BACKGROUND: UC Irvine’s Chao Family Comprehensive Cancer Center (CFCCC) is one of only 41 NCI-Designated Comprehensive Cancer Centers in the United States and specific to Orange County. The CFCCC’s collaborative advanced imaging translational research efforts with the Beckman Laser Institute and Medical Clinic (BLIMC) are also unique to UC Irvine. More importantly, for patients living in Orange County and surrounding districts, access to state-of-the art and developing imaging technologies in addition to optimized and advanced skin cancer treatment are exclusively available at UC Irvine. We have developed a Skin Disease Oriented Team (S-DOT), which is focused on aspects for skin cancer treatment ranging from prevention to screening and early detection to advanced cancer therapy.
PROPOSAL: The Skin Disease Oriented Team (S-DOT) is a multidisciplinary group comprised of UC Irvine affiliated investigators from the disciplines of dermatology, pathology, oncology, surgery, engineering, optics, public health, epidemiology, and biostatistics. The S-DOT engages investigators who have an interest in translational science, comparative effectiveness research, optical imaging, and drug discovery for the detection and treatment of skin cancer. A multidisciplinary team will meet quarterly with the objective of identifying scientific collaborative and grant writing opportunities. Importantly, the S-DOT will encompass the Schools of Medicine, Biological Sciences, Physical Sciences, and Engineering. The S-DOT will carry out basic clinical and translational research co-coordinated by the CFCCC and under the auspices of the CFCCC, the Laser and Medical Microbeam Program (LAMMP) at the Beckman Laser Institute and Medical Clinic (BLIMC) and the Department of Dermatology.
Spatial Frequency Domain Imaging (SFDI) (Durkin, Tromberg)
Spatial Frequency Domain Imaging (SFDI) is a non-contact and scan free optical imaging technology that can be used to quantify tissue structure and function. A structured illumination scheme is coupled with spatial frequency domain light transport models to generate maps of tissue absorption and reduced scattering parameters over a depth averaged volume (0-5 mm) below the tissue surface. There are currently three kinds of SFDI systems:
1. Research grade system: Absorption maps can be recovered at multiple wavelengths to extract tissue constituents such as oxy-hemoglobin, deoxy-hemoglobin, tissue oxygen saturation, melanin, water content, and lipid fraction. Reduced scattering maps are used to characterize optical path length as well as cellular size and density. The system is a research grade system and has a scalable field of view (1mm - 10cm) as well as broad spectral tunability in the 650-1000 nm range . It is applicable for preclinical [6-8] and clinical investigations [9, 10] although the range of motion of the instrument is limited, making access to some anatomic locations difficult. Data acquisition times range from 1-30 seconds depending on the application and the number of wavelengths and spatial frequencies employed. Motion artifacts and complicated surface topology are challenges in clinical settings but have been addressed.
2. LED based Clinical system: This system, based on 4 wavelength LEDs, is designed to image a fixed field of view (13.5 cm x 10.5 cm) with limited spectral capability. Absorption maps can be recovered to extract tissue constituents such as oxy-hemoglobin, deoxy-hemoglobin, tissue oxygen saturation. Imaging times range from 1-10 seconds depending on the application. Motion artifacts and complicated surface topology are challenges in clinical settings but have been addressed. The system is lightweight (12lbs) and housed in a compact enclosure that is mounted on an articulating arm attached to a cart. The system is less than ideal for animal models given the large field of view.
3. Spatially Modulated Quantitative Spectroscopy: This is the least mature of the spatial frequency domain approaches and in fact does not provide a traditional image, but instead is used to perform quantitative spectroscopy on a single “pixel” (2mm x 2mm) of tissue. This technique does span the range from 450 – 1000 nm, which engenders an improved ability to separate melanin concentration from oxy and deoxy-hemoglobin concentration. It is also capable of measuring water fraction and lipid concentration although to date our studies on normal skin have failed to pick up lipid signal. This system can be used for either small animal or in-vivo human studies.
Laser Speckle Imaging (LSI) (Choi lab) LSI enables noninvasive, wide-field imaging (several square centimeters, can be changed somewhat depending on the requirements of the application) of the degree of motion of moving objects. We typically use LSI to characterize blood-flow dynamics in biological tissues. The technology is similar to the more-common laser Doppler perfusion imaging (LDPI); in fact, investigations by other groups have shown the equivalence of LSI and LDPI assessments of blood-flow changes. The primary advantages of LSI over LDPI are its considerably higher spatial and temporal resolution, lower cost, and simplicity (only a laser, camera, and PC are required). The method is easily integrated with other camera-based imaging modalities, such as fluorescence and diffuse reflectance imaging and can be used for both small animal imaging  and in-vivo human studies.
Optical Coherence Tomography (OCT) (Chen Lab) Optical Coherence Tomography (OCT) is a non-invasive, non-contact imaging modality that is an optical analog to ultrasound. It can be used to obtain micrometer-scale, cross-sectional imaging of biological tissue. The high spatial resolution of the OCT structural in-vivo image provides immediate and localized tissue structure information. Functional OCT (F-OCT), is an extension of OCT for functional imaging of tissue microcirculation and birefringence [16-18]. Doppler OCT, for example, can map 3-D microvasculature of skin tissue down to capillary level . Fourier domain (FD) F-OCT system is available for collaborative projects that can be used to image tissue morphology and blood vessels simultaneously.
Multiphoton Microscopy based Imaging/Spectroscopy. There are three multiphoton microscopy systems at BLI that can be used to investigate changes in skin. In general, they are all sensitive to (a) cellular metabolism (NADH/FAD) and elastin fibers as intrinsic sources of two-photon excited fluorescence (TPEF) signals, (b) fluorescent dyes conjugated to molecular probes as extrinsic sources of TPEF and (c) collagen fibers, astroglial helical filaments, myosin and microtubules as intrinsic sources of second-harmonic generated light (SHG). The third system (MDM) is sensitive to items (a) – (c) as well as water and lipids.
1) Zeiss LSM510 for multiphoton microscopy (MPM) and spectroscopy (Balu, Krasieva)
The Zeiss laser scanning microscopy (LSM) system relies on the simultaneous detection of the TPEF SHG signals from biological tissues. The benefits of this system include hyperspectral imaging capability, the broad range tunability of the excitation and emission and the user-friendly interface. It has a flexible extension arm for in vivo imaging of animal models or human subjects, but is not portable and imaging must be done in the microscopy lab.
2) MPTflex for in-vivo multiphoton microscopy (MPM) (Balu, Krasieva)
MPTflex (JenLab, Germany) is a clinical multiphoton tomography system that simultaneously detects TPEF and SHG signals. It is portable and equipped with an articulating arm allowing MPM images to be acquired from almost any region of the skin. This is a novel instrument that is the only one of its kind in the US. It is currently used in clinical studies for imaging melanocytic nevi and pigmented lesions suspected of melanoma  in order to determine the sensitivity and specificity of MPM for early diagnosis of this disease. The microscopy platform has a relatively large footprint. It can be used in the lab environment or the BLI Advanced Technology Suite (ATS).
3) Multi-dimensional microscopy (MDM) system (Balu, Krasieva, Potma)
The laser scanning multi-dimensional microscopy (MDM) system is capable of simultaneously recording coherent anti-Stokes Raman scattering (CARS), TPEF and SHG microscopy images. The main advantages of this system include the multi-modality feature (CARS is sensitive to water and lipids) and the photon-counting detection method, resulting in high detection sensitivity. It is also equipped with a home-built extension arm for in-vivo optical imaging experiments involving animal models and human subjects. The microscopy platform has a relatively large footprint and it is not portable. It can be used in the lab environment only.
Custom Light Source for Photodynamic Therapy (PDT) (Kelly)
A Photodynamic Therapy Laser system with the following components has been purchased as part of an NIH Shared Instrumentation Grant (SIG) and will be housed at the Beckman Laser Institute. The system has a modular design. The modularity will allow separating different wavelengths for different anatomic locations. This laser system will be the most comprehensive system for PDT available in the United States. It will allow us to investigate and provide PDT for a wide range of basic science and clinical/translational research protocols. All wavelengths are continuous. Three Modules have been purchased and defined below:
633 nm +/- 3 nm at 3 watts
652 nm +/- 3 nm at 4 watts
819 nm +/- 5 nm at 4 watts
664 nm +/- 3 nm at 2 watts
670 nm +/- 3 nm at 2 watts
577 nm +/- 3 nm at 3 watts
All ports are standard SMA connectors. The following light delivery units were purchased:
4 Colorectal probes
5 Cylindrical Diffusers 10 mm; 400 micron and 600 micron fibers
5 Cylindrical diffusers 20 mm; 400 micron and 600 micron fibers
5 Cylindrical diffusers 30 mm; 400 micron and 600 micron fibers
Frontal Light Distributor
Microlens Diffuser for Dermatology
Associate Professor, Department of Surgery, Beckman Laser Institute & Medical Clinic.
Dr. Durkin’s research program focuses on development and application of quantitative, in-vivo optical spectroscopy and imaging techniques that can be used to non-invasively access functional and structural information in superficial tissue volumes. The emphasis of his research is on the development of quantitative near infrared spectroscopy and Spatial Frequency Domain (SFD) imaging (also referred to as Modulated Imaging: MI) and application of these approaches to clinically compelling problems.
DR. KRISTEN M. KELLY, CO-LEADER
Associate Professor & Clinical Vice Chief, Department of Dermatology, School of Medicine.
Dr. Kelly’s research focuses include the following:
Clinical translation of novel light based imaging and therapeutic methods; Photodynamic therapy of cutaneous lesions; treatment of cutaneous vascular lesions including port wine stains and hemangiomas; and cutaneous angiogenesis. She has over 15 years of experience in bringing technologies developed in the labs of the Beckman Laser Institute and UC Irvine to patients. Dr. Kelly is board certified in dermatology and a fellow of the American Academy of Dermatology.
DR. KENNETH G.
Associate Professor, Department of Dermatology, School of Medicine
Dr. Linden is co-director and melanoma expert with UC Irvine Healthcare’s Melanoma Center at the Chao Family Comprehensive Cancer Center. Dr. Linden also practices general and surgical dermatology at Gottschalk Medical Plaza on the UC Irvine campus. He is a diplomat of the American Board of Dermatology and a fellow of the American Academy of Dermatology. Dr Linden is the Pigmented Lesion Program Co-Director, along with Dr. Janellen Smith.