasmon resonance in a nanostructure. As well as enhancing Raman signals from chemicals present, these resonances also indicate the presence of other substances by shifts in the resonant wavelength. Lars Gunnarsson and Alexandre Dmitriev from Chalmers University in Sweden demonstrated an ultralow limit of detection of just several pg cm⁻² (or several tens of attomoles cm⁻²) using the localized surface plasmon resonances of an array of nanodisks [6]. Compared with nanoparticles that have points or sharp corners such as rice, star and crescent shapes, sensing from plasmons in nanodisks can be more difficult. Yet the team developed a cost-effective approach using nanodisks in an array with low periodicity so that the spectral characteristics reflect those of a single disc. As they point out in their report on the work, 'These experiments pave the way towards an ultra-sensitive yet compact biodetection platform for point-of-care diagnostics applications.'

An alternative use of nanostructures for biosensing is by electronic detection, where DNA sequencing through nanopores is a prime example [7]. Molecules in saline solution can be detected as they pass through the pore by the change in the impedance. New fabrication protocols have also provided the means for producing chips designed around this nanopore-type sensor with additional insulating layers to reduce noise [8]. Rahim Esfandyarpour and colleagues at Stanford University and Stanford Genome Technology Center in the US modified the approach by using arrays of nanoneedles [9]. Detection occurs as molecules pass through the eye of the needle in a similar manner to the use of nanopores but by adopting a needle-type structure the researchers take advantage of 3D diffusion of the molecules for a higher hit rate, easier integration into a handheld device and for use in vivo, parallel processing using an individual on-chip amplifier and read-out system on the nanoneedles and a lower susceptibility to fluidic noise.

In their review in this issue [1] Martinez and colleagues provide an overview of applications of one-dimensional nanostructure arrays for cells, and not only for detecting cellular activity with unprecedented spatiotemporal accuracy but also modifying this activity. They describe how the nanostructures can be used for probing cells, drug delivery, as electrodes to monitor cell activity and to guide cells to form a network or even an artificial neural network. They note trends in the way different cells respond to nanostructure arrays of various densities and geometries and how this can be affected by the cell handling techniques used in each experiment.

While the authors emphasize the challenge of managing the maze of variables in these systems the outlook seems optimistic. 'Despite the fact that many different types of nanostructure platforms have been characterized so far, often unique in their combination of variables (material, topography, cells, methods) the obtained results are encouragingly in many cases similar despite the many different experimental conditions,' they conclude. The recognition of the similarities in results from different experimental conditions would seem to herald an exciting epoch in the field. As Alfred Nobel, founder of the Nobel Prize, once said, 'One can state, without exaggeration, that the observation of and the search for similarities and differences are the basis of all human knowledge' [10].