2017 TECHNICAL SUMMARIES

[Pages:578]CONNECTING MINDS. ADVANCING LIGHT.

2017 TECHNICAL SUMMARIES

BIOS

The Moscone Center San Francisco, California, USA Conferences + Courses 28 January?2 February 2017 Photonics West Exhibition 31 January?2 February 2017 BIOS Expo 28?29 January 2017

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The Moscone Center San Francisco, California, USA

DATES Conferences & Courses 28 January?2 February 2017

EXHIBITIONS BIOS EXPO: 28?29 JANUARY 2017 Photonics West Exhibition: 31 January?2 February 2017

SYMPOSIUM CHAIRS: James Fujimoto Massachusetts Institute of Technology (USA)

R. Rox Anderson, M.D. Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard School of Medicine (USA)

Contents

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Photonics in Dermatology and Plastic Surgery. . . . . . . . . . . . . . . . 3 Therapeutics and Diagnostics in Urology. . . . . . . . . . . . . . . . . . . . . 14 Optical Imaging, Therapeutics, and Advanced Technology in Head and Neck Surgery and Otolaryngology. . . . . . . . . . . . . . 23 Endoscopic Microscopy XII. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Optical Techniques in Pulmonary Medicine IV. . . . . . . . . . . . . . . . 40 Diagnostic and Therapeutic Applications of Light in Cardiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 Diagnosis and Treatment of Diseases in the Breast and Reproductive System III . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Lasers in Dentistry XXIII . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Ophthalmic Technologies XXVII. . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 Visualizing and Quantifying Drug Distribution in Tissue. . . . . . . 90 Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XXVI. . 95 Mechanisms of Photobiomodulation Therapy XII. . . . . . . . . . . . 107 Molecular-Guided Surgery: Molecules, Devices, and Applications III. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 Clinical and Translational Neurophotonics. . . . . . . . . . . . . . . . . . 126 Neural Imaging and Sensing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 Optogenetics and Optical Manipulation. . . . . . . . . . . . . . . . . . . . . 151 Optical Coherence Tomography and Coherence Domain Optical Methods in Biomedicine XXI. . . . . . . . . . . . . . . . . . . . . . . 158 Advanced Biomedical and Clinical Diagnostic and Surgical Guidance Systems XV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190 Optics and Biophotonics in Low-Resource Settings III. . . . . . . 203 Design and Quality for Biomedical Technologies X. . . . . . . . . . . 212 Multimodal Biomedical Imaging XII. . . . . . . . . . . . . . . . . . . . . . . . 223 Optical Fibers and Sensors for Medical Diagnostics and Treatment Applications XVII . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 Optical Tomography and Spectroscopy of Tissue XII . . . . . . . . 240

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Optical Biopsy XV: Toward Real-Time Spectroscopic Imaging and Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261 Microfluidics, BioMEMS, and Medical Microsystems XV . . . . . . 275 Optical Interactions with Tissue and Cells XXVIII. . . . . . . . . . . . 287 Dynamics and Fluctuations in Biomedical Photonics XIV. . . . . 301 Photons Plus Ultrasound: Imaging and Sensing 2017 . . . . . . . . 316 Biophotonics and Immune Responses XII. . . . . . . . . . . . . . . . . . . 369 Energy-based Treatment of Tissue and Assessment IX. . . . . . . 379 Optical Elastography and Tissue Biomechanics IV. . . . . . . . . . . 388 Imaging, Manipulation, and Analysis of Biomolecules, Cells, and Tissues XV. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401 Multiphoton Microscopy in the Biomedical Sciences XVII. . . . 421 Three-Dimensional and Multidimensional Microscopy: Image Acquisition and Processing XXIV. . . . . . . . . . . . . . . . . . . . 446 Single Molecule Spectroscopy and Superresolution Imaging X. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 460 Optical Diagnostics and Sensing XVII: Toward Point-of-Care Diagnostics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470 Adaptive Optics and Wavefront Control for Biological Systems III. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482 Quantitative Phase Imaging III . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495 Biophysics, Biology and Biophotonics II: the Crossroads. . . . . . 511 High-Speed Biomedical Imaging and Spectroscopy II: Toward Big Data Instrumentation and Management . . . . . . . . . 518 Nanoscale Imaging, Sensing, and Actuation for Biomedical Applications XIV. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531 Colloidal Nanoparticles for Biomedical Applications XII. . . . . 543 Reporters, Markers, Dyes, Nanoparticles, and Molecular Probes forBiomedical Applications IX. . . . . . . . . . . . . . . . . . . . . . 555 Plasmonics in Biology and Medicine XIV . . . . . . . . . . . . . . . . . . . 565 Frontiers in Biological Detection: From Nanosensors to Systems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 572

SPIE is the international society for optics and photonics, an educational not-for-profit organization founded in 1955 to advance light-based science and technology. The Society serves nearly 264,000 constituents from approximately 166 countries, offering conferences and their published proceedings, continuing education, books, journals, and the SPIE Digital Library in support of interdisciplinary information exchange, professional networking, and patent precedent. SPIE provided more than $5.2 million in support of education and outreach programs in 2015.

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Conference 10037: Photonics in Dermatology and Plastic Surgery

Saturday - Sunday 28?29 January 2017

Part of Proceedings of SPIE Vol. 10037 Photonics in Dermatology and Plastic Surgery

10037-1, Session 1

Handheld spatial frequency domain spectrographic imager for depth-sensitive, quantitative spectroscopy of skin tissue

Rolf B. Saager, An N. Dang, Anthony J. Durkin, Beckman Laser Institute and Medical Clinic, Univ. of California, Irvine (United States)

Spatial Frequency Domain Spectroscopy (SFDS) is an optical technique that quantitatively characterizes structured tissue composition in depth; a critical need for both non-invasive Melanoma screening and staging. The development of this technique and associated depth sensitive models, however, have been based off of a benchtop, point-spectroscopy system that is cumbersome to use and transport, thereby limiting its translation to investigations involving clinical populations. To that end, a handheld, line imaging implementation of SFDS has been fabricated.

We present the design of this portable system that not only enables SFDS to be used in clinical settings, but also generates images of tissue in depth. This instrument features a modified commercial micro-projector to deliver custom, broadband illumination patterns on to tissue and a custom, compact line imaging spectrometer to collect diffusely reflected visible and near infrared light at ~1nm spectral resolution and ~50 micron spatial resolution at the surface of tissue. The system performance was validated through phantom studies, using the original SFDS point-spectroscopy system as reference. Initial in-vivo results from pigmented lesions acquired under IRB approved protocols are also provided to illustrate the potential for this model-based, depth segmentation imaging modality.

10037-2, Session 1

Spectral biopsy for skin cancer diagnosis: initial clinical results

Austin Moy, Xu Feng, Hieu Nguyen, Yao Zhang, The Univ. of Texas at Austin (United States); Kate Sebastian, Seton Healthcare Family (United States); Jason Reichenberg, Dell Medical School, The Univ. of Texas at Austin (United States); James W. Tunnell, The Univ. of Texas at Austin (United States)

Skin cancer is the most common form of cancer in the United States and is a recognized public health issue. Diagnosis of skin cancer involves biopsy of the suspicious lesion followed by histopathology. Biopsies, which involve excision of the lesion, are invasive, at times unnecessary, and are costly procedures (~$2.8B/year in the US). An unmet critical need exists to develop a non-invasive and inexpensive screening method that can eliminate the need for unnecessary biopsies. To address this need, our group has reported on the continued development of a noninvasive method that utilizes multimodal spectroscopy towards the goal of a "spectral biopsy" of skin. Our approach combines Raman spectroscopy, fluorescence spectroscopy, and diffuse reflectance spectroscopy to collect comprehensive optical property information from suspicious skin lesions. We previously described an updated spectral biopsy system that allows acquisition of all three forms of spectroscopy through a single fiber optic probe and is composed of off-the-shelf OEM components that are smaller, cheaper, and enable a more clinic-friendly system. We present initial patient data acquired with the spectral biopsy system, the first from an extensive clinical study (n = 250) to characterize its performance in identifying skin cancers (basal cell carcinoma, squamous cell carcinoma, and melanoma). We also present our first attempts at analyzing this initial set of clinical data using statisticalbased models, and with models currently being developed to extract biophysical information from the collected spectra, all towards the goal of noninvasive skin cancer diagnosis.

10037-3, Session 1

Intraoperative imaging of nonmelanoma skin cancers using polarization-enhanced reflectance and fluorescence technique

Anna N. Yaroslavsky, Xin Feng, Univ. of Massachusetts Lowell (United States); Victor A. Neel, Massachusetts General Hospital (United States)

Nonmelanoma skin cancer (NMSC) is the most common human cancer. It is often curable by surgery. Therefore, there is a strong need for accurate removal of these neoplasms, to ensure higher cure rate combined with maximum tissue preservation. Polarization-enhanced reflectance and fluorescence imaging (PERFI) has been reported as a new bedside method that uses fluorescent chromophores to image NMSC ex vivo. This study extends the use of PERFI to in-vivo intraoperative imaging of NMSC.

In this pilot study subjects were recruited from patients with biopsyconfirmed nonmelanoma skin cancer, scheduled to be treated by Mohs micrographic surgery. Sterile methylene blue (MB) was diluted to 0.2 mg/ cc in anaesthetic solution and infused by deep dermal infiltration into the peritumoral space. After in vivo reflectance and fluorescence imaging, Mohs surgery was performed. After the first stage of Mohs, the surgical wound was re-imaged. Each excised piece of skin was imaged ex vivo. Then the excised lesion was processed for routine histopathology. Optical images were processed and compared with histopathology. Eight cases were imaged. In all subjects, the contrast agent, MB, was preferentially retained in the tumor. The injection of MB was well tolerated. We observed a transient blue staining of the treated area, which disappeared completely within 1 week in all of the patients. The ex vivo images correlated well with histopathology. In vivo images qualitatively delineated the tumor margins. Based on these results we concluded that the developed technique may provide an efficient rapid intraoperative optical tool for demarcating NMSC during surgery.

10037-4, Session 1

Skin mircorelief as a diagnostic tool

Lioudmila Tchvialeva, Jamie Phillips, Haishan Zeng, BC Cancer Research Ctr. (Canada); David McLean, Harvey Lui, The Univ. of British Columbia (Canada); Tim K. Lee, BC Cancer Research Ctr. (Canada)

Skin surface roughness is an important property for differentiating skin diseases. Recently, roughness has also been identified as a potential diagnostic indicator in the early detection of skin cancer. Objective quantification is usually carried out by creating silicone replicas of the skin and then measuring the replicas. We have developed an alternative in-vivo technique to measure skin roughness based on laser speckle. Laser speckle is the interference pattern produced when coherent light is used to illuminate a rough surface and the backscattered light is imaged. Acquiring speckle contrast measurements from skin phantoms with controllable roughness, we created a calibration curve by linearly interpolating between measured points. This calibration curve accounts for internal scattering and is designed to evaluate skin microrelief whose root-mean-square roughness is in the range of 10-60 micrometers. To validate the effectiveness of our technique, we conducted a study to measure 243 skin lesions including actinic keratosis (8), basal cell carcinoma (24), malignant melanoma (31), nevus (73), squamous cell carcinoma (19), and seborrheic keratosis (79). The average roughness values ranged from 26 to 57 micrometers. Malignant melanoma was ranked as the smoothest and squamous cell carcinoma as the roughest lesion. An ANOVA test confirmed that malignant melanoma has significantly smaller roughness than other lesion types. Our results suggest that skin microrelief can be used to detect malignant melanoma from other skin conditions.

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Conference 10037: Photonics in Dermatology and Plastic Surgery

10037-5, Session 1

Physiological basis for noninvasive skin cancer diagnosis using diffuse reflectance spectroscopy

Yao Zhang, James W. Tunnell, The Univ. of Texas at Austin (United States); Mia K. Markey, The Univ. of Texas at Austin (United States) and The Univ. of Texas MD Anderson Cancer Ctr. (United States)

Diffuse reflectance spectroscopy offers a noninvasive, fast, and lowcost alternative to visual screening and biopsy for skin cancer diagnosis. We have previously acquired reflectance spectra from 137 lesions in 76 patients and determined the capability of spectral diagnosis using principal component analysis (PCA). However, it is not well elucidated why spectral analysis enables tissue classifications. To provide the physiological basis, we used the Monte Carlo look-up table (MCLUT) model to extract physiological parameters from those clinical data. The MCLUT model results in the following physiological parameters: oxygen saturation, hemoglobin concentration, melanin concentration, vessel radius, and scattering parameters. Based on these physiological parameters, logistic regression classifiers were created, and classification results were compared with histopathology of the lesions. Using numerical cut-offs for these physiological parameters, we achieved higher sensitivity and specificity for most of classifications compared to our previous PCA results. The best classification is basal cell carcinomas versus normal skin with a sensitivity and specificity of 100% and 84%, respectively. Physiological parameters show that cancerous skin tissue has significantly lower oxygen saturation, higher hemoglobin concentration, lower scattering, and larger vessel radius, compared to normal tissue. These results demonstrate the potential of diffuse reflectance spectroscopy for detection of early precancerous changes in tissue. In addition, a diagnostic algorithm that combines these physiological parameters holds promise for a non-invasive diagnosis of skin cancer. Our model provides insight to cancer physiology by extracting physiological parameters that pathologists are familiar with.

10037-39, Session 1

Quantification of changes in skin hydration and sebum after tape stripping using Infrared spectroscopy

Anna A. Ezerskaia, Philips Research (Netherlands) and Technische Univ. Delft (Netherlands); Silvania F. Pereira, H. Paul Urbach, Technische Univ. Delft (Netherlands); Babu Varghese, Philips Research (Netherlands)

The stratum corneum is the outermost layer of the epidermis and it plays the role of the barrier to water loss. Stratum corneum is composed of the corneocytes and an intercellular lipid bilayer matrix. The hydration and sebum retaining ability of the skin is primarily related to the stratum corneum [1]. Optimal balance between skin lipids and water is reported as essential indicator of skin integrity and functionality, whereas disrupted balance is found in different dermatological disorders such as psoriasis, atopic eczema, edema, rosacea [2]. Tape stripping of human stratum corneum has been used in skin physiology research for example to measure skin barrier function, to quantify the penetration of drugs and to evaluate different skin disorders [3].

Many biophysical methods have been reported for measuring skin hydration and sebum levels independently. However, no non-contact devices and methods have been reported for the quantitative spatial mapping of these components simultaneously. Recently we demonstrated the feasibility of a non-invasive short wave infrared spectroscopic technique for simultaneous measurement of oiliness and hydration levels of the skin [4]. The method is based on differential detection in the spectral region around 1720 nm between the optimal wavelengths corresponding to the lipid vibrational bands that lay "in between" the prominent water absorption bands.

The aim of this study is to quantify the depth resolved changes in skin hydration and sebum levels after tape stripping using the infrared spectroscopic set-up and compare the results with conventional devices such as Corneometer and Sebumeter. We demonstrate that differential detection in the spectral range around 1720 nm allows accurate and sensitive depth profiling of stratum corneum sebum and hydration levels. We anticipate that short wave infrared spectroscopic technique combined with tape stripping can provide much more-quantitative and more reliable skin barrier function information in contrast to conventionally employed biophysical methods.

10037-6, Session 2

Wavenumber selection based analysis in Raman spectroscopy improves skin cancer diagnostic specificity at high sensitivity levels

Jianhua Zhao, The Univ. of British Columbia (Canada) and BC Cancer Research Ctr. (Canada); Haishan Zeng, BC Cancer Research Ctr. (Canada) and The Univ. of Biritish Columbia (Canada); Sunil Kalia, Harvey Lui, The Univ. of British Columbia (Canada)

Background: Raman spectroscopy is a non-invasive optical technique which can measure molecular vibrational modes within tissue. A largescale clinical study (n = 518) has demonstrated that real-time Raman spectroscopy could distinguish malignant from benign skin lesions with good diagnostic accuracy; this was validated by a follow-up independent study (n = 127). Objective: Most of the previous diagnostic algorithms have typically been based on analyzing the full band of the Raman spectra, either in the fingerprint or high wavenumber regions. Our objective in this presentation is to explore wavenumber selection based analysis in Raman spectroscopy for skin cancer diagnosis. Methods: A wavenumber selection algorithm was implemented using variably-sized wavenumber windows, which were determined by the correlation coefficient between wavenumbers. Wavenumber windows were chosen based on accumulated frequency from leave-one-out cross-validated stepwise regression or least and shrinkage selection operator (LASSO). The diagnostic algorithms were then generated from the selected wavenumber windows using multivariate statistical analyses, including principal component and general discriminant analysis (PC-GDA) and partial least squares (PLS). A total cohort of 645 confirmed lesions from 573 patients encompassing skin cancers, precancers and benign skin lesions were included. Lesion measurements were divided into training cohort (n = 518) and testing cohort (n = 127) according to the measurement time. Result: The area under the receiver operating characteristic curve (ROC) improved from 0.861?0.891 to 0.891?0.911 and the diagnostic specificity for sensitivity levels of 0.99-0.90 increased respectively from 0.17?0.65 to 0.20?0.75 by selecting specific wavenumber windows for analysis. Conclusion: Wavenumber selection based analysis in Raman spectroscopy improves skin cancer diagnostic specificity at high sensitivity levels.

10037-7, Session 2

Melanoma and basal cell carcinoma control with Raman and fluorescence spectroscopy in visible and NIR regions

Ivan A. Bratchenko, Dmitry N. Artemyev, Oleg O. Myakinin, Yulia A. Hristophorova, Samara Univ. (Russian Federation); Alexander A. Moryatov, Sergey V. Kozlov, Samara State Medical Univ. (Russian Federation); Valery P. Zakharov, Samara Univ. (Russian Federation)

One of the most dangerous forms of cancer is malignant melanoma as

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Conference 10037: Photonics in Dermatology and Plastic Surgery

melanomas cause more than 76% of skin cancer deaths. Russia cancer mortality rates are nearly twice as high as in the UK or the USA. In this regard it is necessary to find a new instrumental ways of early cancer detection. The aim of this study was to develop a rapid, highly sensitive method of tumor analysis involving the combination of RS and AF techniques in visible and NIR regions.

All experimental studies were approved by the ethical committee of Samara State Medical University. AF was stimulated in visible and NIR regions by two lasers 457nm and 785 nm, while Raman signal was acquired only in NIR region. More than 100 skin tissue samples containing melanoma and basal cell carcinoma were tested. All spectra were registered for neoplasms and surrounding normal tissues. Shape of AF and Raman spectra is caused by porphyrins, keratins, flavins, melanin and lipids. For tissue type determination six criteria were used. These criterions uses intensity of Raman bands in 1340, 1450 and 1650 cm-1, AF spectral local maxima positions and intensity, and AF curvature in NIR region.

For melanoma and basal cell carcinoma separation every criterion demonstrates accuracy from 58 to 83%. Combined applying of these criteria allows for skin cancer detection with more than 96% accuracy. These results demonstrate high potential of the proposed method, as analysis of Raman and AF spectra is simple and may be used in mass screening applications.

10037-9, Session 3

Skin cancer margin analysis within minutes with FFOCT

Eug?nie Dalimier, LLTech SAS (France); Lauren Ogrich, Diego Morales, Carrie Ann Cusack, Mark Abdelmalek, Drexel Univ. College of Medicine (United States); Claude Boccara, LLTech SAS (France); John Durkin, Drexel Univ. College of Medicine (United States)

Non-melanoma skin cancer (NMSC) is the most common cancer. Treatment consists of surgical removal of the skin cancer. Traditional excision involves the removal of the visible skin cancer with a significant margin of normal skin. On cosmetically sensitive areas, Mohs micrographic tissue is the standard of care. Mohs uses intraoperative microscopic margin assessment which minimizes the surgical defect and can help reduce the recurrence rate by a factor of 3. The current Mohs technique relies on frozen section tissue slide preparation which significantly lengthens operative time and requires on-site trained histotechnicians. Full-Field Optical Coherence Tomography (FFOCT) is a novel optical imaging technique which provides a quick and efficient method to visualize cancerous areas in minutes, without any preparation or destruction of the tissue. This study aimed to evaluate the potential of FFOCT for the analysis of skin cancer margins during Mohs surgery.

Over 150 images of Mohs specimens were acquired intraoperatively with FFOCT before frozen section analysis. The imaging procedure took less than 5 minutes for each specimen. No artifacts on histological preparation were found arising from FFOCT manipulation; however frozen section artifact was readily seen on FFOCT. An atlas was established with FFOCT images and corresponding histological slides to reveal FFOCT reading criteria of normal and cancerous structures. Blind analysis showed high concordance between FFOCT and histology.

FFOCT can potentially reduce recurrence rates while maintaining short surgery times, optimize clinical workflow, and decrease healthcare costs. For the patient, this translates into smaller infection risk, decreased stress, and better comfort.

10037-10, Session 3

Peri-operative imaging of cancer margins with reflectance confocal microscopy during Mohs micrographic surgery: feasibility of a videomosaicing algorithm

Eileen S. Flores, Oriol Yelamos, Miguel A. Cordova, Kivanc Kose, William Phillips, Anthony Rossi, Kishwer Nehal, Milind Rajadhyaksha, Memorial Sloan-Kettering Cancer Ctr. (United States)

Reflectance confocal microscopy (RCM) imaging shows promise for guiding surgical treatment of skin cancers. Recent technological advancements such as the introduction of the handheld version of the reflectance confocal microscope, video acquisition and video-mosaicking have improved RCM as an emerging tool to evaluate cancer margins during routine surgical skin procedures such as Mohs micrographic surgery (MMS). Detection of residual non-melanoma skin cancer (NMSC) tumor during MMS is feasible, as demonstrated by the introduction of real-time perioperative imaging on patients in the surgical setting. Our study is currently testing the feasibility of a new mosaicking algorithm for peri-operative RCM imaging of NMSC cancer margins on patients during MMS.

We report progress toward imaging and image analysis on sixty patients, who presented for MMS at the MSKCC Dermatology service. The first 10 patients were used as a training set to establish an RCM imaging algorithm, which is being implemented on the remaining test set of 50 patients. RCM imaging, using 35% AlCl3 for nuclear contrast, was performed pre- and intra-operatively with the Vivascope 3000 (Caliber ID). Imaging was performed in quadrants in the wound, to simulate the Mohs surgeon's examination of pathology. Videos were taken at the epidermal and deep dermal margins. Our Mohs surgeons assessed all videos and video-mosaics for quality and correlation to histology.

Overall, our RCM video-mosaicking algorithm is feasible. RCM videos and video-mosaics of the epidermal and dermal margins were found to be of clinically acceptable quality. Assessment of cancer margins was affected by type of NMSC, size and location. Among the test set of 50 patients, 10 cases have been analyzed thus far and these show acceptable imaging quality, resolution and contrast. Visualization of nuclear and cellular morphology of residual BCC tumor and normal skin features could be detected in the peripheral and deep dermal margins. We observed correlation between the RCM videos/video-mosaics and the corresponding histology for presence of tumor in all 10 lesions. Further analyses of the remaining 40 cases are in progress.

Peri-operative RCM imaging shows promise for improved and faster detection of cancer margins and guiding MMS in the surgical setting.

10037-11, Session 3

Deep learning based classification of morphological patterns in reflectance confocal microscopy to guide noninvasive diagnosis of melanocytic lesions

Kivanc Kose, Memorial Sloan-Kettering Cancer Ctr. (United States); Alican Bozkurt, Northeastern Univ. (United States); Setareh Ariafar, Memorial Sloan-Kettering Cancer Ctr. (United States); Christi A. Alessi-Fox, Caliber Imaging & Diagnostics, Inc. (United States); Melissa Gill, SkinMedical Research and Diagnostics, P.L.L.C. (United States); Jennifer G. Dy, Dana H. Brooks, Northeastern Univ. (United States); Milind Rajadhyaksha, Memorial Sloan-Kettering Cancer Ctr. (United States)

In this study we present a deep learning based classification algorithm

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Conference 10037: Photonics in Dermatology and Plastic Surgery

for discriminating morphological patterns that appear in RCM mosaics of melanocytic lesions collected at the dermal epidermal junction (DEJ). These patterns are classified into 6 distinct types in the literature: background, meshwork, ring, clod, mixed, and aspecific. Clinicians typically identify these morphological patterns by examination of their textural appearance at 10X magnification. To mimic this process we divided mosaics into smaller regions, which we call tiles, and classify each tile in a deep learning framework. We used previously acquired DEJ mosaics of lesions deemed clinically suspicious, from 20 different patients, which were then labelled according to those 6 types by 2 expert users. We tried three different approaches for classification, all starting with a publicly available convolutional neural network (CNN) trained on natural image, consisting of a series of convolutional layers followed by a series of fully connected layers: (1) We fine-tuned this network using training data from the dataset. (2) Instead, we added an additional fully connected layer before the output layer network and then re-trained only last two layers, (3) We used only the CNN convolutional layers as a feature extractor, encoded the features using a bag of words model, and trained a support vector machine (SVM) classifier. Sensitivity and specificity were generally comparable across the three methods, and in the same ranges as our previous work using SURF features with SVM . Approach (3) was less computationally intensive to train but more sensitive to unbalanced representation of the 6 classes in the training data. However we expect CNN performance to improve as we add more training data because both the features and the classifier are learned jointly from the data.

*First two authors share first authorship.

10037-12, Session 3

Video-mosaicking of in vivo reflectance confocal microscopy images for noninvasive examination of skin lesions

Kivanc Kose, Memorial Sloan-Kettering Cancer Ctr. (United States); Mengran Gou, Northeastern Univ. (United States); Oriol Yelamos, Miguel A. Cordova, Anthony Rossi, Kishwer S. Nehal, Memorial Sloan-Kettering Cancer Ctr. (United States); Octavia I. Camps, Jennifer G. Dy, Dana H. Brooks, Northeastern Univ. (United States); Milind Rajadhyaksha, Memorial Sloan-Kettering Cancer Ctr. (United States)

In this report we describe a computer vision based pipeline to convert in-vivo reflectance confocal microscopy (RCM) videos collected with a handheld system into large field of view (FOV) mosaics. For many applications such as imaging of hard to access lesions, intraoperative assessment of MOHS margins, or delineation of lesion margins beyond clinical borders, raster scan based mosaicing techniques have clinically significant limitations. In such cases, clinicians often capture RCM videos by freely moving a handheld microscope over the area of interest, but the resulting videos lose large-scale spatial relationships. Videomosaicking is a standard computational imaging technique to register, and stitch together consecutive frames of videos into large FOV high resolution mosaics. However, mosaicing RCM videos collected in-vivo has unique challenges: (i) tissue may deform or warp due to physical contact with the microscope objective lens, (ii) discontinuities or "jumps" between consecutive images and motion blur artifacts may occur, due to manual operation of the microscope, and (iii) optical sectioning and resolution may vary between consecutive images due to scattering and aberrations induced by changes in imaging depth and tissue morphology. We addressed these challenges by adapting or developing new algorithmic methods for videomosaicking, specifically by modeling non-rigid deformations, followed by automatically detecting discontinuities (cut locations) and, finally, applying a datadriven image stitching approach that fully preserves resolution and tissue morphologic detail without imposing arbitrary pre-defined boundaries. We will present example mosaics obtained by clinical imaging of both melanoma and non-melanoma skin cancers. The ability to combine freehand mosaicing for handheld microscopes with preserved cellular resolution will have high impact application in diverse clinical settings, including lowresource healthcare systems.

10037-13, Session 4

In vivo multiphoton microscopy of the eyelid skin

Ana Batista, Univ. des Saarlandes (Germany) and Jenlab GmbH (Germany); Hans Georg Breunig, Jenlab GmbH (Germany); Aisada Uchugonova, Karsten K?nig, Univ. des Saarlandes (Germany) and JenLab GmbH (Germany)

Multiphoton microscopy (MPM) has become an important imaging method for non-invasive and high-resolution imaging of the skin. Due to the nonlinear excitation three dimensional information is intrinsically provided. In combination with fluorescence lifetime imaging microscopy, it is possible to obtain both structural and metabolic data.

Human in vivo measurements are usually limited to easy accessible regions. However, often specific body part such as the eyelid are of interest for the cosmetic industry. By using the multiphoton certified clinical imaging tomograph MPTflex this limitation can be overcome. It's articulated mirrorarm and scanning head enables the measurement of otherwise difficult access areas.

We were able to characterize the epidermal and dermal layers of the eyelid skin of human volunteers in vivo using the endogenous autofluorescence intensity, lifetime, and second-harmonic generation signals. Skin properties such epidermal and epidermal-dermal junction thicknesses were also assessed. The influence of eye cosmetic products on the skin was investigated.

10037-14, Session 4

In vivo multiphoton-microscopy of laserinduced optical breakdown in human skin

Mihaela Balu, Griffin Lentsch, Beckman Laser Institute and Medical Clinic, Univ. of California, Irvine (United States); Dorota Korta M.D., Univ. of California, Irvine (United States); Karsten Konig, Univ. des Saarlandes (Germany) and JenLab GmbH (Germany); Kristen M. Kelly, Univ. of California, Irvine (United States); Bruce J. Tromberg, Beckman Laser Institute and Medical Clinic, Univ. of California, Irvine (United States); Christopher B. Zachary M.D., Univ. of California, Irvine (United States)

We use a multiphoton microscopy (MPM)-based clinical microscope (MPTflex, JenLab, Germany) to describe changes in human skin following treatment with a fractional non-ablative laser (PicoWay, Candela).

The treatment was based on a fractionated picosecond Nd:YAG laser (1064 and 532nm, 3mJ and 1.5mJ (no attenuation), respectively maximum energy/ pulse, 100 microbeams/6mmx6mm). Improvements in skin appearance resulting from treatment with this laser have been noted but optimizing the efficacy depends on a thorough understanding of the specific skin response to treatment.

MPM is a nonlinear laser scanning microscopy technique that features subcellular resolution and label-free molecular contrast. MPM contrast in skin is derived from second-harmonic generation of collagen and two-photon excited fluorescence of NADH/FAD+, elastin, keratin, melanin.

In this pilot study, two areas on the arm of a volunteer (skin type II) were treated with the picoWay laser (1064nm, 3mJ; 532nm, 1.5mJ; 1pass). The skin response to treatment was imaged in-vivo at 8 time points over the following 4 weeks. MPM revealed micro-injuries present in epidermis. Damaged individual cells were distinguished after 3h and 24h from treatment with both wavelengths. Pigmented cells were particularly damaged in the process, suggesting that melanin is the main absorber and the primary target for laser induced optical breakdown. At later time points, clusters of cellular necrotic debris were imaged across the treated epidermis. These results represent the groundwork for future longitudinal

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Conference 10037: Photonics in Dermatology and Plastic Surgery

studies on expanded number of subjects to understand the response to treatment in different skin types at different laser parameters, critical factors in optimizing treatment outcomes.

10037-15, Session 4

3D imaging of hematoxylin and eosin stained thick tissues with a sub-femtoliter resolution by using Cr:forsterite-laserbased nonlinear microscopy

Chien-Ting Kao, Institute of Biomedical Electronics and Bioinformatics, National Taiwan Univ. (Taiwan); Ming-Liang Wei, Molecular Imaging Ctr. National Taiwan Univ. (Taiwan); Yi-Hua Liao M.D., National Taiwan Univ. Hospital (Taiwan); Chi-Kuang Sun, Institute of Photonics and Optoelectronics, National Taiwan Univ. (Taiwan) and Molecular Imaging Ctr., National Taiwan Univ. (Taiwan)

Intraoperative assessment of excision tissues during cancer surgery is clinically important. The assessment is used to be guided by the examination for residual tumor with frozen pathology, while it is time consuming for preparation and is with low accuracy for diagnosis. Recently, reflection confocal microscopy (RCM) and nonlinear microscopy (NLM) were demonstrated to be promising methods for surgical border assessment. Intraoperative RCM imaging may enable detection of residual tumor directly on skin cancers patients during Mohs surgery. The assessment of benign and malignant breast pathologies in fresh surgical specimens was demonstrated by NLM. Without using hematoxylin and eosin (H&E) that are common dyes for histopathological diagnosis, RCM was proposed to image in vivo by using aluminum chloride for nuclear contrast on surgical wounds directly, while NLM was proposed to detect two photon fluorescence nuclear contrast from acrdine orange staining. In this paper, we propose and demonstrate 3D imaging of H&E stained thick tissues with a subfemtoliter resolution by using Cr:forsterite-laser-based NLM. With a 1260 nm femtosecond Cr:forsterite laser as the excitation source, the hematoxylin will strongly enhance the third-harmonic generation (THG) signals, while eosin will illuminate strong fluorescence under three photon absorption. Compared with previous works, the 1260 nm excitation light provide high penetration and low photodamage to the exercised tissues so that the possibility to perform other follow-up examination will be preserved. The THG and three-photon process provides high nonlinearity so that the super resolution in 3D is now possible. The staining and the contrast of the imaging is also fully compatible with the current clinical standard on frozen pathology thus facilitate the rapid intraoperative assessment of excision tissues. This work is sponsored by National Health Research Institutes and supported by National Taiwan University Hospital.

10037-16, Session 5

In vivo characterization of structural and optical properties of human skin by combined photothermal radiometry and diffuse reflectance spectroscopy

Nina Verdel, Jo?ef Stefan Institute (Slovenia); Ana Marin, Faculty of Mathematics and Physics, Univ. of Ljubljana (Slovenia); Luka Vidovi?, Jo?ef Stefan Institute (Slovenia); Matija Milani?, Jo?ef Stefan Institute (Slovenia) and Faculty of Mathematics and Physics, Univ. of Ljubljana (Slovenia); Boris Majaron, Jo?ef Stefan Institute (Slovenia)

We have recently demonstrated the potential of pulsed photothermal radiometry (PPTR) for in vivo characterization of laser interaction with human skin in several relevant scenarios, both in research and clinical

settings. Most of these applications involved reconstruction of the laserinduced temperature depth profiles by solving the inverse problem of heat diffusion and infrared emission form the skin surface.

Quantitative assessment of the structural properties and presence of specific chromophores (e.g., melanin, hemoglobin) at the irradiated site, however, requires solving an additional inverse problem, namely that of light transport inside the skin. This process hinges on several assumptions, such as the scattering properties of the involved tissues. While the latter are listed in literature, they are also lkely to vary with anatomical location, person's age, gender, lifestyle (smoking), etc., which inevitably introduces systematic errors to the assessed values.

In an attempt to resolve this issue, we complement the PPTR measurements with another non-invasive technique, diffuse reflectance spectroscopy (DRS) in the visible spectral range. Both data sets are analyzed using numerical models of optical and thermal transport in multi-layered tissue structures, coupled with multidimensional optimization algorithms (i.e., inverse Monte Carlo). This avoids the limited validity of the diffuse approximation solutions near the irradiated skin surface and enables us to account for the finite diameter of the sample opening on the integrating sphere used for DRS measurements.

We find that combining the two techniques considerably improves the accuracy and robustness of structural and spectroscopic characterization of human skin at the selected test site.

10037-18, Session 5

Quantitative assessment of graded burn wounds using a commercial and research grade laser speckle imaging (LSI) system

Adrien Ponticorvo, Rebecca A. Rowland, Bruce Yang, Ben Lertsakdadet, Christian Crouzet, Beckman Laser Institute and Medical Clinic, Univ. of California, Irvine (United States); Nicole Bernal, Univ. of California, Irvine (United States); Bernard Choi, Anthony J. Durkin, Beckman Laser Institute and Medical Clinic, Univ. of California, Irvine (United States)

Burn wounds are often characterized by injury depth which then dictates wound management strategy. While most superficial burns and full thickness burns can be diagnosed through visual inspection, clinicians have difficulty accurately diagnosing burns that fall between these extremes. Accurately diagnosing burn severity in a timely manner is critical for starting appropriate treatment plans at the earliest time points to improve patient outcomes. To address this challenge, research groups have studied the use of commercial laser Doppler imaging (LDI) systems to objectively characterize burn-wound severity. Despite initial promising findings, LDI systems are not commonplace in part due to the limited utility of LDI during the initial 48 hours after burn injury. Such a delay decreases the efficacy of LDI and inevitably contributes to an increased length of stay for burn patients. Furthermore, commercial LDI systems are being phased out in favor of laser speckle imaging (LSI) systems that can provide similar information with faster acquisition speeds. Here we studied the performance of a commercial LSI system (Pericam PSI, Perimed AB) in a controlled environment using intralipid (1%) flowing through a tissue-simulating phantom, and also in a controlled burn study in which wounds of graded severity were created on a Yorkshire pig. The burn wounds were monitored for five days and burn depths verified using histological analysis. In addition to the commercial LSI system, a research grade LSI system was used to compare quantitatively the performance of both systems and also better understand the "Perfusion Unit" output of commercial systems.

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Conference 10037: Photonics in Dermatology and Plastic Surgery

10037-19, Session 5

Findings toward the miniaturization of a laser speckle contrast device for skin roughness measurements

Daniel C. Louie, Univ. of British Columbia (Canada); Lioudmilla Tchvialeva, Univ. of British Columba (Canada); Haishan Zeng, Univ. of British Columbia (Canada) and British Columbia Cancer Agency (Canada); Tim K. Lee, Univ. of British Columba (Canada) and British Columbia Cancer Agency (Canada)

Skin roughness is an important parameter in the characterization of skin and skin lesions, particularly for the purposes of skin cancer detection. Our group had previously constructed a laser speckle contrast device that is able to detect the roughness in microrelief of the skin. This paper reports on findings made for the further miniaturization of our existing portablysized device. These findings include the feasibility of adopting a laser diode without temperature control, and the use of a single CCD camera for detection. The coherence length of a laser is a crucial criterion for speckle measurements as it must be within a specific range. The coherence length of a commercial grade 405 nm laser diode was found to be of an appropriate length. Also, after a short warm-up period the coherence length of the laser was found to remain relatively stable, even without temperature control. Although the laser's temperature change during operation may affect its power output and the shape of its spectrum, these are only minor factors in speckle contrast measurements. Our second finding is the construction of a calibration curve to relate speckle measurements to roughness using only parallel polarization from one CCD camera. This was created using experimental data from metal roughness standards, and validated using measurements on skin phantoms and in-vivo skin. These improvements are important steps forward in the ongoing development of the laser speckle contrast device, especially towards a clinical device to measure skin roughness and evaluate skin lesions.

10037-20, Session 6

Optical microscopy of targeted drug delivery and local distribution in skin of a topical minocycline: implications in translational research and guidance for therapeutic dose selection

Maiko Hermsmeier, Tanvee Sawant, Diana Lac, Akira Yamamoto, Xin Chen, Susan Y. Huang, Usha Nagavarapu, BioPharmX, Inc. (United States); Conor L. Evans, Wellman Ctr. for Photomedicine (United States); Kin Foong Chan, AnnaMarie Daniels, BioPharmX, Inc. (United States)

Acne vulgaris is a chronic inflammatory skin condition commonly resulting in negative aesthetic and social impacts on those affected. Minocycline, currently available as an oral antibiotic for moderate to severe acne, has a known minimum inhibitory concentration (MIC) for the acne-causing bacterium Propionibacterium acnes (P. acnes) in vitro, with its anti-inflammatory properties also eliciting inhibitory effects on pro-inflammatory molecules. A novel topical gel composition containing solubilized minocycline (BPX-01) has been developed to directly deliver the drug to the skin. Because minocycline is a known fluorophore, fluorescence microscopy and concurrent quantitative measurements were performed on excised human facial skin dosed with different concentrations, in order to determine the spatial distribution of the drug and quantification of its local concentration in the epidermis and the pilosebaceous unit where P. acnes generally reside. Local minocycline delivery confirmed achievement of an adequate therapeutic dose to support clinical studies. Subsequently, a 4-week double-blind, randomized, vehicle controlled clinical study was

performed to assess the safety and efficacy of 1% minocycline BPX-01 applied daily. No instances of cutaneous toxicity were reported, and a greater than 1 log reduction of P. acnes count was observed at week 4 with statistical significance from baseline and vehicle control. In addition, no detectable amounts of minocycline in the plasma were reported, suggesting the potential of this new formulation to diminish the known systemic adverse effects associated with oral minocycline. Follow-on clinical plans are underway to further establish the safety of BPX-01 and to evaluate its efficacy against inflammatory acne lesions in a 225 patient multi-center dose-finding study.

10037-21, Session 6

Light emitting fabric for photodynamic treatment of actinic keratosis

Elise Thecua, INSERM (France); Claire Vicentini, INSERM (France) and Ctr. Hospitalier Regional Univ. de Lille (France); ANNE-SOPHIE VIGNION, FABIENNE LECOMTE, PASCAL DELEPORTE, U1189 - ONCO-THAI - Image Assisted Laser Therapy for Oncology (France); Laurent Mortier, Ctr. Hospitalier Regional Univ. de Lille (France) and INSERM (France); Rolf-Markus Szeimies, Knappschaftskrankenhaus Recklinghausen (Germany); Serge R. Mordon, INSERM (France)

Induced by sun damages, actinic keratosis (AK) are usually present on the scalp, shoulders or arms of the patients and thus are easily reachable by light, making photodynamic therapy (PDT) one of the first line treatments. The planar shape of current light sources used for PDT does not permit to deliver a homogeneous light on lesions located on curved parts of the human body, and may leads to under-treatment of some of these lesions. Moreover, PDT is known to be very painful, and may force the patient to ask for premature end of the treatment.

To address these issues, a new device based on light emitting fabrics (LEF) was developed. The integration of optical fibers into flexible textile structures, by using knitting or weaving processes was the first step of our work.

The predetermined macro-bending of optical fibers, led to a homogeneous side emission of light over the entire surface of the fabric. Tests showed that additional curvatures when applying the LEF on non-planar surfaces had no impact on light delivery and proved that LEF can adapt to the human morphology.

The ability of the LEF, coupled with a 635nm LASER source, to deliver a homogeneous light to lesions is currently assessed in two clinical trials for the treatment of AK of the scalp by PDT. The low irradiance and progressive activation of the photosensitizer ensured a significant pain reduction (0,3 ? 0,6 /10), compared to discomfort levels experienced by patients during a conventional PDT session (4,8 ? 1,3 /10).

10037-22, Session 6

Measuring temperature induced phase change kinetics in subcutaneous fatty tissues using near infrared spectroscopy (NIRS), magnetic resonance spectroscopy and optical coherence tomography

Amir Y. Sajjadi, Stefan A. Carp, Dieter Manstein, Massachusetts General Hospital (United States)

Monitoring phase transition in adipose tissue and formation of lipid crystals is important in Cryo-procedures such as cryosurgery or Selective Cryolipolysis (SC). In this work, we exploited a Near-Infrared Spectroscopy (NIRS) method to monitor the onset of fat freezing/melting. Concurrent

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