Metasurfaces provide opportunities for wavefront control, flat optics, and subwavelength light focusing. We developed an imaging-based nanophotonic method for detecting mid-infrared molecular fingerprints and implemented it for the chemical identification and compositional analysis of surface-bound analytes. Our technique features a two-dimensional pixelated dielectric metasurface with a range of ultrasharp resonances, each tuned to a discrete frequency; this enables molecular absorption signatures to be read out at multiple spectral points, and the resulting information is then translated into a barcode-like spatial absorption map for imaging. The signatures of biological, polymer, and pesticide molecules can be detected with high sensitivity, covering applications such as biosensing and environmental monitoring. Our chemically specific technique can resolve absorption fingerprints without the need for spectrometry, frequency scanning, or moving mechanical parts, thereby paving the way toward sensitive and versatile miniaturized mid-infrared spectroscopy devices.

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Imaging-based molecular barcoding with pixelated dielectric metasurfaces.

Infrared spectroscopy is a powerful tool widely used in research and industry for a label-free and unambiguous identification of molecular species. Inconveniently, its application to spectroscopic analysis of minute amounts of materials, for example, in sensing applications, is hampered by the low infrared absorption cross-sections. Surface-enhanced infrared spectroscopy using resonant metal nanoantennas, or short “resonant SEIRA”, overcomes this limitation. Resonantly excited, such metal nanostructures feature collective oscillations of electrons (plasmons), providing huge electromagnetic fields on the nanometer scale. Infrared vibrations of molecules located in these fields are enhanced by orders of magnitude enabling a spectroscopic characterization with unprecedented sensitivity. In this Review, we introduce the concept of resonant SEIRA and discuss the underlying physics, particularly, the resonant coupling between molecular and antenna excitations as well as the spatial extent of the enhancement and...

Surface-Enhanced Infrared Spectroscopy Using Resonant Nanoantennas.

Cells must duplicate their mass in order to proliferate. Glucose and glutamine are the major nutrients consumed by proliferating mammalian cells, but the extent to which these and other nutrients contribute to cell mass is unknown. We quantified the fraction of cell mass derived from different nutrients and found that the majority of carbon mass in cells is derived from other amino acids, which are consumed at much lower rates than glucose and glutamine. While glucose carbon has diverse fates, glutamine contributes most to protein, suggesting that glutamine's ability to replenish tricarboxylic acid cycle intermediates (anaplerosis) is primarily used for amino acid biosynthesis. These findings demonstrate that rates of nutrient consumption are indirectly associated with mass accumulation and suggest that high rates of glucose and glutamine consumption support rapid cell proliferation beyond providing carbon for biosynthesis.

Amino Acids Rather than Glucose Account for the Majority of Cell Mass in Proliferating Mammalian Cells

Progress in nanotechnology is enabled by and dependent on the availability of measurement methods with spatial resolution commensurate with nanomaterials' length scales. Chemical imaging techniques, such as scattering scanning near-field optical microscopy (s-SNOM) and photothermal-induced resonance (PTIR), have provided scientists with means of extracting rich chemical and structural information with nanoscale resolution. This review presents some basics of infrared spectroscopy and microscopy, followed by detailed descriptions of s-SNOM and PTIR working principles. Nanoscale spectra are compared with far-field macroscale spectra, which are widely used for chemical identification. Selected examples illustrate either technical aspects of the measurements or applications in materials science. Central to this review is the ability to record nanoscale infrared spectra because, although chemical maps enable immediate visualization, the spectra provide information to interpret the images and characterize the sample. The growing breadth of nanomaterials and biological applications suggest rapid growth for this field.

Infrared Imaging and Spectroscopy Beyond the Diffraction Limit

Vibrational spectroscopies, based on infrared absorption and/or Raman scattering provide a detailed fingerprint of a material, based on the chemical content. Diagnostic and prognostic tools based on these technologies have the potential to revolutionise our clinical systems leading to improved patient outcome, more efficient public services and significant economic savings. However, despite these strong drivers, there are many fundamental scientific and technological challenges which have limited the implementation of this technology in the clinical arena, although recent years have seen significant progress in addressing these challenges. This review examines (i) the state of the art of clinical applications of infrared absorption and Raman spectroscopy, and (ii) the outstanding challenges, and progress towards translation, highlighting specific examples in the areas of in vivo, ex vivo and in vitro applications. In addition, the requirements of instrumentation suitable for use in the clinic, strategies for pre-processing and statistical analysis in clinical spectroscopy and data sharing protocols, will be discussed. Emerging consensus recommendations are presented, and the future perspectives of the field are assessed, particularly in the context of national and international collaborative research initiatives, such as the UK EPSRC Clinical Infrared and Raman Spectroscopy Network, the EU COST Action Raman4Clinics, and the International Society for Clinical Spectroscopy.

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Clinical applications of infrared and Raman spectroscopy: state of play and future challenges

Chemical imaging in the field of vibrational spectroscopy is developing into a promising tool to complement digital histopathology. Applications include screening of biopsy tissue via automated recognition of tissue/cell type and disease state based on the chemical information from the spectrum. For integration into clinical practice, data acquisition needs to be speeded up to implement a rack based system where specimens are rapidly imaged to compete with current visible scanners where 100's of slides can be scanned overnight. Current Fourier transform infrared (FTIR) imaging with focal plane array (FPA) detectors are currently the state-of-the-art instrumentation for infrared absorption chemical imaging, however recent development in broadly tunable lasers in the mid-IR range is considered the most promising potential candidate for next generation microscopes. In this paper we test a prototype quantum cascade laser (QCL) based spectral imaging microscope with a focus on discrete frequency chemical imaging. We demonstrate how a protein chemical image of the amide I band (1655 cm−1) of a 2 × 2.4 cm2 breast tissue microarray (TMA) containing over 200 cores can be measured in 9 min. This result indicates that applications requiring chemical images from a few key wavelengths would be ideally served by laser-based microscopes.

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Large scale infrared imaging of tissue micro arrays (TMAs) using a tunable Quantum Cascade Laser (QCL) based microscope

Understanding metabolism is indispensable in unraveling the mechanistic basis of many physiological and pathological processes However, in situ metabolic imaging tools are still lacking Here we introduce a framework for mid-infrared (MIR) metabolic imaging by coupling the emerging high-information-throughput MIR microscopy with specifically designed IR-active vibrational probes We present three categories of small vibrational tags including azide bond, 13C-edited carbonyl bond and deuterium-labeled probes to interrogate various metabolic activities in cells, small organisms and mice Two MIR imaging platforms are implemented including broadband Fourier transform infrared microscopy and discrete frequency infrared microscopy with a newly incorporated spectral region (2,000-2,300 cm-1) Our technique is uniquely suited to metabolic imaging with high information throughput In particular, we performed single-cell metabolic profiling including heterogeneity characterization, and large-area metabolic imaging at tissue or organ level with rich spectral information

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Mid-infrared metabolic imaging with vibrational probes.

Accurate early diagnosis is critical to patient survival, management and quality of life. Biofluids are key to early diagnosis due to their ease of collection and intimate involvement in human function. Large-scale mid-IR imaging of dried fluid deposits offers a high-throughput molecular analysis paradigm for the biomedical laboratory. The exciting advent of tuneable quantum cascade lasers allows for the collection of discrete frequency infrared data enabling clinically relevant timescales. By scanning targeted frequencies spectral quality, reproducibility and diagnostic potential can be maintained while significantly reducing acquisition time and processing requirements, sampling 16 serum spots with 0.6, 5.1 and 15% relative standard deviation (RSD) for 199, 14 and 9 discrete frequencies respectively. We use this reproducible methodology to show proof of concept rapid diagnostics; 40 unique dried liquid biopsies from brain, breast, lung and skin cancer patients were classified in 2.4 cumulative seconds against 10 non-cancer controls with accuracies of up to 90%.

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Introducing Discrete Frequency Infrared Technology for High-Throughput Biofluid Screening.

The utilization of the broad gain bandwidth available from quantum cascade (QC) devices is considered The performance of homo- geneous and heterogeneous QC gain media is explored in an external- cavity configuration Paradigms for realizing fixed wavelength or broad tuning performance of QC devices are considered C 2010 Society of Photo-

Utilizing broad gain bandwidth in quantum cascade devices

Mid-infrared spectroscopic imaging is a rapidly emerging technique in biomedical research and clinical diagnostics that takes advantage of the unique molecular fingerprint of cells, tissue and biofluids to provide a rich biochemical image without the need for staining. Spectroscopic analysis allows for the objective classification of biological material at a molecular level.1 This “label free” molecular imaging technique has been applied to histology, cytology, surgical pathology, microbiology and stem cell research, and can be used to detect subtle changes to the genome, proteome and metabolome.2,3,4 The new wealth of biochemical information made available by this technique has the distinct potential to improve cancer patient outcome through the identification of earlier stages of disease, drug resistance, new disease states and high-risk populations.4 However, despite the maturity of this science, instrumentation that provide increased sample throughput, improved image quality, a small footprint, low maintenance and require minimal spectral expertise are essential for clinical translation.

Jeremy Rowlette

Papers

Large scale infrared imaging of tissue micro arrays (TMAs) using a tunable Quantum Cascade Laser (QCL) based microscope

Mid-infrared metabolic imaging with vibrational probes.

Introducing Discrete Frequency Infrared Technology for High-Throughput Biofluid Screening.

Utilizing broad gain bandwidth in quantum cascade devices

Quantum cascade laser-based mid-infrared spectrochemical imaging of tissue and biofluids