Alan Stockdale

First-in-human pilot study of a spatial frequency domain oxygenation imaging system.

Oxygenation measurements are widely used in patient care. However, most clinically available instruments currently consist of contact probes that only provide global monitoring of the patient (e.g., pulse oximetry probes) or local monitoring of small areas (e.g., spectroscopy-based probes). Visualization of oxygenation over large areas of tissue, without a priori knowledge of the location of defects, has the potential to improve patient management in many surgical and critical care applications. In this study, we present a clinically compatible multispectral spatial frequency domain imaging (SFDI) system optimized for surgical oxygenation imaging. This system was used to image tissue oxygenation over a large area (16×12 cm) and was validated during preclinical studies by comparing results obtained with an FDA-approved clinical oxygenation probe. Skin flap, bowel, and liver vascular occlusion experiments were performed on Yorkshire pigs and demonstrated that over the course of the experiment, relative changes in oxygen saturation measured using SFDI had an accuracy within 10% of those made using the FDA-approved device. Finally, the new SFDI system was translated to the clinic in a first-in-human pilot study that imaged skin flap oxygenation during reconstructive breast surgery. Overall, this study lays the foundation for clinical translation of endogenous contrast imaging using SFDI.

The FLARE intraoperative near-infrared fluorescence imaging system: a first-in-human clinical trial in perforator flap breast reconstruction.

Background: The ability to determine flap perfusion in reconstructive surgery is still primarily based on clinical examination. In this study, the authors demonstrate the use of an intraoperative, near-infrared fluorescence imaging system for evaluation of perforator location and flap perfusion. Methods: Indocyanine green was injected intravenously in six breast cancer patients undergoing a deep inferior epigastric perforator flap breast reconstruction after mastectomy. Three dose levels of indocyanine green were assessed using the fluorescence-assisted resection and exploration (FLARE) imaging system. This system uses light-emitting diodes for fluorescence excitation, which is different from current commercially available systems. In this pilot study, the operating surgeons were blinded to the imaging results. Results: Use of the FLARE system was successful in all six study subjects, with no complications or sequelae. Among the three dose levels, 4 mg per injection resulted in the highest observed contrast-to-background ratio, signal-to-background ratio, and signal-to-noise ratio. However, because of small sample size, the authors did not have sufficient power to detect statistical significance for these pairwise comparisons at the multiple-comparison adjusted type I error of 0.017. Six milligrams per injection provided a similar contrast-to-background ratio but also a higher residual background signal. Conclusion: Based on this pilot study, the authors conclude that near-infrared assessment of perforator flap breast reconstruction is feasible with a light-emitting diode–based system, and that a dose of 4 mg of indocyanine green per injection yields the best observed contrast-to-background ratio compared with a dose of 2 or 6 mg for assessment of flap perfusion.

Real-Time Simultaneous Near-Infrared Fluorescence Imaging of Bile Duct and Arterial Anatomy

BACKGROUND We hypothesized that two independent wavelengths of near-infrared (NIR) fluorescent light could be used to identify bile ducts and hepatic arteries simultaneously, and intraoperatively. MATERIALS AND METHODS Three different combinations of 700 and 800 nm fluorescent contrast agents specific for bile ducts and arteries were injected into N = 10 35-kg female Yorkshire pigs intravenously. Combination 1 (C-1) was methylene blue (MB) for arterial imaging and indocyanine green (ICG) for bile duct imaging. Combination 2 (C-2) was ICG for arterial imaging and MB for bile duct imaging. Combination 3 (C-3) was a newly developed, zwitterionic NIR fluorophore ZW800-1 for arterial imaging and MB for bile duct imaging. Open and minimally invasive surgeries were imaged using the fluorescence-assisted resection and exploration (FLARE) surgical imaging system and minimally invasive FLARE (m-FLARE) imaging systems, respectively. RESULTS Although the desired bile duct and arterial anatomy could be imaged with contrast-to-background ratios (CBRs) ≥ 6 using all three combinations, each one differed significantly in terms of repetition and prolonged imaging. ICG injection resulted in high CBR of the liver and common bile duct (CBD) and prolonged imaging time (120 min) of the CBD (C-1). However, because ICG also resulted in high background of liver and CBD relative to arteries, ICG produced a lower arterial CBR (C-2) at some time points. C-3 provided the best overall performance, although C-2, which is clinically available, did enable effective laparoscopy. CONCLUSIONS We demonstrate that dual-channel NIR fluorescence imaging provides simultaneous, real-time, and high resolution identification of bile ducts and hepatic arteries during biliary tract surgery.

Near-Infrared Fluorescence Imaging of Thoracic Duct Anatomy and Function in Open Surgery and Video-Assisted Thoracic Surgery

OBJECTIVE Chylothorax resulting from thoracic duct damage is often difficult to identify and repair. We hypothesized that near-infrared fluorescent light could provide sensitive, real-time, high-resolution intraoperative imaging of thoracic duct anatomy and function. METHODS In 16 rats, 4 potential near-infrared fluorescent lymphatic tracers were compared in terms of signal strength and imaging time: indocyanine green, the carboxylic acid of IRDye 800CW (LI-COR, Lincoln, Neb), indocyanine green adsorbed to human serum albumin, and IRDye 800CW conjugated covalently to human serum albumin. Optimal agent was validated in 8 pigs approaching human size (n = 6 by open surgery with FLARE imaging system [Beth Israel Deaconess Medical Center, Boston, Mass] and n = 2 by video-assisted thoracoscopic surgery minimally invasive [m-FLARE] imaging system [Beth Israel Deaconess Medical Center]). Lymphatic tracer injection site, dose, and timing were optimized. RESULTS For signal strength, sustained imaging time, and clinical translatability, the best lymphatic tracer was indocyanine green, which is already Food and Drug Administration approved for other indications. In pigs, a simple subcutaneous injection of indocyanine green into lower leg (≥ 36 μg/kg), provided thoracic duct imaging with onset of about 5 minutes after injection, sustained imaging for at least 60 minutes after injection, and signal-to-background ratio of at least 2. With this technology, normal thoracic duct flow, collateral flow, injury models, and repair models could all be observed under direct visualization. CONCLUSIONS Near-infrared fluorescent light could provide sensitive, sustained, real-time imaging of thoracic duct anatomy and function during both open and video-assisted thoracoscopic surgery in animal models.

A novel pilot study using spatial frequency domain imaging to assess oxygenation of perforator flaps during reconstructive breast surgery

IntroductionAlthough various methods exist for monitoring flaps during reconstructive surgery, surgeons primarily rely on assessment of clinical judgment. Early detection of vascular complications improves rate of flap salvage. Spatial frequency domain imaging (SFDI) is a promising new technology that provides oxygenation images over a large field of view. The goal of this clinical pilot study is to use SFDI in perforator flap breast reconstruction. MethodsThree women undergoing unilateral breast reconstruction after mastectomy were enrolled for our study. The SFDI system was deployed in the operating room, and images acquired over the course of the operation. Time points included images of each hemiabdominal skin flap before elevation, the selected flap after perforator dissection, and after microsurgical transfer. ResultsSpatial frequency domain imaging was able to measure tissue oxyhemoglobin concentration (ctO2Hb), tissue deoxyhemoglobin concentration, and tissue oxygen saturation (stO2). Images were created for each metric to monitor flap status and the results quantified throughout the various time points of the procedure. For 2 of 3 patients, the chosen flap had a higher ctO2Hb and stO2. For 1 patient, the chosen flap had lower ctO2Hb and stO2. There were no perfusion deficits observed based on SFDI and clinical follow-up. ConclusionsThe results of our initial human pilot study suggest that SFDI has the potential to provide intraoperative oxygenation images in real-time during surgery. With the use of this technology, surgeons can obtain tissue oxygenation and hemoglobin concentration maps to assist in intraoperative planning; this can potentially prevent complications and improve clinical outcome.

Real-time endoscopic guidance using near-infrared fluorescent light for thoracic surgery

Lung cancer is the leading cause of cancer death in the United States, accounting for 28% of all cancer deaths. Standard of care for potentially curable lung cancer involves preoperative radiographic or invasive staging, followed by surgical resection. With recent adjuvant chemotherapy and radiation studies showing a survival advantage in nodepositive patients, it is crucial to accurately stage these patients surgically in order to identify those who may benefit. However, lymphadenectomy in lung cancer is currently performed without guidance, mainly due to the lack of tools permitting real-time, intraoperative identification of lymph nodes. In this study we report the design and validation of a novel, clinically compatible near-infrared (NIR) fluorescence thoracoscope for real-time intraoperative guidance during lymphadenectomy. A novel, NIR-compatible, clinical rigid endoscope has been designed and fabricated, and coupled to a custom source and a dual channel camera to provide simultaneous color and NIR fluorescence information to the surgeon. The device has been successfully used in conjunction with a safe, FDA-approved fluorescent tracer to detect and resect mediastinal lymph nodes during thoracic surgery on Yorkshire pigs. Taken together, this study lays the foundation for the clinical translation of endoscopic NIR fluorescence intraoperative guidance and has the potential to profoundly impact the management of lung cancer patients.

Preclinical and clinical validation of a novel oxygenation imaging system

Introduction: Two major disadvantages of currently available oxygenation probes are the need for contact with the skin and long measurement stabilization times. A novel oxygenation imaging device based on spatial frequency domain and spectral principles has been designed, validated preclinically on pigs, and validated clinically on humans. Importantly, this imaging system has been designed to operate under the rigorous conditions of an operating room. Materials and Methods: Optical properties reconstruction and wavelength selection have been optimized to allow fast and reliable oxyhemoglobin and deoxyhemoglobin imaging under realistic conditions. In vivo preclinical validation against commercially available contact oxygenation probes was performed on pigs undergoing arterial and venous occlusions. Finally, the device was used clinically to image skin flap oxygenation during a pilot study on women undergoing breast reconstruction after mastectomy. Results: A novel illumination head containing a spatial light modulator (SLM) and a novel fiber-coupled high power light source were constructed. Preclinical experiments showed similar values between local probes and the oxygenation imaging system, with measurement times of the new system being < 500 msec. During pilot clinical studies, the imaging system was able to provide near real-time oxyHb, deoxyHb, and saturation measurements over large fields of view (> 300 cm2). Conclusion: A novel optical-based oxygenation imaging system has the potential to replace contact probes during human surgery and to provide quantitative, wide-field measurements in near real-time.

A dual oxygenation and fluorescence imaging platform for reconstructive surgery

There is a pressing clinical need to provide image guidance during surgery. Currently, assessment of tissue that needs to be resected or avoided is performed subjectively, leading to a large number of failures, patient morbidity, and increased healthcare costs. Because near-infrared (NIR) optical imaging is safe, noncontact, inexpensive, and can provide relatively deep information (several mm), it offers unparalleled capabilities for providing image guidance during surgery. These capabilities are well illustrated through the clinical translation of fluorescence imaging during oncologic surgery. In this work, we introduce a novel imaging platform that combines two complementary NIR optical modalities: oxygenation imaging and fluorescence imaging. We validated this platform during facial reconstructive surgery on large animals approaching the size of humans. We demonstrate that NIR fluorescence imaging provides identification of perforator arteries, assesses arterial perfusion, and can detect thrombosis, while oxygenation imaging permits the passive monitoring of tissue vital status, as well as the detection and origin of vascular compromise simultaneously. Together, the two methods provide a comprehensive approach to identifying problems and intervening in real time during surgery before irreparable damage occurs. Taken together, this novel platform provides fully integrated and clinically friendly endogenous and exogenous NIR optical imaging for improved image-guided intervention during surgery.