Nicholas Stone

• BSc, MSc, MSc, PhD, MBA
• Professor and Deputy Pro Vice Chancellor of Faculty at University of Exeter

Prostate cancer remains the most common male cancer; however, treatment regimens remain unclear in some cases due to a lack of agreement in current testing methods. Therefore, there is an increasing need to identify novel biomarkers to better counsel patients about their treatment options. Microcalcifications offer one such avenue of exploration. M...

Introduction Ductal carcinoma in situ (DCIS) is a potential precursor to invasive breast cancer (IBC). The trajectory of an individual’s DCIS, if it will progress to IBC or remain as DCIS is difficult to predict. Currently >80% of DCIS is detected through mammographic screening of breast calcifications. Despite the close association of calcificatio...

We designed and optimized a dual-functional photothermal agent that performs as a nanoheater and real-time optical thermometer by leveraging gold nanoparticle (AuNP) self-assembly and anti-Stokes thermometry. We engineered colloidally stable fractal AuNP clusters with well-defined nanogaps to absorb strongly in the near-infrared and enhance anti-St...

During post chemotherapy surgery for ovarian cancer, it is important to ensure that any residual disease is carefully assessed and removed. The assessment remains subjective, despite clear evidence of the benefits of complete macroscopic resection. In this work, we have considered Raman spectroscopy as a possible tool for residual disease assessmen...

The year of 2024 marks the 50th anniversary of the discovery of surface-enhanced Raman spectroscopy (SERS). Over recent years, SERS has experienced rapid development and become a critical tool in biomedicine with its unparalleled sensitivity and molecular specificity. This review summarizes the advancements and challenges in SERS substrates, nanota...

X-ray diffraction is widely used to characterise the mineral component of calcified tissue. Broadening of the diffraction peaks yields valuable information on the size of coherently diffracting domains, sometimes loosely described as crystallite size or crystallinity. These domains are markedly anisotropic, hence a single number describing their si...

In this work, we demonstrate the synthesis of gold nanoraspberries (AuNRB) using a HEPES buffer at room temperature. The study aimed to identify and compare the physicochemical conditions of the AuNRB and gold nanospheres (AuNS) of similar size to a selected set of reporter molecules. The dispersion stability of shape-controlled and AuNS of similar...

Predicting long-term recurrence of disease in breast cancer (BC) patients remains a significant challenge for patients with early stage disease who are at low to intermediate risk of relapse as determined using current clinical tools. Prognostic assays which utilize bulk transcriptomics ignore the spatial context of the cellular material and are, t...

Many different types of nanoparticles have been developed for photothermal therapy (PTT), but directly comparing their efficacy as heaters and determining how they will perform when localized at depth in tissue remains complex. To choose the optimal nanoparticle for a desired hyperthermic therapy, it is vital to understand how efficiently different...

There is cumulative evidence that lipid metabolism plays a key role in the pathogenesis of various neurodegenerative disorders including Alzheimer’s disease (AD). Visualising lipid content in a non-destructive label-free manner can aid in elucidating the AD phenotypes towards a better understanding of the disease. In this study, we combined multipl...

The absorption of terahertz (THz) radiation by water molecules facilitates its application to several biomedical applications such as cancer detection. Therefore, it is critical for the THz technologies to be characterised with water content in a sample. In this paper, we analyse gelatine phantoms in the THz frequency range, with continuously varyi...

Non-invasive detection of surface enhanced Raman spectroscopy (SERS) signals from deep within tissue represents a common challenge in many biological and clinical applications including disease diagnosis and therapy monitoring. Such signals are typically weak and not readily discernible from often much larger Raman and fluorescence background signa...

To achieve multifunctional properties using nanocomposites, selectively locating nanofillers in specific areas by tailoring a mixture of two immiscible polymers has been widely investigated. Forming a phase-separated structure from entirely miscible molecules is rarely reported, and the related mechanisms to govern the formation of assemblies from...

Rationale and objectives The potential of breast microcalcification chemistry to provide clinically valuable intelligence is being increasingly studied. However, acquisition of crystallographic details has, to date, been limited to high brightness, synchrotron radiation sources. This study, for the first time, evaluates a laboratory-based system th...

Here we propose Guided PCA, a simple approach to ensure the spectrum of a key target moiety is consistly provided in a high ranking principal component.

Optimal oncological results and patient outcomes are achieved in surgery for early breast cancer with breast conserving surgery (BCS) where this is appropriate. A limitation of BCS occurs when cancer is present at, or close, to the resection margin - termed a 'positive' margin - and re-excision is recommended to reduce recurrence rate. This is occu...

Ductal carcinoma in-situ (DCIS) accounts for 20-25% of all new breast cancer diagnoses. DCIS has an uncertain risk of progression to invasive breast cancer and a lack of predictive biomarkers may result in relatively high levels (~ 75%) of overtreatment. To identify unique prognostic biomarkers of invasive progression, crystallographic and chemical...

In this work we demonstrate an advanced concept of a charge-shifting charge-coupled device (CCD) read-out combined with shifted excitation Raman difference spectroscopy (SERDS) capable of operating at up to 10 kHz acquisition rates for the effective mitigation of fast-evolving interfering backgrounds in Raman spectroscopy. This rate is 10-fold fast...

Introduction: Ductal carcinoma in situ (DCIS) is a non-obligatory precursor to invasive breast cancer (IBC). Currently there are no reliable markers to indicate if DCIS will progress IBC after an initial treatment, or if it will remain as DCIS. Because of this uncertainty, standard treatment for DCIS includes surgery with or without radiotherapy. B...

Microcalcifications play an important role in cancer detection. They are evaluated by their radiological and histological characteristics but it is challenging to find a link between their morphology, their composition and the nature of a specific type of breast lesion. Whilst there are some mammographic features that are either typically benign or...

Introduction: Microcalcifications are a common feature in mammographic detection of ductal carcinoma in situ (DCIS), and occur in >80% of cases. Known to be present as type I (calcium oxalate-CaO) and type II (carbonated calcium hydroxyapatite-CHAP) microcalcifications, their association with DCIS and their role in the progression of DCIS to invasi...

Background Oesophageal cancer (OC) accounts for 3% of all new cancer diagnosis in the UK. Presentation is often late, reflected in a poor 5-year survival rate of 12%. The importance of identifying lymph node (LN) metastases has been demonstrated as the single biggest prognostic factor. The current ‘gold standard’ diagnosis of LN metastases is from...

Information about the structure and composition of biopsy specimens can assist in disease monitoring and diagnosis. In principle, this can be acquired from Raman and infrared (IR) hyperspectral images (HSIs) that encode information about how a sample’s constituent molecules are arranged in space. Each tissue section/component is defined by a unique...

Information about the structure and composition of biopsy specimens can assist in disease monitoring and diagnosis. In principle, this can be acquired from Raman and infrared (IR) hyperspectral images (HSIs) that encode information about how a sample's constituent molecules are arranged in space. Each tissue section/component is defined by a unique...

By incorporating 1-(2-aminoethyl)piperazine (AEPIP) into a commercial epoxy blend, a bicontinuous microstructure is produced with the selective localization of amine-functionalized graphene nanoplatelets (A-GNPs). This cured blend underwent self-assembly, and the morphology and topology were observed via spectral imaging techniques. As the selectiv...

Objectives The importance of consistent terminology in describing the appearance of breast calcifications in mammography is well recognised. Imaging of calcifications using electron microscopy is a globally growing field of research. We therefore suggest that the time is ripe to develop a lexicon of terms for classifying the micromorphology of brea...

Purpose The differential diagnosis of epithelial misplacement from invasive cancer in the colon is a challenging endeavour, augmented by the introduction of bowel cancer population screening. The main aim of the work is to test, as a proof-of concept study, the ability of the infrared spectroscopic imaging approach to differentiate epithelial mispl...

Detection of solid tumours through tissue− from depths relevant to humans− has been a significant challenge for biomedical Raman spectroscopy. The combined use of surface enhanced Raman scattering (SERS) imaging agents with deep Raman spectroscopy (DRS), i.e., surface enhanced deep Raman spectroscopy (SEDRS), offer prospects for overcoming such obs...

Ductal carcinoma in situ (DCIS) is frequently associated with breast calcification. This study combines multiple analytical techniques to investigate the heterogeneity of these calcifications at the micrometre scale. X-ray diffraction, scanning electron microscopy and Raman and Fourier-transform infrared spectroscopy were used to determine the phys...

The development of new effective cancer treatment methods has attracted much attention, mainly due to the limited efficacy and considerable side effects of currently used cancer treatment methods such as radiation therapy and chemotherapy. Photothermal therapy based on the use of plasmonically resonant metallic nanoparticles has emerged as a promis...

Aim Soft tissue sarcomas (STS) are a comparatively unusual cluster of tumours; they arise from mesenchymal tissues. Surgery remains the primary and the only potentially curative treatment for most STS subtypes. Existing intraoperative margin assessment techniques are inadequate and the current gold standard for resection margin assessment of STS is...

Introduction: Ductal carcinoma in situ (DCIS) is a potential precursor of invasive breast cancer. The uncertain trajectory of DCIS, to progress to invasive disease or to remain in situ, currently drives treatment, despite lack of proven benefit. Therefore, understanding the molecular features of the DCIS trajectory may prevent overtreatment of this...

Background Improving diagnosis of ductal carcinoma in situ (DCIS) before surgery is important in choosing optimal patient management strategies. However, patients may harbor occult invasive disease not detected until definitive surgery. Purpose To assess the performance and clinical utility of mammographic radiomic features in the prediction of occ...

In this study, Monte Carlo simulations were created to investigate the distribution of Raman signals in tissue phantoms and to validate the arctk code that was used. The aim was to show our code is capable of replicating experimental results in order to use it to advise similar future studies and to predict the outcomes. The experiment performed to...

Microcalcifications are early markers of breast cancer and can provide valuable prognostic information to support clinical decision-making. Current detection of calcifications in breast tissue is based on X-ray mammography, which involves the use of ionizing radiation with potentially detrimental effects, or MRI scans, which have limited spatial re...

The interface between the intervertebral disc and the vertebral body is important to the discs' biomechanics and physiology, and is widely implicated in its pathology. This study aimed to explore biochemically and structurally the bony endplate, cartilage endplate and intervertebral disc, below the nucleus and below the annulus in healthy bovine ta...

Spatially offset Raman spectroscopy (SORS) is a technique for interrogating the subsurface composition of turbid samples noninvasively. This study generically addresses a fundamental question relevant to a wide range of SORS studies, which is how deep SORS probes for any specific spatial offset when analyzing a turbid sample or, in turn, what magni...

Large-scale intracellular signaling during developmental growth or in response to environmental alterations are largely orchestrated by chromatin within the cell nuclei. Chemical and conformational modifications of the chromatin architecture are critical steps in the regulation of differential gene expression and ultimately cell fate determination....

Spatially offset Raman spectroscopy (SORS) is a spectroscopic technique that allows for the non-invasive chemical characterization of diffusely scattering materials, ranging from opaque plastics to biological tissues. SORS has been explored for a range of applications, including disease diagnosis, the detection of explosives through unopened contai...

The first near infrared window in biological tissue (λ ∼ 700–950 nm) is of great interest for its potential to safely deliver light based diagnosis and therapeutic interventions, especially in the burgeoning field of nano-theranostics. In this context, Raman spectroscopy is increasingly being used to provide rapid non-invasive chemical molecular an...

We propose a new method for estimating the reduced scattering coefficient, μ s ′, of turbid homogeneous samples using Spatially Offset Raman Spectroscopy (SORS). The concept is based around the variation of Raman signal with SORS spatial offset that is strongly μ s ′-dependent, as such, permitting the determination of μ s ′. The evaluation is carri...

Large-scale intracellular signalling during developmental growth or in response to environmental alterations are largely orchestrated by chromatin within the cell nuclei. Chemical and conformational modifications of the chromatin architecture are critical steps in the regulation of differential gene expression and ultimately cell fate determination...

Breast Conserving Surgery (BCS) for breast cancer aims for optimal oncological results with minimal tissue excision. Positive margins due to insufficient resection results in significant numbers of patients requiring re‐excision, which could be resolved with intra‐operative margin analysis (IMA). High wavenumber (HWN) Raman Spectroscopy (RS) examin...

In this work, we report the application of Raman microspectroscopy for analysis of the refractive index of a range of tissue phantoms. Using both a custom-developed setup with visible laser source and a commercial micro-spectrometer with near infrared laser, we measured the Raman spectra of gelatin hydrogels at various concentrations. By building a...

The variable configuration of Raman spectroscopic platforms is one ofthe major obstacles in establishing Raman spectroscopy as a valuable physicochemicalmethod within real-world scenarios such as clinical diagnostics. For such real worldapplications like diagnostic classification, the models should ideally be usable to predictdata from different se...

In recent years, Raman spectroscopy has undergone major advancements in its ability to probe deeply through turbid media such as biological tissues. This progress has been facilitated by the advent of a range of specialist techniques based around spatially offset Raman spectroscopy (SORS) to enable non-invasive probing of living tissue through dept...

Many problems in mechanobiology urgently require characterization of the micromechanical properties of cells and tissues. Brillouin light scattering has been proposed as an emerging optical elastography technique to meet this need. However, the information contained in the Brillouin spectrum is still a matter of debate because of fundamental proble...

Spatially offset Raman spectroscopy (SORS) allows chemical characterisation of biological tissues at depths of up to two orders of magnitude greater than conventional Raman spectroscopy. In this study, we demonstrate the use of SORS for the non-invasive prediction of depth of an inclusion within turbid media (e.g. biological tissues) using only ext...

In this work, we report the application of Raman microspectroscopy for analysis of the refractive index of a range of tissue phantoms. Using both a custom-developed setup with visible laser source and a commercial micro-spectrometer with near infrared laser, we measured the Raman spectra of gelatin hydrogels at various concentrations. By building a...

Esophagus tissue classification models based on FT‐IR imaging data were successfully created (AUC>0.95). The conditions for translating a histopathological FT‐IR based model to a fast Quantum Cascade Laser (QCL) system microscope were investigated. Further details can be found in the article by Danuta Liberda, Michael Hermes, Paulina Koziol, Nick S...

Numerous developments in optical biomedical imaging research utilizing gold nanostructures as contrast agents have advanced beyond basic research towards demonstrating potential as diagnostic tools; some of which are translating into clinical applications. Recent advances in optics, lasers and detection instrumentation along with the extensive, yet...

Here we demonstrate conceptually the capability of deep Raman spectroscopy to monitor non-invasively changes in the water content within biological tissues. Water was added by injection into an isolated tissue volume (20 mm diameter disk of 5 mm thickness); representing a 20% increase in overall mass, which was equivalent to a 5% increase in the wa...

Nanotheranostics, which combines optical multiplexed disease detection with therapeutic monitoring in a single modality, has the potential to propel the field of nanomedicine toward genuine personalized medicine. Currently employed mainstream modalities using gold nanoparticles (AuNPs) in diagnosis and treatment are limited by a lack of specificity...

The technical progress in fast Quantum Cascade Laser (QCL) microscopy offers a platform where chemical imaging becomes feasible for clinical diagnostics. QCL systems allow the integration of previously developed FT‐IR based pathology recognition models in a faster workflow. The translation of such models requires a systematic approach, focusing onl...

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.

Biological materials presenting early signs of cancer would be beneficial for cancer screening/diagnosis. In this respect, the suitability of potentially exploiting mucus in colorectal cancer was tested using infrared spectroscopy in combination with statistical modeling. Twenty-six paraffinized colon tissue biopsy sections containing mucus regions...

Here we demonstrate the simultaneous recovery of multiplexed physical information of surface‐enhanced Raman scattering (SERS) nanoparticles (pH and depth) using deep Raman spectroscopy. As has been shown previously and in accordance with theory, inelastically scattered photons arising from spectral peaks that are suitably separated can exhibit diff...

We present a systematic characterization of the optical properties (µa and µs’) of nine representative ex vivo porcine tissues over a broadband spectrum (650-1100 nm). We applied time-resolved diffuse optical spectroscopy measurements for recovering the optical properties of porcine tissues depicting a realistic representation of the tissue heterog...

Brillouin spectroscopy, based on the inelastic scattering of light from thermally driven acoustic waves or phonons [1], holds great promise in the field of life sciences as it provides functionally relevant micromechanical information in a contactless all-optical manner [2]. Due to the complexity of biological systems such as cells and tissues, whi...

Optical theranostic applications demand near‐infrared (NIR) localized surface plasmon resonance (LSPR) and maximized electric field at nanosurfaces and nanojunctions, aiding diagnosis via Raman or optoacoustic imaging, and photothermal‐based therapies. To this end, multiple permutations and combinations of plasmonic nanostructures and molecular “gl...

Many problems in mechanobiology urgently require characterisation of the micromechanical properties of the fibrous proteins of cells and tissues. Brillouin light scattering has been proposed as a new optical elastography technique to meet this need, but the information contained in the Brillouin spectrum is still a matter of debate. Here we investi...

Microcalcifications are important diagnostic indicators of disease in breast tissue. Tissue microenvironments differ in many aspects between normal and cancerous cells, notably extracellular pH and glycolytic respiration. Hydroxyapatite microcalcification microstructure is also found to differ between tissue pathologies, including differential ion...

Raman Spectroscopy, a form of vibrational spectroscopy, has the ability to provide sensitive and specific biochemical analysis of tissue. This review article provides an in- depth analysis of the suitability of different Raman Spectroscopy techniques in providing intra-operative margin analysis in a range of solid tumour pathologies. Surgical excis...

This work presents recent developments in spatially offset (SO) and transmission Raman spectroscopy (TRS) for noninvasive detection and depth prediction of a single SERS inclusion located deep inside ex‐vivo biological tissues. The concept exploits the differential attenuation of Raman bands brought about by their different absorption due to tissue...

With the rapid development of nanotechnology during the last decades, the ability to detect and control individual objects at the nanoscale has enabled us to deal with complex biomedical challenges. In cancer imaging, novel nanoparticles (NPs) offer promising potential to identify single cancer cells and precisely label larger areas of cancer tissu...

The dynamic architecture of chromatin, the macromolecular complex comprised primarily of DNA and histones, is vital for eukaryotic cell growth. Chemical and conformational changes to chromatin are important markers of functional and developmental processes in cells. However, chromatin architecture regulation has not yet been fully elucidated. There...

There is much interest in using nano-sensors to monitor biologically relevant species such as glucose, or cellular pH, as these often become dysregulated in diseases such as cancer. This information is often inaccessible at depth in biological tissue, due to the highly scattering nature of tissue. Here we show that gold nanoparticles labelled with...

We propose a novel approach for the prediction of the depth of a single buried object within a turbid medium combining Spatially Offset Raman Spectroscopy (SORS) and Transmission Raman Spectroscopy (TRS) and relying on differential attenuation of individual Raman bands brought about by the spectral variation of matrix absorption (and scattering). T...

In this work we demonstrate, to the best of our knowledge, a novel wide field-of-view upconversion system, supporting upconversion of monochromatic mid-infrared (mid-IR) images, e.g., for hyperspectral imaging (HSI). An optical parametric oscillator delivering 20 ps pulses tunable in the 2.3–4 μm range acts as a monochromatic mid-IR illumination so...

Background: Liquid biopsies offer a promising alternative to tissue samples, providing non-invasive diagnostic approaches or serial monitoring of disease evolution. However, certain challenges remain, and the full potential of liquid biopsies has yet to be reached. Here we report several methodological approaches to interrogate liquid biopsies usin...

Background: Microcalcifications resulting from calcium deposition in the mammary gland play a central role in the early detection of breast cancer [1]. However, the relationship between their occurrence in the breast and cancer progression remains poorly understood. Our approach is to use vibrational spectroscopy and imaging, which is non-invasive,...

Here we demonstrate light mediated heating of nanoparticles confined deep inside mammalian tissue, whilst directly monitoring their temperature non-invasively using a form of deep Raman spectroscopy, T-SESORS.

Light scattering limits the penetration depth of non-invasive Raman spectroscopy in biological media. While safe levels of irradiation may be adequate to analyze superficial tissue, scattering of the pump beam reduces the Raman signal to undetectable levels deeper within the tissue. Here we demonstrate how wavefront shaping techniques can significa...