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Mean Raman spectra after normalization to their mean intensity of top layer-only and sub layer-only measurements. The main peak of the top layer (light blue) was found at a wavenumber shift of 1,439.5 cm⁻¹ and the main peak of the sub layer (dark blue) was found at 732.5 cm⁻¹.
Source publication
A novel clinical Raman probe for sampling superficial tissue to improve in vivo detection of epithelial malignancies is compared to a non-superficial probe regarding depth response function and signal-to-noise ratio. Depth response measurements were performed in a phantom tissue model consisting of a polyethylene terephthalate disc in an 20%-Intral...
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Citations
... The backscattered Raman photons are first collected by the ball lens, longpass filtered to block Raman excitation light from entering the collection fiber and generating interfering Raman spectra, then passed through the incorporated polarizer before entering the collection fiber. One notes that unlike the common multi-fiber-based Raman probe incorporating a circular bandpass filter surrounded by doughnut-shaped longpass filter [13,14], both the bandpass and longpass filters utilized are square-shaped ( Fig. 1), which are easier to cut, thereby simplifying the filtering design. Besides, the polarizer incorporated into the developed Raman probe functioned as a "polarization gating" to further enhance the superficial epithelium Raman signal collection in synergy with the beveled fibers. ...
We report on the development of a two-beveled-fiber polarized (TBFP) fiber-optic Raman probe coupled with a ball lens for in vivo superficial epithelial Raman measurements in endoscopy. The two-beveled fibers positioned symmetrically along a ball lens, in synergy with paired parallel-polarized polarizers integrated between the fibers and the ball lens, maximize the Raman signal excitation and collection from the superficial epithelium where gastrointestinal (GI) precancer arises. Monte Carlo (MC) simulations and two-layer tissue phantom experiments show that the probe developed detects ∼90% of the Raman signal from the superficial epithelium. The suitability of the probe developed for rapid (<3 s) superficial epithelial Raman measurements is demonstrated on fresh swine esophagus, stomach, and colon tissues, followed by their differentiation with high accuracies (92.1% for esophagus [sensitivity: 89.3%, specificity: 93.2%], 94.1% for stomach [sensitivity: 86.2%, specificity: 97.2%], and 94.1% for colon [sensitivity: 93.2%, specificity: 94.7%]). The presented results suggest the great potential of the developed probe for enhancing in vivo superficial epithelial Raman measurements in endoscopy.
... All these components are enclosed in a stainless steel needle of diameter 2.1mm. This probe called as the non-superficial Raman probe [102]. They showed that the normalized intensity of amide I (1657cm -1 ) reduced noticeably over the course of pregnancy, which was more prominent in the last month of pregnancy. ...
... Using the same external dimensions of the above-mentioned non-superficial probe, another probe was designed with change in the optical components called as superficial Raman probe by (EmVision, USA) shown in Figure 5a (right) [102]. The size of the central incidence fiber O'Brien et al. [103] presented a visually guided optical Raman probe for the assessment of biochemical changes throughout pregnancy is shown in Figure 5b. ...
Introduction
Fiber optic probe based in-vivo spectroscopy techniques are fast and highly objective methods for intraoperative diagnoses and minimally invasive surgical interventions for all procedures where endoscopic observations are carried out for cancers of different types. The Raman spectral features provide molecular fingerprint-type information and can reveal the subjects’ pathological state in label-free manner, making endoscopy multiplexed fiber optic probe-based devices with the potential for translation from bench to bedside for routine applications.
Areas Covered
This review provides a general overview of different fiber-optic probes for in-vivo measurements with emphasis on Raman spectroscopy for biomedical application. Various aspects such as fiber-optic probe, radiation source, detector, and spectrometer for extracting optimum spectral features have also been discussed.
Expert opinion
: Optical spectroscopy-based fiber probe systems with “Chip-on-Tip” technology, combined with machine learning, can in the near future, become a complimentary diagnostic tool to magnetic resonance imaging (MRI), computed tomography (CT) scan, ultrasound, etc. Hyperspectral imaging and fluorescence-based devices are in the advanced stage of technology readiness level (TRL), and with advances in lasers and miniature spectroscopy systems, probe-based Raman devices are also coming up.
... Bergholt et al. used this high wavenumber system in combination with a foot pedal control switch and auditory feedback to the gastroenterologist during colonoscopy diagnosis [85]. Another team, Agenant et al., developed a novel Raman probe that could take measurements at the depth of 0-200 µm (average urothelium depth), the adequate level for superficial tissue sampling, in order to improve in vivo diagnosis of urothelial carcinoma [86]. This novel probe was comparted of seven collection fibers, one excitation fiber and two component front lens [86]. ...
... Another team, Agenant et al., developed a novel Raman probe that could take measurements at the depth of 0-200 µm (average urothelium depth), the adequate level for superficial tissue sampling, in order to improve in vivo diagnosis of urothelial carcinoma [86]. This novel probe was comparted of seven collection fibers, one excitation fiber and two component front lens [86]. Figure 4 shows the different geometries of fiber-optics probes used in clinical applications such as endoscopic probes without any focusing optics, confocal endoscopic probes, and fiber probes for side-viewing [87]. ...
... Bergholt et al. used this high wavenumber system in combination with a pedal control switch and auditory feedback to the gastroenterologist during colonos diagnosis [85]. Another team, Agenant et al., developed a novel Raman probe that c take measurements at the depth of 0-200 μm (average urothelium depth), the adeq level for superficial tissue sampling, in order to improve in vivo diagnosis of uroth carcinoma [86]. This novel probe was comparted of seven collection fibers, one excit fiber and two component front lens [86]. ...
Simple Summary
Cancer still constitutes one of the main global health challenges. Novel approaches towards understanding the molecular composition of the disease can be employed as adjuvant tools to current oncological applications. Raman spectroscopy has been contemplated and pursued to serve as a noninvasive, real time, in vivo tool which may uncover the molecular basis of cancer and simultaneously offer high specificity, sensitivity, and multiplexing capacity, as well as high spatial and temporal resolution. In this review, the potential impact of Spontaneous Raman spectroscopy in clinical applications related to cancer diagnosis and surgical removal is analyzed. Moreover, the coupling of Raman systems with modern instrumentation and machine learning methods has been explored as a prominent enhancement factor towards a personalized approach promoting objectivity and accuracy in surgical oncology.
Abstract
Accurate in situ diagnosis and optimal surgical removal of a malignancy constitute key elements in reducing cancer-related morbidity and mortality. In surgical oncology, the accurate discrimination between healthy and cancerous tissues is critical for the postoperative care of the patient. Conventional imaging techniques have attempted to serve as adjuvant tools for in situ biopsy and surgery guidance. However, no single imaging modality has been proven sufficient in terms of specificity, sensitivity, multiplexing capacity, spatial and temporal resolution. Moreover, most techniques are unable to provide information regarding the molecular tissue composition. In this review, we highlight the potential of Raman spectroscopy as a spectroscopic technique with high detection sensitivity and spatial resolution for distinguishing healthy from malignant margins in microscopic scale and in real time. A Raman spectrum constitutes an intrinsic “molecular finger-print” of the tissue and any biochemical alteration related to inflammatory or cancerous tissue state is reflected on its Raman spectral fingerprint. Nowadays, advanced Raman systems coupled with modern instrumentation devices and machine learning methods are entering the clinical arena as adjunct tools towards personalized and optimized efficacy in surgical oncology.
... It is important to note that the changes seen in the measured Raman spectra come from a probing volume that is approximately hemispherical in shape, with 0.5 mm diameter and ca. 1-2 mm depth (Agenant et al., 2014). This irradiated area consists of an ensemble of skin surface layer and subdermal region, interstitial fluid, capillaries filled with blood, etc., all of which contribute to the signal. ...
Non-invasive measurement methods offer great benefits in the field of medical diagnostics with molecular-specific techniques such as Raman spectroscopy which is increasingly being used for quantitative measurements of tissue biochemistry in vivo. However, some important challenges still remain for label-free optical spectroscopy to be incorporated into the clinical laboratory for routine testing. In particular, non-analyte-specific variations in tissue properties introduce significant variability of the spectra, thereby preventing reliable calibration. For measurements of blood analytes such as glucose, we propose to decrease the interference from individual tissue characteristics by exploiting the known dynamics of the blood-tissue matrix. We reason that by leveraging the natural blood pulse rhythm, the signals from the blood analytes can be enhanced while those from the static components can be effectively suppressed. Here, time-resolved measurements with subsequent pulse frequency estimation and phase-sensitive detection are proposed to recover the Raman spectra correlated with the dynamic changes at blood-pulse frequency. Pilot in vivo study results are presented to establish the benefits as well as outline the challenges of the proposed method in terms of instrumentation and signal processing.
... The clinical application space driving innovative probe designs is vast, and has recently been reviewed [1]. Broadly, these applications can be grouped into three depth ranges: superficial (10-200 µm) [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16], subsurface (200-2000 µm) [17][18][19][20][21][22], and deep (greater than 2000 µm) [23][24][25][26][27]; examples of such applications are provided in Table 1. Raman probe designs have been developed within each of these depth categories to optimize data collection for specific applications as reviewed by Stevens et al. [28]. ...
... Each of these probe designs collects a volume-averaged signal from the sample beneath the probe tip. However, with proper care to consider the application, one can achieve dramatically improved signal detection from the targeted sample depth [10,30,35,36]. Epithelial cancers and precancers (bladder [10], cervix [2,16], colon [5,12], esophagus [3], lung [8], nasophrynx [15], oral cavity [9], skin [6,7], & stomach [4]) ...
... However, with proper care to consider the application, one can achieve dramatically improved signal detection from the targeted sample depth [10,30,35,36]. Epithelial cancers and precancers (bladder [10], cervix [2,16], colon [5,12], esophagus [3], lung [8], nasophrynx [15], oral cavity [9], skin [6,7], & stomach [4]) ...
In vivo Raman spectroscopy has been utilized for the non-invasive, non-destructive assessment of tissue pathophysiology for a variety of applications largely through the use of fiber optic probes to interface with samples of interest. Fiber optic probes can be designed to optimize the collection of Raman-scattered photons from application-dependent depths, and this critical consideration should be addressed when planning a study. Herein we investigate four distinct probe geometries for sensitivity to superficial and deep signals through a Monte Carlo model that incorporates Raman scattering and fluorescence. Experimental validation using biological tissues was performed to accurately recapitulate in vivo scenarios. Testing in biological tissues agreed with modeled results and revealed that microlens designs had slightly enhanced performance at shallow depths (< 1 mm), whereas all of the beampath-modified designs yielded more signal from deep within tissue. Simulation based on fluence maps generated using ray-tracing in the absence of optical scattering had drastically different results as a function of depth for each probe compared to the biological simulation. The contrast in simulation results between the non-scattering and biological tissue phantoms underscores the importance of considering the optical properties of a given application when designing a fiber optic probe. The model presented here can be easily extended for optimization of entirely novel probe designs prior to fabrication, reducing time and cost while improving data quality.
... The probes are bundles of coaxially arranged fibers with the filter elements at the tips. These filters are cut into desired shapes, a small disk of band pass filter for the central excitation fiber and a donut-like shape long pass filter for the surrounding collection fibers [256,257]. Additionally, a two-component front lens is integrated at the distal ends of the probes to enhance overlapping the analytical volume (outer diameter < 2 mm). Diagnosis of abnormalities in coronary artery [258], brain [76,254,255], bowel [244], and cervix [75] has been demonstrated by several groups using these probes so far. ...
When light is incident to a biological tissue surface, combinations of optical processes occur, such as reflection, absorption, elastic and non-elastic scattering, and fluorescence. Analysis of these light interactions with the tissue provides insight into the metabolic and pathological state of the tissue. Furthermore, in vivo diagnosis of diseases using optical spectroscopy enables in situ rapid clinical decisions without invasive biopsies. For in vivo scenarios, incident light can be delivered in a highly localized manner to tissue via optical fibers, which are placed within the working channels of minimally invasive clinical tools, such as endoscopes. There has been extensive development in the accuracy and specificity of these optical spectroscopy techniques since the earliest in vivo examples were published in the academic literature in the early '90s, and there are now commercially available systems that have undergone medical and clinical trials. In this review, several types of optical spectroscopy techniques (elastic optical scattering spectroscopy, fluorescence spectroscopy, Raman spectroscopy, and multimodal spectroscopy) for the diagnosis and monitoring of diseases states of tissue in an in vivo setting are introduced and explored. Examples of the latest and most impactful works for each technique are then critically reviewed. Finally, current challenges and unmet clinical needs are discussed, followed by future opportunities, such as point-based spectroscopies for robot-guided surgical interventions.
... Such translation allowed the control of focal depth within the sample and thus enabled depth-sensitive measurements. In a recent publication, Agenant et al [55] reported development of a clinical superficial Raman probe based on the confocal detection with a phantom model. ...
In recent years, Raman spectroscopy has been suggested and validated as a potential tool for non-invasive and near
real-time diagnosis of various tissue abnormalities. Despite its usefulness in certain situations, a major shortcoming
of its conventional experimental configuration is that the measured Raman signal at a given point on the surface of
an interrogated tissue is volume-integrated (over the sub-surface depths) and therefore, it does not contain the desired
information of the sub-surface tissue layers having different Raman characteristics. Measurement of depth-wise Raman
signal is important because it can provide the layer-specific biochemical (and morphological) information of a given
tissue required for complete tissue analysis. A brief overview of the existing as well as a few novel methods reported
recently for measuring depth-dependent Raman signatures in layered turbid media like biological tissues is presented
in this article.
... 57 Custom-made commercial probes are also in widespread use. Agenant et al. 58 compared a nonsuperficial (or volume probe) 59 with a superficial Raman probe, both from EMVision LLC 60 (Loxahatchee, Florida) with respect to their sampling range. Both use seven collection fibers surrounding a single excitation fiber. ...
... Using a layered phantom model, they found that the optimal sampling range of the superficial probe is between 0 and 200 μm and for the nonsuperficial probe between 0 and 300 μm. 58 With this range, the superficial probe measures close to the origin of urothelial carcinomas 100 to 200 μm below the surface. It is designed to comply with the regulations of the Medical Device Directive, made of biocompatible materials, and can withstand repeated plasma (STERRAD ® ) sterilization. ...
... 115,122 Sterilization is realized mostly by either cold gas ethylene oxide or Sterrad R (Advanced Sterilization Products, Irvine, California). 58,108 To save costs, unfiltered probes have also been investigated and would make single-use probes more feasible as reprocessing can damage the probe or alter its spectral behavior. 81 For some applications, a large excitation spot is preferred as a larger laser intensity can be used while still complying with the maximum permissible exposure (MPE) guidelines. ...
Atrial fibrillation (AF) is the most common cardiac arrhythmia and has high patient morbidity. One of the root causes of AF is initiating triggers from atrial myocardium extending into the pulmonary veins. Visualizing the muscular bundles of myocardial extension is essential to guide the catheter radio-frequency ablation and confirm the curative tissue necrosis thereafter. We applied optical coherence tomography (OCT) for direct visualization of cardial muscle extension in myocardium pulmonary junction. Two perspectives (cross-sectional and en face images) are presented for imaging myocardial extensions. The results demonstrated that cross-sectional images can quickly locate the myocardium pulmonary junction. And en face images provide depth-resolved arrangement information of muscular bundles in the myocardium pulmonary junction. The results indicated that OCT could potentially be used to guide catheter radio-frequency ablation for treatment of AF.
... 57 Custom-made commercial probes are also in widespread use. Agenant et al. 58 compared a nonsuperficial (or volume probe) 59 with a superficial Raman probe, both from EMVision LLC 60 (Loxahatchee, Florida) with respect to their sampling range. Both use seven collection fibers surrounding a single excitation fiber. ...
... Using a layered phantom model, they found that the optimal sampling range of the superficial probe is between 0 and 200 μm and for the nonsuperficial probe between 0 and 300 μm. 58 With this range, the superficial probe measures close to the origin of urothelial carcinomas 100 to 200 μm below the surface. It is designed to comply with the regulations of the Medical Device Directive, made of biocompatible materials, and can withstand repeated plasma (STERRAD ® ) sterilization. ...
... 115,122 Sterilization is realized mostly by either cold gas ethylene oxide or Sterrad R (Advanced Sterilization Products, Irvine, California). 58,108 To save costs, unfiltered probes have also been investigated and would make single-use probes more feasible as reprocessing can damage the probe or alter its spectral behavior. 81 For some applications, a large excitation spot is preferred as a larger laser intensity can be used while still complying with the maximum permissible exposure (MPE) guidelines. ...
For more than two decades, Raman spectroscopy has found widespread use in biological and medical applications. The instrumentation and the statistical evaluation procedures have matured, enabling the lengthy transition from ex-vivo demonstration to in-vivo examinations. This transition goes hand-in-hand with many technological developments and tightly bound requirements for a successful implementation in a clinical environment, which are often difficult to assess for novice scientists in the field. This review outlines the required instrumentation and instrumentation parameters, designs, and developments of fiber optic probes for the in-vivo applications in a clinical setting. It aims at providing an overview of contemporary technology and clinical trials and attempts to identify future developments necessary to bring the emerging technology to the clinical end users. A comprehensive overview of in-vivo applications of fiber optic Raman probes to characterize different tissue and disease types is also given.
... 57 Custom-made commercial probes are also in widespread use. Agenant et al. 58 compared a nonsuperficial (or volume probe) 59 with a superficial Raman probe, both from EMVision LLC 60 (Loxahatchee, Florida) with respect to their sampling range. Both use seven collection fibers surrounding a single excitation fiber. ...
... Using a layered phantom model, they found that the optimal sampling range of the superficial probe is between 0 and 200 μm and for the nonsuperficial probe between 0 and 300 μm. 58 With this range, the superficial probe measures close to the origin of urothelial carcinomas 100 to 200 μm below the surface. It is designed to comply with the regulations of the Medical Device Directive, made of biocompatible materials, and can withstand repeated plasma (STERRAD ® ) sterilization. ...
... 115,122 Sterilization is realized mostly by either cold gas ethylene oxide or Sterrad R (Advanced Sterilization Products, Irvine, California). 58,108 To save costs, unfiltered probes have also been investigated and would make single-use probes more feasible as reprocessing can damage the probe or alter its spectral behavior. 81 For some applications, a large excitation spot is preferred as a larger laser intensity can be used while still complying with the maximum permissible exposure (MPE) guidelines. ...
For more than two decades, Raman spectroscopy has found widespread use in biological and medi- cal applications. The instrumentation and the statistical evaluation procedures have matured, enabling the lengthy transition from ex-vivo demonstration to in-vivo examinations. This transition goes hand-in-hand with many technological developments and tightly bound requirements for a successful implementation in a clinical environment, which are often difficult to assess for novice scientists in the field. This review outlines the required instrumentation and instrumentation parameters, designs, and developments of fiber optic probes for the in-vivo applications in a clinical setting. It aims at providing an overview of contemporary technology and clinical trials and attempts to identify future developments necessary to bring the emerging technology to the clinical end users. A comprehensive overview of in-vivo applications of fiber optic Raman probes to characterize different tissue and disease types is also given.
