Chemical sensing and imaging with pulsed terahertz radiation
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- Cite this article as:
- Walther, M., Fischer, B.M., Ortner, A. et al. Anal Bioanal Chem (2010) 397: 1009. doi:10.1007/s00216-010-3672-1
Over the past decade, terahertz spectroscopy has evolved into a versatile tool for chemically selective sensing and imaging applications. In particular, the potential to coherently generate and detect short, and hence, broadband terahertz pulses led to the development of efficient and compact spectrometers for this interesting part of the electromagnetic spectrum, where common packaging materials are transparent and many chemical compounds show characteristic absorptions. Although early proof-of-principle demonstrations have shown the great potential of terahertz spectroscopy for sensing and imaging, the technology still often lacks the required sensitivity and suffers from its intrinsically poor spatial resolution. In this review we discuss the current potential of terahertz pulse spectroscopy and highlight recent technological advances geared towards both enhancing spectral sensitivity and increasing spatial resolution.
KeywordsTerahertz spectroscopyTerahertz imagingLab-on-chip
In recent years the popular press, companies, and research institutes have frequently reported on the great potential of terahertz radiation for medical, biological, and security-related sensing and imaging. The terahertz frequency range of the electromagnetic spectrum indeed offers a range of exciting possibilities for chemical sensing [1, 2], characterization of biological material [3, 4], standoff detection of explosives  and biological warfare agents , the analysis of low-frequency vibrations in RNA, DNA, and proteins [7–10], as well as the detection of skin cancer , to name only a few examples. Although these reports fueled enthusiastic and sometimes unrealistic expectations for this new technology, the prudent researcher in the laboratory views its potential from a slightly more realistic angle.
Since the pioneering work by Auston et al.  and Grischkowsky et al. , who introduced ultrafast laser techniques to generate and detect short and broad-bandwidth pulses of terahertz radiation, a number of experimental barriers in this spectral range have been overcome, and today compact terahertz spectrometers are commercially available. Over the past 5 years an extended atlas of molecule-specific spectra in this spectral range has been accumulated and the general applicability for chemically selective characterization and imaging has been demonstrated. However, for many realistic applications in chemical analysis and imaging of biological systems, the technology still lacks the required sensitivity and also suffers from its intrinsically poor spatial resolution.
Here, we discuss selected examples of chemical sensing applications by terahertz pulse spectroscopy and review recent technological advances geared towards both enhancing spectral sensitivity, e.g., by confining the terahertz fields to waveguides, and increasing spatial resolution well beyond the diffraction limit, by near-field microscopy techniques.
In contrast to the radio and microwave parts of the electromagnetic spectrum, as well as the infrared and visible regime, where efficient electronic or optical radiation sources have been widely available, there has been a lack of efficient coherent sources and detectors for terahertz radiation in the past. The advent of modern femtosecond laser technology in the early 1990s helped to bridge this gap in the electromagnetic spectrum. Such ultrashort pulse lasers allow the generation and detection of short pulses of terahertz radiation, either in nonlinear optical crystals [16, 17] or by photoconductive antennas . Terahertz pulses produced by these methods correspond to short bursts of broadband far-infrared light, which can readily be used for spectroscopic applications in this interesting part of the spectrum. Based on this technology, the terahertz time-domain spectroscopy (TDS) approach has been developed and eventually established as a powerful spectroscopic tool.
The terahertz detector typically consists of an H-shaped electrode structure (5-μm gap) processed on a photoconductive material. Fast photoconductors, e.g., low-temperature-grown GaAs, are typically used to provide the required fast response of the terahertz detector. By scanning a variable delay, one can continuously delay the laser pulse that gates the detector with respect to the incoming terahertz pulse, allowing direct sampling of the temporal profile of the electric field of each pulse trace.
Chemical sensing and substance identification
As discussed already, terahertz vibrational spectra represent characteristic fingerprints for many chemical substances; hence, this technology may be used for contactless substance identification. The terahertz spectrum of sucrose shown in Fig. 3, for example, exhibits various absorption bands, with their central frequencies, widths, and absorption strengths being characteristic for this particular compound, rendering its spectrum clearly differentiable from the spectra of other sugars . This chemical specificity of terahertz spectra opens up a range of useful applications in basic research, industry, or for security applications. As an example, we have shown previously that closely related chemical substances such as acetylsalicylic acid (aspirin) and its chemical precursors (hydroxylated benzoic acids) can be clearly differentiated . Moreover, by comparing relative absorption strengths, one can perform a quantitative analysis, allowing mixing ratios in mixtures to be determined, which is potentially useful to detect unwanted contamination during drug production in the pharmaceutical industry.
In conventional terahertz TDS the pulsed terahertz beam is guided through free space by collimating and focusing optics (lenses or mirrors) to the object under investigation and, depending on the setup, either the transmitted or the reflected terahertz pulses are subsequently detected. Transmission spectroscopy is preferred if the sample is sufficiently transparent as is the case for many solid-state systems, such as plastics and molecular crystals. Many liquids, however—in particular polar liquids such as water and alcohols—strongly absorb terahertz radiation. In this case, terahertz TDS in reflection geometry is typically used to probe their dielectric properties [20–23].
Protein-bound retinals play the role of biological chromophores in rhodopsin and bacteriorhodopsin, and the isomerization of the retinal chromophore represents the primary step in their photocycle. The structural selectivity of terahertz spectroscopy implies its potential for sensing structural changes in chromophores, through identifying vibrational modes, which can act as a probe of their isomeric state. Unfortunately, most isomerization experiments require the chromophores to be dissolved in liquids rather than bound in a crystal lattice, which results in extremely overdamped vibrational modes and, hence, broadened absorption bands.
Often, current terahertz TDS systems do not fulfill the high requirements for potential application in chemical sensing and bioanalysis. Fundamental obstacles are mainly related to the insufficient spectral sensitivity of this approach. For instance, conventional free-space spectroscopy methods, as described in the previous subsection, typically require at least some milligrams or microliters of a sample substance to be selectively detected. In many realistic applications, however, only few nanograms to micrograms (or picoliters to nanoliters) are available, e.g., as spots on biochips.
An even more promising approach pioneered by the Grischkowsky group uses parallel metallic plates as waveguides [30–33]. Using these parallel-plate waveguides, they have shown that less than 100 µg of a crystalline sample  or liquid layers of only few nanometers are sufficient to determine the spectrum .
Finally, terahertz waveguides may also be integrated as microstrip lines together with a terahertz emitter and detector on a single chip, potentially in combination with microfluidic channels, allowing for very compact and highly miniaturized terahertz sensors . It can only be speculated that with expected further advancements of waveguide-based terahertz systems the sensitivities required for many biochemical sensing applications may eventually be achievable.
Not only spectral but also spatial information can be obtained by terahertz TDS. This is particularly useful for investigating strongly inhomogeneous systems, as is the case for many biological samples, such as plants and biological cells.
Terahertz near-field microscopy
Note that each spatial pixel of the image corresponds to an individual terahertz pulse scan and thus contains spectral information over the entire bandwidth covered by our experiment (50 GHz to 3 THz). Consequently, near-field microscopy can also be applied for chemically sensing small spots of substances, similar to the result in Fig. 8, however with much better spatial resolution.
Although current terahertz TDS systems have the potential for chemically selective sensing and imaging, they still suffer from limited sensitivity and an intrinsically poor spatial resolution. Presumably, in the near future systems based on terahertz waveguides will be able to achieve the high sensitivities required for useful sensing applications in chemical or biochemical analytics. This approach also has the capability to implement very compact terahertz spectrometers, e.g., by integrating the terahertz emitter, detector, and waveguide on a single centimeter-sized chip. Various lab-on-chip applications may be feasible.
Near-field imaging methods have the potential to push achievable spatial resolutions for terahertz imaging from millimeters into the micrometer and eventually the nanometer regime. Terahertz near-field images of semiconductor devices with nanometer resolution have been reported recently .
Increasing sensitivities together with better spatial resolutions will lead to a significant reduction of sample amounts required in broadband terahertz spectroscopy, eventually paving the way for useful sensing and imaging applications (chemical, biological, medical, or environmental).
M.W. acknowledges funding by the Deutsche Forschungsgemeinschaft (DFG) through grant no. WA 2641, by the Baden-Württemberg Ministry for Science and Arts Research Seed Capital (RiSC) for young researchers, and by the University of Freiburg.