Publications by authors named "Yoshitomo Ashitate"

35 Publications

Resection of mediastinal goiter extending to the carina with use of artificial pneumothorax, two-lung ventilation, and thoracoscopy, with the patient in a prone position.

Gen Thorac Cardiovasc Surg 2019 Jun 24;67(6):561-565. Epub 2018 Aug 24.

Department of Surgery, Tonan Hospital, Kita-4 Nishi-7, Chuo-ku, Sapporo, Hokkaido, 060-0004, Japan.

A 67-year-old woman was presented with a mediastinal tumor extending from the left lobe of the thyroid and passing through the posterior trachea, causing displacement of the esophagus to the left side of the patient and then descending into the right side of the mediastinum to below the carina. Surgery was performed under two-lung ventilation with the patient in a prone position; general anesthesia was performed with a single-lumen tube combined with artificial pneumothorax. In thoracoscopic surgery, we were able to confirm and preserve anatomical structures. After detachment of the tumor at the level of the left and right subclavian arteries, the patient was placed supine, a cervical incision was added, and the tumor was extracted. The tumor was diagnosed as a nonmalignant mediastinal goiter (MG). No such surgical report was found in the literature, and one would be useful for this new approach to MG removal.
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http://dx.doi.org/10.1007/s11748-018-0998-7DOI Listing
June 2019

Endocrine-specific NIR fluorophores for adrenal gland targeting.

Chem Commun (Camb) 2016 Aug;52(67):10305-8

Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA and Gordon Center for Medical Imaging, Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

The adrenal glands (AGs) are relatively small yet require definitive identification during their resection, or more commonly their avoidance. To enable image-guided surgery involving the AGs, we have developed novel near-infrared (NIR) fluorophores that target the AGs after a single intravenous injection, which provided dual-NIR image-guided resection or avoidance of the AGs during both open and minimally-invasive surgery.
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http://dx.doi.org/10.1039/c6cc03845jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4982771PMC
August 2016

Intraoperative Hemifacial Composite Flap Perfusion Assessment Using Spatial Frequency Domain Imaging: A Pilot Study in Preparation for Facial Transplantation.

Ann Plast Surg 2016 Feb;76(2):249-55

From the *Division of Plastic and Reconstructive Surgery, Department of Surgery, †Division of Hematology and Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; ‡Division of Cancer Diagnostics and Therapeutics, Hokkaido University Graduate School of Medicine, Sapporo, Japan; §Department of Biomedical Engineering, Boston University; ∥Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston; and ¶Curadel, LLC, Worcester, MA.

Background: Vascularized composite allotransplantation represents an important advancement in the field of reconstructive microsurgery and has continued to increase in popularity. The significant clinical morbidity associated with flap failure represents an important barrier to even more widespread use of these techniques. Early identification of vascular compromise has been associated with a higher salvage rate, yet most surgeons rely only on clinical assessment intraoperatively. Spatial frequency domain imaging (SFDI) presents a noncontact, objective measurement of tissue oxygenation over a large field of view. This study aims to evaluate the use of SFDI technology in hemifacial composite flap compromise as could occur during facial transplant.

Methods: Six composite hemifacial flaps were created in three 35-kg Yorkshire pigs and continuously imaged using SFDI before, during, and after 15-minute selective vascular pedicle occlusion. Arterial and venous clamping trials were performed for each flap. Changes in oxyhemoglobin concentration, deoxyhemoglobin concentration, and total hemoglobin were quantified over time.

Results: The SFDI successfully measured changes in oxygenation parameters in all 6 composite tissue flaps. Significant changes in oxyhemoglobin, deoxyhemoglobin, and total hemoglobin were seen relative to controls. Early and distinct patterns of alteration were noted in arterial and in venous compromise relative to one another.

Conclusions: The need for noninvasive, reliable assessment of composite tissue graft viability is apparent, given the morbidity associated with flap failure. The results of this study suggest that SFDI technology shows promise in providing intraoperative guidance with regard to pedicle vessel integrity during reconstructive microsurgery.
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http://dx.doi.org/10.1097/SAP.0000000000000631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712079PMC
February 2016

700-nm Zwitterionic Near-Infrared Fluorophores for Dual-Channel Image-Guided Surgery.

Mol Imaging Biol 2016 Feb;18(1):52-61

Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Room SL-436A, Boston, MA, 02215, USA.

Purpose: The purpose of this study was to develop a family of 700-nm zwitterionic pentamethine indocyanine near-infrared fluorophores that would permit dual-channel image-guided surgery.

Procedures: Three complementary synthetic schemes were used to produce novel zwitterionic chemical structures. Physicochemical, optical, biodistribution, and clearance properties were compared to Cy5.5, a conventional pentamethine indocyanine now used for biomedical imaging.

Results: ZW700-1a, ZW700-1b, and ZW700-1c were synthesized, purified, and analyzed extensively in vitro and in vivo. All molecules had extinction coefficients ≥199,000 M(-1) cm(-1), emission ≥660 nm, and stability ≥99 % after 24 h in warm serum. In mice, rats, and pigs, ≥80 % of the injected dose was completely eliminated from the body via renal clearance within 4 h. Either alone or conjugated to a tumor targeting ligand, ZW700-1a permitted dual-channel, high SBR, and simultaneous imaging with 800-nm NIR fluorophores using the FLARE® imaging system.

Conclusions: Novel 700-nm zwitterionic NIR fluorophores enable dual-NIR image-guided surgery.
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http://dx.doi.org/10.1007/s11307-015-0870-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684479PMC
February 2016

Near-infrared imaging for the assessment of anastomotic patency, thrombosis, and reperfusion in microsurgery: a pilot study in a porcine model.

Microsurgery 2015 May 9;35(4):309-14. Epub 2015 Jan 9.

Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.

Background: Advances in microsurgical techniques have increased the use of free tissue transfer. Methods of intraoperative flap perfusion assessment, however, still rely primarily on subjective evaluation of traditional clinical parameters. Anastomotic thrombosis, if not expeditiously identified and revised, can result in flap loss with significant associated morbidity. This study aims to evaluate the use of near-infrared (NIR) fluorescence imaging in the assessment of microsurgical anastomotic patency, thrombosis, and vascular revision.

Materials And Methods: A model of pedicle thrombosis was created using bilateral abdominal flaps isolated on deep superior epigastric vascular pedicles in four Yorkshire pigs. Following flap elevation, microvascular arterial and venous anastomoses were performed unilaterally, preserving an intact contralateral control flap. Thrombosis was induced at the arterial anastomosis site using ferric chloride, and both flaps imaged using NIR fluorescence angiography. The thrombosed vascular segments were subsequently excised and new anastomoses performed to restore flow. Follow-up imaging of both flaps was then obtained to confirm patency using fluorescence imaging technology.

Results: Pedicled abdominal flaps were created and successful anastomotic thrombosis was induced unilaterally in each pig. Fluorescence imaging technology identified large decreases in tissue perfusion of the thrombosed flap within 2 minutes. After successful revision anastomosis, NIR imaging demonstrated dramatic increase in flow to the reconstructed flap, but intensity did not return to pre-thrombosis levels.

Conclusions: Early identification of anastomotic thrombosis is important in successful free tissue transfer. Real-time, intraoperative evaluation of flap perfusion, anastomotic thrombosis, and successful revision can be performed using NIR fluorescence imaging.
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http://dx.doi.org/10.1002/micr.22376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467576PMC
May 2015

Microscopic validation of macroscopic in vivo images enabled by same-slide optical and nuclear fusion.

J Nucl Med 2014 Nov 16;55(11):1899-904. Epub 2014 Oct 16.

Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts

Unlabelled: It is currently difficult to determine the molecular and cellular basis for radioscintigraphic signals obtained during macroscopic in vivo imaging. The field is in need of technology that helps bridge the macroscopic and microscopic regimes. To solve this problem, we developed a fiducial marker (FM) simultaneously compatible with 2-color near-infrared (NIR) fluorescence (700 and 800 nm), autoradiography, and conventional hematoxylin-eosin (HE) histology.

Methods: The FM was constructed from an optimized concentration of commercially available human serum albumin, 700- and 800-nm NIR fluorophores, (99m)Tc-pertechnetate, dimethyl sulfoxide, and glutaraldehyde. Lymphangioleiomyomatosis cells coexpressing the sodium iodide symporter and green fluorescent protein were labeled with 700-nm fluorophore and (99m)Tc-pertechnatate and then administered intratracheally into CD-1 mice. After in vivo SPECT imaging and ex vivo SPECT and NIR fluorescence imaging of the lungs, 30-μm frozen sections were prepared and processed for 800-nm NIR fluorophore costaining, autoradiography, and HE staining on the same slide using the FMs to coregister all datasets.

Results: Optimized FMs, composed of 100 μM unlabeled human serum albumin, 1 μM NIR fluorescent human serum albumin, 15% dimethyl sulfoxide, and 3% glutaraldehyde in phosphate-buffered saline (pH 7.4), were prepared within 15 min, displayed homogeneity and stability, and were visible by all imaging modalities, including HE staining. Using these FMs, tissue displaying high signal by SPECT could be dissected and analyzed on the same slide and at the microscopic level for 700-nm NIR fluorescence, 800-nm NIR fluorescence, autoradiography, and HE histopathologic staining.

Conclusion: When multimodal FMs are combined with a new technique for simultaneous same-slide NIR fluorescence imaging, autoradiography, and HE staining, macroscopic in vivo images can now be studied unambiguously at the microscopic level.
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http://dx.doi.org/10.2967/jnumed.114.141606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4384685PMC
November 2014

Prototype nerve-specific near-infrared fluorophores.

Theranostics 2014 7;4(8):823-33. Epub 2014 Jun 7.

1. Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215. ; 7. Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735, South Korea.

Nerve preservation is an important issue during most surgery because accidental transection or injury results in significant morbidity, including numbness, pain, weakness, or paralysis. Currently, nerves are still identified only by gross appearance and anatomical location during surgery, without intraoperative image guidance. Near-infrared (NIR) fluorescent light, in the wavelength range of 650-900 nm, has the potential to provide high-resolution, high-sensitivity, and real-time avoidance of nerve damage, but only if nerve-specific NIR fluorophores can be developed. In this study, we evaluated a series of Oxazine derivatives to highlight various peripheral nerve structures in small and large animals. Among the targeted fluorophores, Oxazine 4 has peak emission near into the NIR, which provided nerve-targeted signal in the brachial plexus and sciatic nerve for up to 12 h after a single intravenous injection. In addition, recurrent laryngeal nerves were successfully identified and highlighted in real time in swine, which could be preserved during the course of thyroid resection. Although optical properties of these agents are not yet optimal, chemical structure analysis provides a basis for improving these prototype nerve-specific NIR fluorophores even further.
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http://dx.doi.org/10.7150/thno.8696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063980PMC
February 2015

Simultaneous mapping of pan and sentinel lymph nodes for real-time image-guided surgery.

Theranostics 2014 24;4(7):693-700. Epub 2014 Apr 24.

1. Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA ; 5. Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735, South Korea.

The resection of regional lymph nodes in the basin of a primary tumor is of paramount importance in surgical oncology. Although sentinel lymph node mapping is now the standard of care in breast cancer and melanoma, over 20% of patients require a completion lymphadenectomy. Yet, there is currently no technology available that can image all lymph nodes in the body in real time, or assess both the sentinel node and all nodes simultaneously. In this study, we report an optical fluorescence technology that is capable of simultaneous mapping of pan lymph nodes (PLNs) and sentinel lymph nodes (SLNs) in the same subject. We developed near-infrared fluorophores, which have fluorescence emission maxima either at 700 nm or at 800 nm. One was injected intravenously for identification of all regional lymph nodes in a basin, and the other was injected locally for identification of the SLN. Using the dual-channel FLARE intraoperative imaging system, we could identify and resect all PLNs and SLNs simultaneously. The technology we describe enables simultaneous, real-time visualization of both PLNs and SLNs in the same subject.
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http://dx.doi.org/10.7150/thno.8721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038751PMC
January 2015

Design and characterization of an optimized simultaneous color and near-infrared fluorescence rigid endoscopic imaging system.

J Biomed Opt 2013 Dec;18(12):126018

Beth Israel Deaconess Medical Center, Department of Medicine, 330 Brookline Avenue, Boston, Massachusetts 02215.

We report the design, characterization, and validation of an optimized simultaneous color and near-infrared (NIR) fluorescence rigid endoscopic imaging system for minimally invasive surgery. This system is optimized for illumination and collection of NIR wavelengths allowing the simultaneous acquisition of both color and NIR fluorescence at frame rates higher than 6.8 fps with high sensitivity. The system employs a custom 10-mm diameter rigid endoscope optimized for NIR transmission. A dual-channel light source compatible with the constraints of an endoscope was built and includes a plasma source for white light illumination and NIR laser diodes for fluorescence excitation. A prism-based 2-CCD camera was customized for simultaneous color and NIR detection with a highly efficient filtration scheme for fluorescence imaging of both 700- and 800-nm emission dyes. The performance characterization studies indicate that the endoscope can efficiently detect fluorescence signal from both indocyanine green and methylene blue in dimethyl sulfoxide at the concentrations of 100 to 185 nM depending on the background optical properties. Finally, we performed the validation of this imaging system in vivo during a minimally invasive procedure for thoracic sentinel lymph node mapping in a porcine model.
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http://dx.doi.org/10.1117/1.JBO.18.12.126018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3875528PMC
December 2013

Structure-activity relationship of nerve-highlighting fluorophores.

PLoS One 2013 9;8(9):e73493. Epub 2013 Sep 9.

Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.

Nerve damage is a major morbidity associated with numerous surgical interventions. Yet, nerve visualization continues to challenge even the most experienced surgeons. A nerve-specific fluorescent contrast agent, especially one with near-infrared (NIR) absorption and emission, would be of immediate benefit to patients and surgeons. Currently, there are only three classes of small molecule organic fluorophores that penetrate the blood nerve barrier and bind to nerve tissue when administered systemically. Of these three classes, the distyrylbenzenes (DSBs) are particularly attractive for further study. Although not presently in the NIR range, DSB fluorophores highlight all nerve tissue in mice, rats, and pigs after intravenous administration. The purpose of the current study was to define the pharmacophore responsible for nerve-specific uptake and retention, which would enable future molecules to be optimized for NIR optical properties. Structural analogs of the DSB class of small molecules were synthesized using combinatorial solid phase synthesis and commercially available building blocks, which yielded more than 200 unique DSB fluorophores. The nerve-specific properties of all DSB analogs were quantified using an ex vivo nerve-specific fluorescence assay on pig and human sciatic nerve. Results were used to perform quantitative structure-activity relationship (QSAR) modeling and to define the nerve-specific pharmacophore. All DSB analogs with positive ex vivo fluorescence were tested for in vivo nerve specificity in mice to assess the effect of biodistribution and clearance on nerve fluorescence signal. Two new DSB fluorophores with the highest nerve to muscle ratio were tested in pigs to confirm scalability.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0073493PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3767781PMC
June 2014

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

Ann Plast Surg 2013 Sep;71(3):308-15

Division of Plastic and Reconstructive Surgery, Department of Surgery, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Introduction: Although 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.

Methods: Three 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.

Results: Spatial 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.

Conclusions: The 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.
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http://dx.doi.org/10.1097/SAP.0b013e31828b02fbDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3896306PMC
September 2013

Near-infrared imaging of face transplants: are both pedicles necessary?

J Surg Res 2013 Sep 10;184(1):714-21. Epub 2013 May 10.

Division of Plastic and Reconstructive Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.

Background: Facial transplantation is a complex procedure that corrects severe facial defects due to traumas, burns, and congenital disorders. Although face transplantation has been successfully performed clinically, potential risks include tissue ischemia and necrosis. The vascular supply is typically based on the bilateral neck vessels. As it remains unclear whether perfusion can be based off a single pedicle, this study was designed to assess perfusion patterns of facial transplant allografts using near-infrared (NIR) fluorescence imaging.

Methods: Upper facial composite tissue allotransplants were created using both carotid artery and external jugular vein pedicles in Yorkshire pigs. A flap validation model was created in n = 2 pigs and a clamp occlusion model was performed in n = 3 pigs. In the clamp occlusion models, sequential clamping of the vessels was performed to assess perfusion. Animals were injected with indocyanine green and imaged with NIR fluorescence. Quantitative metrics were assessed based on fluorescence intensity.

Results: With NIR imaging, arterial perforators emitted fluorescence indicating perfusion along the surface of the skin. Isolated clamping of one vascular pedicle showed successful perfusion across the midline based on NIR fluorescence imaging. This perfusion extended into the facial allograft within 60 s and perfused the entire contralateral side within 5 min.

Conclusions: Determination of vascular perfusion is important in microsurgical constructs as complications can lead to flap loss. It is still unclear if facial transplants require both pedicles. This initial pilot study using intraoperative NIR fluorescence imaging suggests that facial flap models can be adequately perfused from a single pedicle.
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http://dx.doi.org/10.1016/j.jss.2013.04.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3758778PMC
September 2013

Near-infrared fluorescence imaging for noninvasive trafficking of scaffold degradation.

Sci Rep 2013 5;3:1198. Epub 2013 Feb 5.

Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Biodegradable scaffolds could revolutionize tissue engineering and regenerative medicine; however, in vivo matrix degradation and tissue ingrowth processes are not fully understood. Currently a large number of samples and animals are required to track biodegradation of implanted scaffolds, and such nonconsecutive single-time-point information from various batches result in inaccurate conclusions. To overcome this limitation, we developed functional biodegradable scaffolds by employing invisible near-infrared fluorescence and followed their degradation behaviors in vitro and in vivo. Using optical fluorescence imaging, the degradation could be quantified in real-time, while tissue ingrowth was tracked by measuring vascularization using magnetic resonance imaging in the same animal over a month. Moreover, we optimized the in vitro process of enzyme-based biodegradation to predict implanted scaffold behaviors in vivo, which was closely related to the site of inoculation. This combined multimodal imaging will benefit tissue engineers by saving time, reducing animal numbers, and offering more accurate conclusions.
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http://dx.doi.org/10.1038/srep01198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3564022PMC
August 2013

Near-infrared lipophilic fluorophores for tracing tissue growth.

Biomed Mater 2013 Feb 25;8(1):014110. Epub 2013 Jan 25.

Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.

Longitudinal monitoring of cell migration, division and differentiation is of paramount importance in cell-based medical treatment. However, currently available optical techniques for tracing cell growth and tissue development are limited in applications due to genetic modification, toxicity and inaccurate detection when utilizing the visible spectrum. We have developed lipophilic near-infrared (NIR) fluorophores with high optical properties and a low background signal that allows longitudinal monitoring of cell proliferation and differentiation. Intracellular labeling efficacy was highly dependent on the physicochemical properties of fluorophores such as lipophilicity, charge, polar surface area and rotational bonds. Among the series of NIR cyanine fluorophores, ESNF 13 showed high solubility in aqueous buffer, high membrane penetration, low cytotoxicity and a long-term signal maintainability with a high signal intensity. This study will guide tissue engineers in designing long-term cell trafficking agents with better physicochemical and optical properties.
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http://dx.doi.org/10.1088/1748-6041/8/1/014110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589718PMC
February 2013

Highly charged cyanine fluorophores for trafficking scaffold degradation.

Biomed Mater 2013 Feb 25;8(1):014109. Epub 2013 Jan 25.

Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA.

Biodegradable scaffolds have been extensively used in the field of tissue engineering and regenerative medicine. However, noninvasive monitoring of in vivo scaffold degradation is still lacking. In order to develop a real-time trafficking technique, a series of meso-brominated near-infrared (NIR) fluorophores were synthesized and conjugated to biodegradable gelatin scaffolds. Since the pentamethine cyanine core is highly lipophilic, the side chain of each fluorophore was modified with either quaternary ammonium salts or sulfonate groups. The physicochemical properties such as lipophilicity and net charge of fluorophores played a key role in the fate of NIR-conjugated scaffolds in vivo after biodegradation. The positively charged fluorophore-conjugated scaffold fragments were found in salivary glands, lymph nodes, and most of the hepatobiliary excretion route. However, halogenated fluorophores intensively accumulated into lymph nodes and the liver. Interestingly, balanced-charged gelatin scaffolds were degraded into urine in a short period of time. These results demonstrate that the noninvasive optical imaging using NIR fluorophores can be useful for the translation of biodegradable scaffolds into the clinic.
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http://dx.doi.org/10.1088/1748-6041/8/1/014109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3600611PMC
February 2013

Targeted zwitterionic near-infrared fluorophores for improved optical imaging.

Nat Biotechnol 2013 Feb 6;31(2):148-53. Epub 2013 Jan 6.

Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

The signal-to-background ratio (SBR) is the key determinant of sensitivity, detectability and linearity in optical imaging. As signal strength is often constrained by fundamental limits, background reduction becomes an important approach for improving the SBR. We recently reported that a zwitterionic near-infrared (NIR) fluorophore, ZW800-1, exhibits low background. Here we show that this fluorophore provides a much-improved SBR when targeted to cancer cells or proteins by conjugation with a cyclic RGD peptide, fibrinogen or antibodies. ZW800-1 outperforms the commercially available NIR fluorophores IRDye800-CW and Cy5.5 in vitro for immunocytometry, histopathology and immunoblotting and in vivo for image-guided surgery. In tumor model systems, a tumor-to-background ratio of 17.2 is achieved at 4 h after injection of ZW800-1 conjugated to cRGD compared to ratios of 5.1 with IRDye800-CW and 2.7 with Cy5.5. Our results suggest that introducing zwitterionic properties into targeted fluorophores may be a general strategy for improving the SBR in diagnostic and therapeutic applications.
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http://dx.doi.org/10.1038/nbt.2468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3568187PMC
February 2013

Preclinical study of near-infrared-guided sentinel lymph node mapping of the porcine lung.

Ann Thorac Surg 2013 Jan 25;95(1):312-8. Epub 2012 Oct 25.

Division of Thoracic Surgery, Brigham & Women's Hospital, Boston, Massachusetts, USA.

Background: The presence of lymph node metastasis is the most important prognostic factor in early non-small cell lung cancer. Our objective was to develop a rapid, simple, and reliable method for thoracic sentinel lymph node (SLN) identification using near-infrared fluorescence imaging and clinically available contrast agents.

Methods: Indocyanine green (ICG) reconstituted in saline, human serum albumin, human fresh frozen plasma, and autologous porcine plasma was evaluated for optimal formulation and dosing for SLN within porcine lungs. Animals were imaged using the fluorescence-assisted resection and exploration for surgery imaging system. The SLN identification rate, time to identification and fluorescence intensity of the SLN, bronchus, and background were measured.

Results: The SLN identification rates varied widely, ranging from 33% to 100% as a function of the carrier used for ICG reconstitution. No significant difference was noted in SLN fluorescence intensity; however, bronchial intensity was significantly higher with ICG: albumin, which resulted in the lowest rate of SLN identification. Subsequent evaluation with 125 μM and 250 μM ICG:porcine plasma resulted in identification of strongly fluorescent SLNs, with identification rates of 93% and 100% and median signal-to-background ratios of 8.5 and 12.15, respectively, in less than 2 minutes in situ.

Conclusions: Near-infrared fluorescence imaging with ICG is a reliable method for SLN mapping in the lung with high sensitivity. Mixing of ICG with plasma resulted in strong SLN fluorescence signal with reliable identification rates.
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http://dx.doi.org/10.1016/j.athoracsur.2012.08.101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3600556PMC
January 2013

cGMP-Compatible preparative scale synthesis of near-infrared fluorophores.

Contrast Media Mol Imaging 2012 Nov-Dec;7(6):516-24

Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.

Image-guided surgery using optical imaging requires the availability of large quantities of clinical-grade fluorophores. We describe the cGMP-compatible synthesis of the zwitterionic heptamethine indocyanine near-infrared fluorophore ZW800-1 at the 10 g scale (~1000 patient doses) using facile and efficient solvent purification, and without the need for column chromatography. ZW800-1 has >90% yield at the final step and >99% purity as measured by fluorescence and evaporative light scatter detection. We describe an analytical framework for qualifying impurities, as well as a detailed analysis of counterion identities. Finally, we report the unique in vivo properties of ZW800-1 in large animals approaching the size of humans, thus laying the foundation for rapid clinical translation of these methods.
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http://dx.doi.org/10.1002/cmmi.1484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448123PMC
August 2013

Simultaneous assessment of luminal integrity and vascular perfusion of the gastrointestinal tract using dual-channel near-infrared fluorescence.

Mol Imaging 2012 Jul-Aug;11(4):301-8

Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Anastomotic complications such as stenosis and leakage in the gastrointestinal (GI) tract can cause high patient morbidity and mortality. To identify the potential preconditions of these complications intraoperatively, we explored the use of two 700 nm near-infrared (NIR) fluorophores administered intraluminally: (1) chlorella, an over-the-counter herbal supplement containing high concentrations of chlorophyll, and (2) methylene blue (MB). In parallel, we administered the 800 nm NIR fluorophore indocyanine green (ICG) intravenously to assess vascular function. Dual-channel, real-time intraoperative imaging and quantitation of the contrast to background ratio (CBR) were performed under normal conditions or after anastomosis or leakage of the stomach and intestines in 35 kg Yorkshire pigs using the Fluorescence-Assisted Resection and Exploration (FLARE) imaging system. Luminal integrity could be assessed with relatively high sensitivity with either chlorella or MB, although chlorella provided significantly higher CBR. ICG angiography provided assessment of blood perfusion of normal, ischemic, and anastomotic areas of the GI tract. Used simultaneously, 700 nm (chlorella or MB) and 800 nm (ICG) NIR fluorescence permitted independent assessment of luminal integrity and vascular perfusion of the GI tract intraoperatively and in real time. This technology has the potential to identify critical complications, such as anastomotic leakage, intraoperatively, when correction is still possible.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3439161PMC
March 2015

Real-time monitoring of tumorigenesis, dissemination, & drug response in a preclinical model of lymphangioleiomyomatosis/tuberous sclerosis complex.

PLoS One 2012 15;7(6):e38589. Epub 2012 Jun 15.

Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.

Background: TSC2-deficient cells can proliferate in the lungs, kidneys, and other organs causing devastating progressive multisystem disorders such as lymphangioleiomyomatosis (LAM) and tuberous sclerosis complex (TSC). Preclinical models utilizing LAM patient-derived cells have been difficult to establish. We developed a novel animal model system to study the molecular mechanisms of TSC/LAM pathogenesis and tumorigenesis and provide a platform for drug testing.

Methods And Findings: TSC2-deficient human cells, derived from the angiomyolipoma of a LAM patient, were engineered to co-express both sodium-iodide symporter (NIS) and green fluorescent protein (GFP). Cells were inoculated intraparenchymally, intravenously, or intratracheally into athymic NCr nu/nu mice and cells were tracked and quantified using single photon emission computed tomography (SPECT) and computed tomography (CT). Surprisingly, TSC2-deficient cells administered intratracheally resulted in rapid dissemination to lymph node basins throughout the body, and histopathological changes in the lung consistent with LAM. Estrogen was found to be permissive for tumor growth and dissemination. Rapamycin inhibited tumor growth, but tumors regrew after the drug treatment was withdrawn.

Conclusions: We generated homogeneous NIS/GFP co-expressing TSC2-deficient, patient-derived cells that can proliferate and migrate in vivo after intratracheal instillation. Although the animal model we describe has some limitations, we demonstrate that systemic tumors formed from TSC2-deficient cells can be monitored and quantified noninvasively over time using SPECT/CT, thus providing a much needed model system for in vivo drug testing and mechanistic studies of TSC2-deficient cells and their related clinical syndromes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0038589PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376142PMC
December 2012

Bone flap perfusion assessment using near-infrared fluorescence imaging.

J Surg Res 2012 Dec 24;178(2):e43-50. Epub 2012 May 24.

Division of Plastic Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.

Background: Microsurgical vascularized bone flaps are a versatile technique for reconstructing large bone defects. However, the assessment of perfusion is challenging, because clinical examination is difficult intraoperatively and often not possible postoperatively. Therefore, it is important to develop techniques to assess the perfusion of vascularized bone flaps and potentially improve the surgical outcomes. Near-infrared (NIR) fluorescence imaging has previously been shown to provide real-time, intraoperative evaluation of vascular perfusion. The present pilot study investigated the ability of NIR imaging to assess the perfusion of vascularized bone flaps.

Methods: Vascularized bone flaps were created in female Yorkshire pigs using well-established models for porcine forelimb osteomyocutaneous flap allotransplantation (n = 8) and hindlimb fibula flaps (n = 8). Imaging of the bone flaps was performed during harvest using the FLARE intraoperative fluorescence imaging system after systemic injection of indocyanine green. Perfusion was also assessed using the standard of care by clinical observation and Doppler ultrasonography. NIR fluorescence perfusion assessment was confirmed by intermittent clamping of the vascular pedicle.

Results: NIR fluorescence imaging could identify bone perfusion at the cut end of the osteotomy site. When the vascular pedicle was clamped or ligated, NIR imaging demonstrated no fluorescence when injected with indocyanine green. With clamp removal, the osteotomy site emitted fluorescence, indicating bone perfusion. The results using fluorescence imaging showed 100% agreement with the clinical observation and Doppler findings.

Conclusions: Vascularized bone transfers have become an important tool in reconstructive surgery; however, no established techniques are available to adequately assess perfusion. The results of our pilot study have indicated that NIR imaging can provide real-time, intraoperative assessment of bone perfusion.
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http://dx.doi.org/10.1016/j.jss.2012.05.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3435470PMC
December 2012

Face transplant perfusion assessment using near-infrared fluorescence imaging.

J Surg Res 2012 Oct 27;177(2):e83-8. Epub 2012 Apr 27.

Division of Plastic Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

Background: Composite tissue allografts (CTAs) including partial face transplantation have been achieved clinically. However, risks of complications including tissue ischemia, rejection, and transplant failure are significant. Safe and effective techniques to assess perfusion are needed to decrease complications in composite tissue flaps. Near-infrared (NIR) fluorescence imaging has been previously shown to provide a real-time, intraoperative evaluation of perfusion. This study investigates the use of NIR imaging in partial face CTA harvest.

Methods: We created hemifacial CTAs (n = 8) using an established porcine model. This included ear cartilage, nerve, lymphoid tissue, muscle, and skin with perfusion by the carotid artery and external jugular vein. We injected animals systemically with indocyanine green and obtained NIR fluorescence images simultaneously with color video. In addition, we assessed the elevated hemifacial flaps using standard of care (i.e., clinical examination and Doppler).

Results: Flap design was facilitated by NIR imaging with localization of perforators to the hemifacial CTA flap. In particular, an arterial and venous phase could be clearly identified. We assessed perfusion of the flap by NIR fluorescence intensity after injection of indocyanine green. Sequential clamping of the artery and vein confirmed correlation of perfusion deficits with NIR imaging as well as with clinical examination and Doppler.

Conclusions: Evaluation and assessment of perfusion are important in facial transplantation. The results from our pilot study indicate that NIR imaging has the capability to assess perfusion of partial facial CTAs. This emergent technology shows promise in assessing tissue perfusion in a composite flap.
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http://dx.doi.org/10.1016/j.jss.2012.04.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3434268PMC
October 2012

Two-wavelength near-infrared fluorescence for the quantitation of drug antiplatelet effects in large animal model systems.

J Vasc Surg 2012 Jul 14;56(1):171-80. Epub 2012 Apr 14.

Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.

Objective: Intraoperative imaging of intravascular thrombi is limited by the inability of visible light to penetrate thick-walled vessels. Near-infrared (NIR) light has relatively high tissue penetration and low autofluorescence and scatter, offering significant advantages. We hypothesized that the development of 700-nm NIR fluorophores for platelet labeling, in conjunction with existing 800-nm NIR fluorophores, would permit simultaneous and separable quantitation of intravascular thrombi and measurement of the antiplatelet effect of drugs.

Methods: We synthesized a series of lipophilic, cationic, polymethine indocyanine dyes (MHI-86, 94, 106, and 114) that emit at approximately 700 nm. Platelet uptake was optimized in vitro and the bioactivity and blood half-life of labeled platelets was characterized in vitro and in vivo. FeCl(3)-induced injury of the femoral arteries and intravascular thrombus formation was performed in 35-kg Yorkshire pigs. A combination of 700-nm and 800-nm NIR fluorophore-labeled platelets was used in conjunction with the fluorescence-assisted resection and exploration imaging system to image and quantify the antiplatelet effect of cilostazol and acetylsalicylic acid.

Results: MHI-114 was incorporated at nearly 4.1 × 10(6) molecules per platelet without affecting platelet function. When infused into pigs, the signal-to-background ratio of MHI-114-labeled platelets exhibited a blood half-life of 16.4 ± 2.2 (mean ± SEM; n = 3) minute and generated a signal-to-background ratio of 2.5 ± 0.5 (mean ± SEM; n = 3) at the site of thrombi. Using dual-NIR-labeled platelet populations, cilostazol and acetylsalicylic acid were found to cause a reduction in platelet incorporation into thrombi of 51 ± 2% and 10 ± 1% (mean ± SEM; n = 3), respectively, relative to vehicle-only treated control thrombi.

Conclusions: New platelet-avid 700-nm NIR fluorophores permit simultaneous two-wavelength NIR fluorescence imaging and quantitation of intravascular thrombi in intact vessels approaching the size of humans and can be used to study the antiplatelet effect of drugs.
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http://dx.doi.org/10.1016/j.jvs.2011.11.058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3389273PMC
July 2012

Intraoperative prediction of postoperative flap outcome using the near-infrared fluorophore methylene blue.

Ann Plast Surg 2013 Mar;70(3):360-5

Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Methylene blue (MB) is a near-infrared fluorophore that provides a stable visual map of skin perfusion after intravenous injection. We explored the capability of MB to predict submental flap postoperative outcome using a single intraoperative measurement. Submental flaps were created in N = 15 pigs and imaged using the FLARE imaging system immediately after surgery and at 72 hours. Using the first 3 pigs, optimal MB dosing was found to be 2.0 mg/kg. Training and validation sets of 6 pigs each were then used for receiver operating characteristic analysis. In the training set, a contrast-to-background ratio (CBR) threshold of 1.24 provided the highest sensitivity and specificity to predict tissue necrosis at 72 hours. In the validation set, this threshold provided a prediction sensitivity of 95.3% and a specificity of 98.0%. We demonstrate that a single intraoperative near-infrared measurement can predict submental flap outcome at 72 hours.
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http://dx.doi.org/10.1097/SAP.0b013e318236babeDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3371147PMC
March 2013

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

J Biomed Opt 2011 Aug;16(8):086015

Beth Israel Deaconess Medical Center, Division of Hematology∕Oncology, Department of Medicine, Boston, Massachusetts 02215, USA.

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.
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http://dx.doi.org/10.1117/1.3614566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3182084PMC
August 2011

Quantitative assessment of nipple perfusion with near-infrared fluorescence imaging.

Ann Plast Surg 2013 Feb;70(2):149-53

Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Preserving the nipple-areolar complex with a nipple-sparing mastectomy improves cosmesis compared with skin-sparing mastectomy. However, complications such as necrosis of the nipple-areolar complex significantly affect cosmetic outcome. Many factors influence nipple-areolar perfusion, and no consensus currently exists on optimal incisional choice. This study evaluates 2 nipple-sparing mastectomy incision models using near-infrared fluorescence to assess perfusion quantitatively. The periareolar and radial incisions were compared with 2 control models in Yorkshire pigs (N = 6). Methylene blue and indocyanine green were injected intravenously, and near-infrared fluorescence images were recorded at 3 time points: before surgery, immediately after (0 hour), and 3 days postoperatively. Contrast-to-background ratio was used to assess perfusion. At 72 hours, radial incisions showed a statistically significantly higher perfusion compared with periareolar incisions (P < 0.05). Based on our findings, radial incisions for nipple-sparing mastectomy may be preferable due to higher perfusion; however, clinical trials are necessary for further assessment.
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http://dx.doi.org/10.1097/SAP.0b013e31822f9af7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3224668PMC
February 2013

Real-time simultaneous near-infrared fluorescence imaging of bile duct and arterial anatomy.

J Surg Res 2012 Jul 14;176(1):7-13. Epub 2011 Jul 14.

Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

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.
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http://dx.doi.org/10.1016/j.jss.2011.06.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3212656PMC
July 2012

Synthesis and in vivo fate of zwitterionic near-infrared fluorophores.

Angew Chem Int Ed Engl 2011 Jul 7;50(28):6258-63. Epub 2011 Jun 7.

Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, SLB-05, Boston, MA 02215, USA.

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http://dx.doi.org/10.1002/anie.201102459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128676PMC
July 2011

Near-infrared fluorescence imaging of thoracic duct anatomy and function in open surgery and video-assisted thoracic surgery.

J Thorac Cardiovasc Surg 2011 Jul 7;142(1):31-8.e1-2. Epub 2011 Apr 7.

Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Mass 02215, USA.

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.
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http://dx.doi.org/10.1016/j.jtcvs.2011.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3118972PMC
July 2011

Nerve-highlighting fluorescent contrast agents for image-guided surgery.

Mol Imaging 2011 Apr;10(2):91-101

Department of Radiology, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Nerve damage is the major morbidity of many surgeries, resulting in chronic pain, loss of function, or both. The sparing of nerves during surgical procedures is a vexing problem because surrounding tissue often obscures them. To date, systemically administered nerve-highlighting contrast agents that can be used for nerve-sparing image-guided surgery have not been reported. In the current study, physicochemical and optical properties of 4,4'-[(2-methoxy-1,4-phenylene)di-(1E)-2,1-ethenediyl]bis-benzenamine (BMB) and a newly synthesized, red-shifted derivative 4-[(1E)-2-[4-[(1E)-2-[4-aminophenyl]ethenyl]-3-methoxyphenyl]ethenyl]-benzonitrile (GE3082) were characterized in vitro and in vivo. Both agents crossed the blood-nerve barrier and blood-brain barrier and rendered myelinated nerves fluorescent after a single systemic injection. Although both BMB and GE3082 also exhibited significant uptake in white adipose tissue, GE3082 underwent a hypsochromic shift in adipose tissue that provided a means to eliminate the unwanted signal using hyperspectral deconvolution. Dose and kinetic studies were performed in mice to determine the optimal dose and drug-imaging interval. The results were confirmed in rat and pig, with the latter used to demonstrate, for the first time, simultaneous fluorescence imaging of blood vessels and nerves during surgery using the FLARE™ (Fluorescence-Assisted Resection and Exploration) imaging system. These results lay the foundation for the development of ideal nerve-highlighting fluorophores for image-guided surgery.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4386639PMC
April 2011