REVIEW Development of tip-enhanced optical spectroscopy for biological applications: a review Alistair P. D. Elfick & Andrew R. Downes & Rabah Mouras Received: 24 July 2009 / Revised: 6 October 2009 / Accepted: 7 October 2009 / Published online: 30 October 2009 # Springer-Verlag 2009 Abstract Tip-enhanced optical spectroscopy is an approach that holds a good deal of promise for the nanoscale character- isation of matter. Tip-enhanced Raman spectroscopy (TERS) has been demonstrated on a variety of samples: inorganic, organic and biological. Imaging using TERS has been shown for carbon nanotubes due to their high scattering efficiency. There are a number of compelling motivations to consider alternative approaches for biological samples; most impor- tantly, the potential for heat damage of biomolecules and long acquisition times. These issues may be addressed through the development of tip-enhanced coherent anti-Stokes Raman scattering microscopy. Keywords TERS . Raman . Near-field . Biological samples . tip-enhanced CARS Introduction Nanotechnology is widely perceived as possessing great potential to bring benefits in a diverse range of applications relating to information/communication technologies, mate- rials development, medicine and the life sciences. The global market value of products incorporating nanotechnology in 2007 was $11.6 billion [1]. This is estimated to grow to some $27 billion by 2013 despite the current global economic downturn; this is attributable to the significant and sustained governmental investments made in nanotechnology research and development. Nanometrology was identified as a research priority due to its important role in underpinning the development of all nanotechnologies. The ability to measure and characterise materials (i.e. to determine physical and chemical properties) at the nanoscale is vital to the realisation and production of reliable nano- materials and nanodevices. Nanometrology includes measure- ments of topographical features, along with the mapping of various properties such as chemical, electrical, magnetic or other properties at the nanoscale. The understanding of physical science at this scale, and the allied improvement in materials/devices, industrial processes and reliability of manufacture, are contingent on enabling advances in nano- metrology. The International Technology Roadmap for Semi- conductors 2007 (ITRS) emphasises the challenges for nanometrology in keeping pace with the reduction in feature size of semiconductor devices. The ITRS emphasises that shrinking feature sizes, tighter control of device parameters and new interconnect materials will provide the main challenges for physical nanometrology methods; “(one technology) gap is meeting the fundamental challenge for materials characterization of imaging and measurement of materials properties at atomic dimensions”. Bionanotechnology may be considered to be the appli- cation of nanotechnology to the biosciences, or the use of biological molecules for applications in nanotechnology, such as self-assembling DNA structures [2]. Instruments developed for nanometrology within bionanotechnology will experience a particular set of challenges in this soft and diffuse world, with the need to maintain an appropriate environment while imaging and the susceptibility of the sample to damage during the imaging process being two key concerns. This review discusses the contribution that recent advances in near-field optics can make to closing the nanotechnology device-measurement gap. We give special A. P. D. Elfick (*) : A. R. Downes : R. Mouras Centre for Biomedical Engineering, The School of Engineering, The University of Edinburgh, Edinburgh EH9 3JL, UK e-mail: Alistair.Elfick@ed.ac.uk Anal Bioanal Chem (2010) 396:45–52 DOI 10.1007/s00216-009-3223-9