Vibrational Biospectroscopy: An Alternative Approach to Endometrial Cancer Diagnosis and Screening.

Endometrial cancer (EC) is the sixth most common cancer and the fourth leading cause of death among women worldwide. Early detection and treatment are associated with a favourable prognosis and reduction in mortality. Unlike other common cancers, however, screening strategies lack the required sensitivity, specificity and accuracy to be successfully implemented in clinical practice and current diagnostic approaches are invasive, costly and time consuming. Such limitations highlight the unmet need to develop diagnostic and screening alternatives for EC, which should be accurate, rapid, minimally invasive and cost-effective. Vibrational spectroscopic techniques, Mid-Infrared Absorption Spectroscopy and Raman, exploit the atomic vibrational absorption induced by interaction of light and a biological sample, to generate a unique spectral response: a "biochemical fingerprint". These are non-destructive techniques and, combined with multivariate statistical analysis, have been shown over the last decade to provide discrimination between cancerous and healthy samples, demonstrating a promising role in both cancer screening and diagnosis. The aim of this review is to collate available evidence, in order to provide insight into the present status of the application of vibrational biospectroscopy in endometrial cancer diagnosis and screening, and to assess future prospects.

Mid-infrared spectral classification of endometrial cancer compared to benign controls in serum or plasma samples.

This study demonstrates a discrimination of endometrial cancer versus (non-cancerous) benign controls based on mid-infrared (MIR) spectroscopy of dried plasma or serum liquid samples. A detailed evaluation was performed using four discriminant methods (LDA, QDA, kNN or SVM) to execute the classification task. The discriminant methods used in the study comprised methods that are widely used in the statistics (LDA and QDA) and machine learning literature (kNN and SVM). Of particular interest, is the impact of discrimination when presented with spectral data from a section of the bio-fingerprint region (1430 cm-1 to 900 cm-1) in contrast to the more extended bio-fingerprint region used here (1800 cm-1 to 900 cm-1). Quality metrics used were the misclassification rate, sensitivity, specificity, and Matthew's correlation coefficient (MCC). For plasma (with spectral data ranging from 1430 cm-1 to 900 cm-1), the best performing classifier was kNN, which achieved a sensitivity, specificity and MCC of 0.865 ± 0.043, 0.865 ± 0.023 and 0.762 ± 0.034, respectively. For serum (in the same wavenumber range), the best performing classifier was LDA, achieving a sensitivity, specificity and MCC of 0.899 ± 0.023, 0.763 ± 0.048 and 0.664 ± 0.067, respectively. For plasma (with spectral data ranging from 1800 cm-1 to 900 cm-1), the best performing classifier was SVM, with a sensitivity, specificity and MCC of 0.993 ± 0.010, 0.815 ± 0.000 and 0.815 ± 0.010, respectively. For serum (in the same wavenumber range), QDA performed best achieving a sensitivity, specificity and MCC of 0.852 ± 0.023, 0.700 ± 0.162 and 0.557 ± 0.012, respectively. Our findings demonstrate that even when a section of the bio-fingerprint region has been removed, good classification of endometrial cancer versus non-cancerous controls is still maintained. These findings suggest the potential of a MIR screening tool for endometrial cancer screening.

Evaluating the cytotoxicity of Ge-Sb-Se chalcogenide glass optical fibres on 3T3 mouse fibroblasts.

In vivo cancer detection based on the mid-infrared molecular fingerprint of tissue is promising for the fast diagnosis and treatment of suspected cancer patients. Few materials are mid-infrared transmissive, even fewer, which can be converted into functional, low-loss optical fibres for in vivo non-invasive testing. Chalcogenide-based glass optical fibres are, however, one of the few. These glasses are transmissive in the mid-infrared and are currently under development for use in molecular sensing devices. The cytotoxicity of these materials is however unknown. The cytotoxicity of Ge-Sb-Se chalcogenide optical glass fibres on 3T3 mouse fibroblast cells is here investigated. Fibres exposed to four different pre-treatment conditions are used: as-drawn (AD), propylamine-etched (PE), oxidised-and-washed (OW) and oxidised (Ox). To achieve the latter two conditions, fibres are treated with H2O2(aqueous (aq.)) and dried to produce a surface oxide layer; this is either washed off (OW) or left on the glass surface (Ox). Cellular response is investigated via 3 day elution and 14 day direct contact trials. The concentration of the metalloids (Ge, Sb and Se) in each leachate was measured via inductively coupled plasma mass spectrometry. Cell viability is assessed using the neutral red assay and scanning electron microscopy. The concentration of Ge, Sb and Se ions after a 3 day dissolution was as follows. In AD leachates, Ge: 0.40 mg L-1, Sb: 0.17 mg L-1, and Se: 0.06 mg L-1. In PE leachates, Ge: 0.22 mg L-1, Sb: 0.15 mg L-1, and Se: 0.02 mg L-1. In Ox leachates, Ge: 823.8 mg L-1, Sb: 2586.6 mg L-1, and Se: 3750 mg L-1. Direct contact trials show confluent cell layers on AD, PE and OW fibres after 14 days, while no cells are observed on the Ox surfaces. A >50% cell viability is observed in AD, PE and OW eluates after 3 days, when compared with Ox eluates (<10% cell viability). Toxicity in Ox is attributed to the notable pH change, from neutral pH 7.49 to acidic pH 2.44, that takes place on dissolution of the surface oxide layer in the growth media. We conclude, as-prepared Ge-Sb-Se glasses are cytocompatible and toxicity arises when an oxide layer is forced to develop on the glass surface.

Experimental Investigation of Actively Q-Switched Er3+:ZBLAN Fiber Laser Operating at around 2.8 µm.

A diode-pumped Q-switched Er3+:ZBLAN double-clad, single-transverse mode fiber laser is practically realized. The Q-switched laser characteristics as a function of pump power, repetition rate, and fiber length are experimentally investigated. The results obtained show that the Q-switched operation with 46 µJ pulse energy, 56 ns long pulses, and 0.821 kW peak power is achieved at a pulse repetition rate of 10 kHz. To the best of our knowledge, this is the highest-ever demonstrated peak power emitted from an actively Q-switched, single-transverse mode Er3+:ZBLAN fiber laser operating near 2.8 µm.

Experimental photoluminescence and lifetimes at wavelengths including beyond 7 microns in Sm3+-doped selenide-chalcogenide glass fibers.

1000 ppmw Sm3+-doped Ge19.4Sb9.7Se67.9Ga3 atomic % chalcogenide bulk glass and unstructured fiber are prepared. Near- and mid-infrared absorption spectra of the bulk glass reveal Sm3+ electronic absorption bands, and extrinsic vibrational absorption bands, due to host impurities. Fiber photoluminescence, centred at 3.75 µm and 7.25 µm, is measured when pumping at either 1300 or 1470 nm. Pumping at 1470 nm enables the photoluminescent lifetime at 7.3 µm to be measured for the first time which was ∼100 µs. This is the longest to date, experimentally observed lifetime in the 6.5-9 µm wavelength-range of a lanthanide-doped chalcogenide glass fiber.

Correction: Prospective on using fibre mid-infrared supercontinuum laser sources for in vivo spectral discrimination of disease.

Correction for 'Prospective on using fibre mid-infrared supercontinuum laser sources for in vivo spectral discrimination of disease' by Angela B. Seddon et al., Analyst, 2018, 143, 5874-5887.

Determining the continuous thermo-optic coefficients of chalcogenide glass thin films in the MIR region using FTIR transmission spectra.

A new method (FTIR continuous dn / dT method, n is refractive index and T temperature) for measuring the continuous thermo-optic coefficients of thin transparent films in the mid-infrared (MIR) spectral region is introduced. The technique is based on Fourier transform infrared (FTIR) transmission spectra measured at different temperatures. It is shown that this method can successfully determine the thermo-optic coefficient of chalcogenide glass thin films (of batch compositions Ge20Sb10Se70 at. % (atomic %) and Ge16As24Se15.5Te44.5 at. %) over the wavelength range from 2 to 25 µm. The measurement precision error is less than ± 11.5 ppm / °C over the wavelength range from 6 to 20 µm. The precision is much better than that provided by the prism minimum deviation method or an improved Swanepoel method.

Experimental observation of gain in a resonantly pumped Pr3+-doped chalcogenide glass mid-infrared fibre amplifier notwithstanding the signal excited-state absorption.

We demonstrate a maximum gain of 4.6 dB at a signal wavelength of 5.28 µm in a 4.1 µm resonantly pumped Pr3+-doped selenide-based chalcogenide glass fibre amplifier of length 109 mm, as well as a new signal excited-stated absorption (ESA) at signal wavelengths around 5.5 µm. This work to the best of our knowledge is the first experimental demonstration of gain at mid-infrared (MIR) wavelengths in a Pr3+-doped chalcogenide fibre amplifier. The signal ESA of the fibre is attributed to the transition 3H6 → (3F4, 3F3) after the pump ESA (3H5 → 3H6) at a pump wavelength of 4.1 µm, which absorbs the MIR signal at wavelengths of 5.37, 5.51 and 5.57 µm, and so spoils the amplifier's performance at these wavelengths. Thus, this signal ESA should be suppressed in a resonantly pumped Pr3+-doped selenide-based chalcogenide fibre amplifier.

Prospective on using fibre mid-infrared supercontinuum laser sources for in vivo spectral discrimination of disease.

Mid-infrared (MIR) fibre-optics may play a future role in in vivo diagnosis of disease, including cancer. Recently, we reported for the first time an optical fibre based broadband supercontinuum (SC) laser source spanning 1.3 to 13.4 µm wavelength to cover the spectral 'fingerprint region' of biological tissue. This work has catalysed the new field of fibre MIR-SC and now very bright sources equivalent to a 'few synchrotrons' have been demonstrated in fibre. In addition, we have made record transparency MIR fibre for routeing the MIR light and reported first-time MIR photoluminescence (with long lifetime) in small-core, rare earth ion doped, MIR fibre - an important step towards MIR fibre lasing at >4 µm wavelength for pumping fibre MIR-SC. First time fibre MIR-SC spectroscopic imaging of colon tissue is described at wavelengths in the 'fingerprint region'.

Correlating structure with non-linear optical properties in xAs40Se60·(1-x)As40S60 glasses.

A series of xAs40Se60·(100 - x)As40S60 glasses, where x = 0, 25, 33, 50, 67, 75 and 100 mol% As40Se60, has been studied using neutron and X-ray total scattering, Raman spectroscopy and (77)Se MAS-NMR. The results are presented with measurements of non-linear refractive indices, n2, and densities. There is no evidence for the formation of homopolar bonds in these glasses, but neutron correlation functions suggest that there is a non-random distribution of sulfur and selenium atoms in sulfur-rich glasses. The average number of sulfur atoms at a distance of 3-4 Å from a selenium atom, nSeS, deviates from a linear variation with x in glasses containing <50 mol% As40Se60; n2 for these glasses also varies non-linearly with x. Importantly, a direct comparison of n2 and nSeS gives a linear correlation, suggesting that n2 may be related to the distribution of chalcogen atoms in the glasses.

Mid-infrared supercontinuum generation to 12.5µm in large NA chalcogenide step-index fibres pumped at 4.5µm.

We present numerical modeling of mid-infrared (MIR) supercontinuum generation (SCG) in dispersion-optimized chalcogenide (CHALC) step-index fibres (SIFs) with exceptionally high numerical aperture (NA) around one, pumped with mode-locked praseodymium-doped (Pr(3+)) chalcogenide fibre lasers. The 4.5um laser is assumed to have a repetition rate of 4MHz with 50ps long pulses having a peak power of 4.7kW. A thorough fibre design optimisation was conducted using measured material dispersion (As-Se/Ge-As-Se) and measured fibre loss obtained in fabricated fibre of the same materials. The loss was below 2.5dB/m in the 3.3-9.4µm region. Fibres with 8 and 10µm core diameters generated an SC out to 12.5 and 10.7µm in less than 2m of fibre when pumped with 0.75 and 1kW, respectively. Larger core fibres with 20µm core diameters for potential higher power handling generated an SC out to 10.6µm for the highest NA considered but required pumping at 4.7kW as well as up to 3m of fibre to compensate for the lower nonlinearities. The amount of power converted into the 8-10µm band was 7.5 and 8.8mW for the 8 and 10µm fibres, respectively. For the 20µm core fibres up to 46mW was converted.

Thulium pumped mid-infrared 0.9-9µm supercontinuum generation in concatenated fluoride and chalcogenide glass fibers.

We theoretically demonstrate a novel approach for generating Mid-InfraRed SuperContinuum (MIR SC) by using concatenated fluoride and chalcogenide glass fibers pumped with a standard pulsed Thulium (Tm) laser (T(FWHM)=3.5ps, P0=20kW, ν(R)=30MHz, and P(avg)=2W). The fluoride fiber SC is generated in 10m of ZBLAN spanning the 0.9-4.1µm SC at the -30dB level. The ZBLAN fiber SC is then coupled into 10cm of As2Se3 chalcogenide Microstructured Optical Fiber (MOF) designed to have a zero-dispersion wavelength (λ(ZDW)) significantly below the 4.1µm InfraRed (IR) edge of the ZBLAN fiber SC, here 3.55µm. This allows the MIR solitons in the ZBLAN fiber SC to couple into anomalous dispersion in the chalcogenide fiber and further redshift out to the fiber loss edge at around 9µm. The final 0.9-9µm SC covers over 3 octaves in the MIR with around 15mW of power converted into the 6-9µm range.

Progress in rare-earth-doped mid-infrared fiber lasers.

The progress, and current challenges, in fabricating rare-earth-doped chalcogenide-glass fibers for developing mid-infrared (IR) fiber lasers are reviewed. For the first time a coherent explanation is forwarded for the failure to date to develop a gallium-lanthanum-sulfide glass mid-IR fiber laser. For the more covalent chalcogenide glasses, the importance of optimizing the glass host and glass processing routes in order to minimize non-radiative decay and to avoid rare earth ion clustering and glass devitrification is discussed. For the first time a new idea is explored to explain an additional method of non-radiative depopulation of the excited state in the mid-IR that has not been properly recognized before: that of impurity multiphonon relaxation. Practical characterization of candidate selenide glasses is presented. Potential applications of mid-infrared fiber lasers are suggested.

Embossing of chalcogenide glasses: monomode rib optical waveguides in evaporated thin films.

Single-mode optical rib waveguides operating at telecommunication wavelengths are successfully patterned via a hot embossing technique in a thermally evaporated chalcogenide glass thin film on a chalcogenide glass substrate. Ellipsometry is used to measure the refractive index dispersion of the pressed film (As(40)Se(60)) and substrate (Ge(17)As(18)Se(65)).