Guillermo J Tearney

Harvard University, Cambridge, Massachusetts, United States

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Publications (210)1049.94 Total impact

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    ABSTRACT: Intracoronary optical frequency domain imaging (OFDI), requires the displacement of blood for clear visualization of the artery wall. Radiographic contrast agents are highly effective at displacing blood however, may increase the risk of contrast-induced nephropathy. Flushing media viscosity, flow rate, and flush duration influence the efficiency of blood displacement necessary for obtaining diagnostic quality OFDI images. The aim of this work was to determine the optimal flushing parameters necessary to reliably perform intracoronary OFDI while reducing the volume of administered radiographic contrast, and assess the influence of flushing media choice on vessel wall measurements. 144 OFDI pullbacks were acquired together with synchronized EKG and intracoronary pressure wire recordings in three swine. OFDI images were graded on diagnostic quality and quantitative comparisons of flushing efficiency and intracoronary cross-sectional area with and without precise refractive index calibration were performed. Flushing media with higher viscosities resulted in rapid and efficient blood displacement. Media with lower viscosities resulted in increased blood-media transition zones, reducing the pullback length of diagnostic quality images obtained. Flushing efficiency was found to increase with increases in flow rate and duration. Calculations of lumen area using different flushing media were significantly different, varying up to 23 % (p < 0.0001). This error was eliminated with careful refractive index calibration. Flushing media viscosity, flow rate, and flush duration influence the efficiency of blood displacement necessary for obtaining diagnostic quality OFDI images. For patients with sensitivity to contrast, to reduce the risk of contrast induced nephrotoxicity we recommend that intracoronary OFDI be conducted with flushing solutions containing little or no radiographic contrast. In addition, our findings show that careful refractive index compensation should be performed, taking into account the specific contrast agent used, in order to obtain accurate intravascular OFDI measurements.
    The international journal of cardiovascular imaging 04/2015; DOI:10.1007/s10554-015-0668-0 · 2.32 Impact Factor
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    ABSTRACT: While optical coherence tomography (OCT) has been shown to be capable of imaging coronary plaque microstructure, additional chemical/molecular information may be needed in order to determine which lesions are at risk of causing an acute coronary event. In this study, we used a recently developed imaging system and double-clad fiber (DCF) catheter capable of simultaneously acquiring both OCT and red excited near-infrared autofluorescence (NIRAF) images (excitation: 633 nm, emission: 680nm to 900nm). We found that NIRAF is elevated in lesions that contain necrotic core – a feature that is critical for vulnerable plaque diagnosis and that is not readily discriminated by OCT alone. We first utilized a DCF ball lens probe and a bench top setup to acquire en face NIRAF images of aortic plaques ex vivo (n = 20). In addition, we used the OCT-NIRAF system and fully assembled catheters to acquire multimodality images from human coronary arteries (n = 15) prosected from human cadaver hearts (n = 5). Comparison of these images with corresponding histology demonstrated that necrotic core plaques exhibited significantly higher NIRAF intensity than other plaque types. These results suggest that multimodality intracoronary OCT-NIRAF imaging technology may be used in the future to provide improved characterization of coronary artery disease in human patients.
    Biomedical Optics Express 04/2015; 6(4). DOI:10.1364/BOE.6.001363 · 3.50 Impact Factor
  • Guillermo J Tearney
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    ABSTRACT: Spectrally encoded confocal microscopy (SECM) is a reflectance confocal microscopy technology that can rapidly image large areas of luminal organs at microscopic resolution. One of the main challenges for large-area SECM imaging in vivo is maintaining the same imaging depth within the tissue when patient motion and tissue surface irregularity are present. In this paper, we report the development of a miniature vari-focal objective lens that can be used in an SECM endoscopic probe to conduct adaptive focusing and to maintain the same imaging depth during in vivo imaging. The vari-focal objective lens is composed of an aspheric singlet with an NA of 0.5, a miniature water chamber, and a thin elastic membrane. The water volume within the chamber was changed to control curvature of the elastic membrane, which subsequently altered the position of the SECM focus. The vari-focal objective lens has a diameter of 5 mm and thickness of 4 mm. A vari-focal range of 240 μm was achieved while maintaining lateral resolution better than 2.6 μm and axial resolution better than 26 μm. Volumetric SECM images of swine esophageal tissues were obtained over the vari-focal range of 260 μm. SECM images clearly visualized cellular features of the swine esophagus at all focal depths, including basal cell nuclei, papillae, and lamina propria.
    Biomedical Optics Express 12/2014; 5(12). DOI:10.1364/BOE.5.004350 · 3.50 Impact Factor
  • Journal of Biomedical Optics 11/2014; 19(11):116005. DOI:10.1117/1.JBO.19.11.116005 · 2.75 Impact Factor
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    ABSTRACT: Intravascular optical coherence tomography (IVOCT) is a well-established method for the high-resolution investigation of atherosclerosis in vivo. Intravascular near-infrared fluorescence (NIRF) imaging is a novel technique for the assessment of molecular processes associated with coronary artery disease. Integration of NIRF and IVOCT technology in a single catheter provides the capability to simultaneously obtain co-localized anatomical and molecular information from the artery wall. Since NIRF signal intensity attenuates as a function of imaging catheter distance to the vessel wall, the generation of quantitative NIRF data requires an accurate measurement of the vessel wall in IVOCT images. Given that dual modality, intravascular OCT-NIRF systems acquire data at a very high frame-rate (>100 frames/s), a high number of images per pullback need to be analyzed, making manual processing of OCT-NIRF data extremely time consuming. To overcome this limitation, we developed an algorithm for the automatic distance-correction of dual-modality OCT-NIRF images. We validated this method by comparing automatic to manual segmentation results in 180 in vivo images from six New Zealand White rabbit atherosclerotic after indocyanine-green injection. A high Dice similarity coefficient was found (0.97 ± 0.03) together with an average individual A-line error of 22 µm (i.e., approximately twice the axial resolution of IVOCT) and a processing time of 44 ms per image. In a similar manner, the algorithm was validated using 120 IVOCT clinical images from eight different in vivo pullbacks in human coronary arteries. The results suggest that the proposed algorithm enables fully automatic visualization of dual modality OCT-NIRF pullbacks, and provides an accurate and efficient calibration of NIRF data for quantification of the molecular agent in the atherosclerotic vessel wall.
    The International Journal of Cardiovascular Imaging 10/2014; DOI:10.1007/s10554-014-0556-z · 2.32 Impact Factor
  • Kengyeh K. Chu, Giovanni J. Ughi, Linbo Liu, Guillermo J. Tearney
    Current Cardiovascular Imaging Reports 10/2014; 7:9308. DOI:10.1007/s12410-014-9308-7
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    ABSTRACT: Mucociliary clearance (MCC) and submucosal glands (SMGs) are major components of airway innate immunity that have impaired function in cystic fibrosis (CF). Although both of these defense systems develop post-natally in the ferret, the lungs of newborn ferrets remain sterile in the presence of a functioning cystic fibrosis transmembrane conductance regulator (CFTR) gene. We evaluated several components of airway innate immunity and inflammation in the early CF ferret lung. At birth, the rates of MCC did not differ between CF and non-CF animals, but the height of the airway surface liquid was significantly reduced in CF newborn ferrets. CF ferrets had impaired MCC after 7 days of age, despite normal rates of ciliogenesis. Only non-CF ferrets eradicated Pseudomonas directly introduced into the lung after birth, while both genotypes could eradicate Staphylococcus. CF bronchioalveolar lavage fluid (BALF) had significantly lower and selective antimicrobial activity against Pseudomonas than non-CF, which was insensitive to changes in pH and bicarbonate. LC-MS-MS and cytokine analysis of BALF from sterile C-sectioned and non-sterile naturally-born animals demonstrated CF-associated disturbances in IL-8, TNFα, and IL-β, and pathways that control immunity and inflammation including the complement system, macrophage functions, mTOR signaling, and eIF2 signaling. Interestingly, during the birth transition, IL-8 was selectively induced in CF BALF, despite no genotypic difference in bacterial load shortly after birth. These results suggest that newborn CF ferrets have defects in both innate immunity and inflammatory signaling that may be important in the early onset and progression of lung disease in these animals.
    American Journal of Respiratory Cell and Molecular Biology 10/2014; DOI:10.1165/rcmb.2014-0250OC · 4.11 Impact Factor
  • 09/2014; 2(03):E135-E140. DOI:10.1055/s-0034-1377177
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    ABSTRACT: The presence of cholesterol crystals is a hallmark of atherosclerosis, but until recently, such crystals have been considered to be passive components of necrotic plaque cores. Recent studies have demonstrated that phagocytosis of cholesterol crystals by macrophages may actively precipitate plaque progression via an inflammatory pathway, emphasizing the need for methods to study the interaction between macrophages and crystalline cholesterol. In this study, we demonstrate the feasibility of detecting cholesterol in macrophages in situ using Micro-Optical Coherence Tomography (µOCT), an imaging modality we have recently developed with 1-µm resolution. Macrophages containing cholesterol crystals frequently demonstrated highly scattering constituents in their cytoplasm on µOCT imaging, and µOCT was able to evaluate cholesterol crystals in cultured macrophage cells. Our results suggest that µOCT may be useful for the detection and characterization of inflammatory activity associated with cholesterol crystals in the coronary artery.
    PLoS ONE 07/2014; 9(7):e102669. DOI:10.1371/journal.pone.0102669 · 3.53 Impact Factor
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    ABSTRACT: Rationale: The mechanisms underlying cystic fibrosis (CF) lung disease pathogenesis are unknown. Objective: To establish mechanisms linking anion transport with the functional microanatomy, we evaluated normal and CF piglet trachea, as well as adult swine trachea in the presence of selective anion inhibitors. Methods: We investigated airway functional microanatomy using micro-optical coherence tomography, a new imaging modality that concurrently quantifies multiple functional parameters of airway epithelium in a co-localized fashion. Main Results: Tracheal explants from wild type swine demonstrated a direct link between periciliary liquid (PCL) hydration and mucociliary transport (MCT) rates, a relationship frequently invoked but never experimentally confirmed. However, in CF airways this relationship was completely disrupted, with greater PCL depths associated with slowest transport rates. This disrupted relationship was recapitulated by selectively inhibiting bicarbonate transport in vitro and ex vivo. CF mucus exhibited increased viscosity in situ due to the absence of bicarbonate transport, explaining defective MCT that occurs even in the presence of adequate PCL hydration. Conclusions: An inherent defect in CF airway surface liquid contributes to delayed MCT beyond that caused by airway dehydration alone, and identifies a fundamental mechanism underlying the pathogenesis of CF lung disease in the absence of antecedent infection or inflammation.
    American Journal of Respiratory and Critical Care Medicine 07/2014; 190(4). DOI:10.1164/rccm.201404-0670OC · 11.99 Impact Factor
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    ABSTRACT: Rationale: Mucociliary clearance, characterized by mucus secretion and its conveyance by ciliary action, is a fundamental physiological process that plays an important role in host defense. While it is known that ciliary activity changes with chemical and mechanical stimuli, the autoregulatory mechanisms that govern ciliary activity and mucus transport in response to normal and pathophysiological variations in mucus are not clear. Objectives: To investigate the autoregulatory mechanisms that govern ciliary activity and mucus transport in response to normal and pathophysiological variations in mucus. Methods: We have developed a high-speed, 1-µm resolution, cross-sectional imaging modality termed Micro-Optical Coherence Tomography (µOCT) that provides the first integrated view of the functional microanatomy of the epithelial surface. We monitored invasion of periciliary liquid layer by mucus in fully-differentiated human bronchial epithelial cultures and full thickness swine trachea using µOCT. We further monitored mucociliary transport and intracellular calcium concentration simultaneously during invasion of periciliary liquid layer by mucus using co-localized µOCT and confocal fluorescence microscopy in cell cultures. Measurements and Main Results: Ciliary beating and mucus transport are upregulated via a calcium dependent pathway when mucus causes a reduction in the periciliary liquid layer and cilia height. When the load exceeds a physiological limit of ~2 microns, this gravity-independent autoregulatory mechanism can no longer compensate, resulting in diminished ciliary motion and abrogation of stimulated mucociliary transport. Conclusions: A fundamental integrated mechanism with specific operating limits governs mucociliary transport in the lung and fails when periciliary layer compression and mucus viscosity exceeds normal physiologic limits.
    American Journal of Respiratory Cell and Molecular Biology 06/2014; DOI:10.1165/rcmb.2013-0499MA · 4.11 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-635. DOI:10.1016/S0016-5085(14)62300-3 · 13.93 Impact Factor
  • Gastrointestinal Endoscopy 05/2014; 79(5):AB513-AB514. DOI:10.1016/j.gie.2014.02.811 · 4.90 Impact Factor
  • Gastrointestinal Endoscopy 05/2014; 79(5):AB136. DOI:10.1016/j.gie.2014.02.090 · 4.90 Impact Factor
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    ABSTRACT: Animal models for cystic fibrosis (CF) have contributed significantly to our understanding of disease pathogenesis. Here we describe development and characterization of the first cystic fibrosis rat, in which the cystic fibrosis transmembrane conductance regulator gene (CFTR) was knocked out using a pair of zinc finger endonucleases (ZFN). The disrupted Cftr gene carries a 16 base pair deletion in exon 3, resulting in loss of CFTR protein expression. Breeding of heterozygous (CFTR+/-) rats resulted in Mendelian distribution of wild-type, heterozygous, and homozygous (CFTR-/-) pups. Nasal potential difference and transepithelial short circuit current measurements established a robust CF bioelectric phenotype, similar in many respects to that seen in CF patients. Young CFTR-/- rats exhibited histological abnormalities in the ileum and increased intracellular mucus in the proximal nasal septa. By six weeks of age, CFTR-/- males lacked the vas deferens bilaterally. Airway surface liquid and periciliary liquid depth were reduced, and submucosal gland size was abnormal in CFTR-/- animals. Use of ZFN based gene disruption successfully generated a CF animal model that recapitulates many aspects of human disease, and may be useful for modeling other CF genotypes, including CFTR processing defects, premature truncation alleles, and channel gating abnormalities.
    PLoS ONE 03/2014; 9(3):e91253. DOI:10.1371/journal.pone.0091253 · 3.53 Impact Factor
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    ABSTRACT: The guest editors introduce a Biomedical Optics Express feature issue that includes contributions from participants at the 2013 conference on Advances in Optics for Biotechnology, Medicine and Surgery XIII.
    Biomedical Optics Express 02/2014; 5(2):560-1. DOI:10.1364/BOE.5.000560 · 3.50 Impact Factor
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    ABSTRACT: Biopsy surveillance protocols for the assessment of Barrett's esophagus can be subject to sampling errors, resulting in diagnostic uncertainty. Optical coherence tomography is a cross-sectional imaging technique that can be used to conduct volumetric laser endomicroscopy (VLE) of the entire distal esophagus. We have developed a biopsy guidance platform that places endoscopically visible marks at VLE-determined biopsy sites. The objective of this study was to demonstrate in human participants the safety and feasibility of VLE-guided biopsy in vivo. A pilot feasibility study. Massachusetts General Hospital. A total of 22 participants were enrolled from January 2011 to June 2012 with a prior diagnosis of Barrett's esophagus. Twelve participants were used to optimize the laser marking parameters and the system platform. A total of 30 target sites were selected and marked in real-time by using the VLE-guided biopsy platform in the remaining 10 participants. Volumetric laser endomicroscopy. Endoscopic and VLE visibility, and accuracy of VLE diagnosis of the tissue between the laser cautery marks. There were no adverse events of VLE and laser marking. The optimal laser marking parameters were determined to be 2 seconds at 410 mW, with a mark separation of 6 mm. All marks made with these parameters were visible on endoscopy and VLE. The accuracies for diagnosing tissue in between the laser cautery marks by independent blinded readers for endoscopy were 67% (95% confidence interval [CI], 47%-83%), for VLE intent-to-biopsy images 93% (95% CI, 78%-99%), and for corrected VLE post-marking images 100% when compared with histopathology interpretations. This is a single-center feasibility study with a limited number of patients. Our results demonstrate that VLE-guided biopsy of the esophagus is safe and can be used to guide biopsy site selection based on the acquired volumetric optical coherence tomography imaging data. (Clinical trial registration number: NCT01439633.).
    Gastrointestinal endoscopy 01/2014; 79(6). DOI:10.1016/j.gie.2013.11.016 · 4.90 Impact Factor
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    Guillermo J. Tearney
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    ABSTRACT: Today's gold standard for medical diagnosis is histology of excised biopsies or surgical specimens where tissue is taken out of the body, processed, sectioned, stained, and looked at under a light microscope by a pathologist. There are many limitations of this technique, including the fact that it is inherently invasive, time consuming, costly, and dangerous for some organs. Furthermore, oftentimes the diseased tissue is not readily seen by visual inspection and as a result the tissue is sampled at a random location, which can be highly inaccurate. If we could instead conduct microscopy inside the body, then we could provide tools for screening, targeting biopsies, making primary disease diagnosis, and guiding intervention on the cellular basis. This promise has motivated the development of a new field, termed in vivo microscopy, the goal of which is to obtain microscopic images from living human patients. Two in vivo microscopy technologies, confocal microscopy and optical coherence tomography, are currently available and in clinical use. Upcoming developments, including whole organ microscopy, swallowable microscopy capsules, molecular imaging, and very high resolution microscopic devices, are in the pipeline and will likely revolutionize how disease is diagnosed and how medicine is practiced in the future.
    Analytical cellular pathology (Amsterdam) 01/2014; 2014:1-1. DOI:10.1155/2014/797108 · 1.76 Impact Factor
  • Circulation 01/2014; 130(A12988). · 14.95 Impact Factor

Publication Stats

8k Citations
1,049.94 Total Impact Points

Institutions

  • 2004–2014
    • Harvard University
      • School of Engineering and Applied Sciences
      Cambridge, Massachusetts, United States
    • Tufts Medical Center
      Boston, Massachusetts, United States
  • 2002–2014
    • Harvard Medical School
      • • Department of Pathology
      • • Department of Otology and Laryngology
      • • Department of Dermatology
      Boston, Massachusetts, United States
  • 2000–2014
    • Massachusetts General Hospital
      • • Department of Pathology
      • • Wellman Center for Photomedicine
      • • Division of Cardiology
      Boston, Massachusetts, United States
  • 2013
    • Columbia University
      • Department of Electrical Engineering
      New York City, NY, United States
  • 2010
    • Lahey Hospital and Medical Center
      Burlington, Massachusetts, United States
  • 1996–2009
    • Massachusetts Institute of Technology
      • • Division of Health Sciences and Technology
      • • Department of Electrical Engineering and Computer Science
      Cambridge, Massachusetts, United States
  • 2007
    • Duke University
      Durham, North Carolina, United States
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 2001
    • Beverly Hospital, Boston MA
      BVY, Massachusetts, United States