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    Evaluation of rabbit tracheal inflammation using optical coherence tomography. Mahmood Usama,Hanna Nevine Mikhail,Han Sugku,Jung Woong-Gyu,Chen Zhonping,Jordan Bryan,Yershov Andrey,Walton Ronald,Brenner Matthew Chest BACKGROUND:Optical coherence tomography (OCT) is an evolving technology that is capable of delivering real-time, high-resolution images of tissues. The purpose of this study was to evaluate the feasibility of using OCT for detecting airway pathology in a septic animal model. METHODS:The tracheas of New Zealand white rabbits were inoculated endobronchially with various concentrations of live Streptococcus pneumoniae bacteria. After the development of pneumonia/sepsis, the animals were killed. OCT tracheal images and corresponding histologic specimens from these experimental animals were compared to control rabbit tracheas for morphologic features and quantitative tracheal mucosal thickness measurements. RESULTS:The results revealed significant airway mucosal thickening in the experimental group that was consistent with tracheal edema. Morphologic changes, including epithelial denuding and mucosal sloughing, were evident in regions of the experimental tracheas. CONCLUSION:This study suggests that OCT is a potentially valuable imaging modality that is capable of evaluating superficial airway pathology with high-resolution in vivo images. Numerous applications of OCT can be envisioned in the realm of pulmonary medicine and thoracic surgery that may substantially increase the precision and accuracy of current bronchoscopic diagnostic and surgical techniques. 10.1378/chest.130.3.863
    Detection of acute smoke-induced airway injury in a New Zealand white rabbit model using optical coherence tomography. Brenner Matthew,Kreuter Kelly,Mukai David,Burney Tanya,Guo Shuguang,Su Jianping,Mahon Sari,Tran Andrew,Tseng Lillian,Ju Johnny,Chen Zhongping Journal of biomedical optics Optical coherence tomography (OCT) is a micron scale high-resolution optical technology that can provide real-time in vivo images noninvasively. The ability to detect airway mucosal and submucosal injury rapidly will be valuable for a range of pulmonary applications including assessment of acute inhalation smoke and burn injury. OCT has the potential ability to monitor the progression of airway injury changes including edema, hyperemia, and swelling, which are critical clinical components of smoke-inhalation injury. New Zealand white male rabbits exposed to cold smoke from standardized unbleached burned cotton administered during ventilation were monitored for 6 h using a 1.8-mm diameter flexible fiberoptic longitudinal probe that was inserted through the endotracheal tube. The thickness of the epithelial, mucosal, and submucosal layers of the rabbit trachea to the tracheal cartilage was measured using a prototype superluminescent diode OCT system we constructed. OCT was able to detect significant smoke-injury-induced increases in the thickness of the tracheal walls of the rabbit beginning very shortly after smoke administration. Airway wall thickness increased to an average of 120% (+/-33%) of baseline values by 5 h following exposure. OCT is capable of providing real-time, noninvasive images of airway injury changes following smoke exposure. These studies suggest that OCT may have the ability to provide information on potential early indicators of impending smoke-inhalation-induced airway compromise. 10.1117/1.2798637
    In vivo optical coherence tomography detection of differences in regional large airway smoke inhalation induced injury in a rabbit model. Brenner Matthew,Kreuter Kelly,Ju Johnny,Mahon Sari,Tseng Lillian,Mukai David,Burney Tanya,Guo Shuguang,Su Jianping,Tran Andrew,Batchinsky Andriy,Cancio Leopoldo C,Narula Navneet,Chen Zhongping Journal of biomedical optics Smoke inhalation injury causes acute airway injury that may result in airway compromise with significant morbidity and mortality. We investigate the ability of high resolution endobronchial optical coherence tomography (OCT) to obtain real-time images for quantitatively assessing regional differences between upper tracheal versus lower tracheal and bronchial airway injury responses to smoke inhalation in vivo using a prototype spectral domain (SLD)-OCT system we constructed, and flexible fiber optic probes. 33 New Zealand White rabbits are intubated and mechanically ventilated. The treatment groups are exposed to inhaled smoke. The OCT probe is introduced through the endotracheal tube and maintained in place for 5 to 6 h. Images of airway mucosa and submucosa are obtained at baseline and at specified intervals postexposure. Starting within less than 15 min after smoke inhalation, there is significant airway thickening in the smoke-exposed animals. This is maintained over 5 h of imaging studies. The lower tracheal airway changes, correlating closely with carboxyhemoglobin levels, are much greater than upper tracheal changes. Significant differences are seen in lower trachea and bronchi after acute smoke inhalation compared to upper trachea as measured in vivo by minimally invasive OCT. OCT is capable of quantitatively detecting regional changes in airway swelling following inhalation injury. 10.1117/1.2939400
    Using optical coherence tomography to improve diagnostic and therapeutic bronchoscopy. Williamson Jonathan P,McLaughlin Robert A,Phillips Martin J,Armstrong Julian J,Becker Sven,Walsh Jennifer H,Sampson David D,Hillman David R,Eastwood Peter R Chest Flexible bronchoscopy is a common procedure that is used in both diagnostic and therapeutic settings but does not readily permit measurement of central airway dimensions. Anatomic optical coherence tomography (a OCT), a modification of conventional optical coherence tomography (OCT), is a novel light-based imaging tool with the capacity to measure the diameter and lumen area of the central airways accurately during bronchoscopy. This study describes the first clinical use of aOCT imaging in the lower airways in three individuals with common endobronchial pathologies. During bronchoscopy, a specialized fiberoptic probe was passed through the biopsy channel of a standard flexible bronchoscope to the site of airway pathology. Airway dimensions were measured from the generated cross-sectional images in three subjects, one with subglottic tracheal stenosis (subject 1), one with malignant left main bronchus (LMB) obstruction (subject 2), and another with severe tracheomalacia (subject 3). Measured dimensions included internal airway diameter, cross-sectional area, and, in subject 1, stenosis length. Tracheal stenosis dimensions, measured using aOCT imaging, correlated with chest CT scan findings and guided the choice of airway stent (subject 1). The airway beyond a malignant obstruction of the LMB, and beyond bronchoscopic view, could be imaged using aOCT, and the distal extent of obstructing tumor identified (subject 2). The severity of newly diagnosed tracheomalacia was able to be quantified using aOCT imaging (subject 3). aOCT imaging during bronchoscopy allows accurate real-time airway measurements and may assist bronchoscopic assessment. 10.1378/chest.08-2800
    Phenotyping airway disease with optical coherence tomography. Coxson Harvey O,Eastwood Peter R,Williamson Jonathan P,Sin Don D Respirology (Carlton, Vic.) Airway diseases are a major concern around the world. However, the pace of new drug and biomarker discovery has lagged behind those of other common disorders such as cardiovascular diseases and diabetes. One major barrier in airway research has been the inability to accurately visualize large or small airway remodelling or dysplastic/neoplastic (either pre or early cancerous) changes using non- or minimally invasive instruments. The advent of optical coherence tomography (OCT) has the potential to revolutionize airway research and management by allowing investigators and clinicians to visualize the airway with resolution approaching histology and without exposing patients to harmful effects of ionizing radiation. Thus, with the aid of OCT, we may be able to accurately determine and quantify the extent of airway remodelling in asthma and chronic obstructive pulmonary disease, detect early pre-cancerous lesions in smokers for chemoprevention, study the upper airway anatomy of patients with obstructive sleep apnea in real time while they are asleep and facilitate optimal selection of stents for those with tracheal obstruction. In this paper, we review the current state of knowledge of OCT and its possible application in airway diseases. 10.1111/j.1440-1843.2010.01888.x
    Monitoring airway mucus flow and ciliary activity with optical coherence tomography. Oldenburg Amy L,Chhetri Raghav K,Hill David B,Button Brian Biomedical optics express Muco-ciliary transport in the human airway is a crucial defense mechanism for removing inhaled pathogens. Optical coherence tomography (OCT) is well-suited to monitor functional dynamics of cilia and mucus on the airway epithelium. Here we demonstrate several OCT-based methods upon an actively transporting in vitro bronchial epithelial model and ex vivo mouse trachea. We show quantitative flow imaging of optically turbid mucus, semi-quantitative analysis of the ciliary beat frequency, and functional imaging of the periciliary layer. These may translate to clinical methods for endoscopic monitoring of muco-ciliary transport in diseases such as cystic fibrosis and chronic obstructive pulmonary disease (COPD). 10.1364/BOE.3.001978
    Real-time subglottic stenosis imaging using optical coherence tomography in the rabbit. Lin Jennifer L,Yau Amy Y,Boyd Jonathon,Hamamoto Ashley,Su Erica,Tracy Lauren,Tracey Lauren,Heidari Andrew E,Wang Alex H,Ahuja Gurpreet,Chen Zhongping,Wong Brian J JAMA otolaryngology-- head & neck surgery IMPORTANCE:Subglottic stenosis (SGS) is a severe, acquired, potentially life-threatening disease that can be caused by endotracheal tube intubation. Newborns and neonates are particularly susceptible to SGS owing to the small caliber of their airway. OBJECTIVE:To demonstrate optical coherence tomography (OCT) capabilities in detecting injury and scar formation using a rabbit model. Optical coherence tomography may provide a noninvasive, bedside or intensive care unit modality for the identification of early airway trauma with the intention of preventing progression to SGS and can image the upper airway through an existing endotracheal tube coupled with a small fiber-optic probe. DESIGN:Rabbits underwent suspension laryngoscopy with induction of of SGS via epithelial injury. This model was used to test and develop our advanced, high-speed, high-resolution OCT imaging system using a 3-dimensional microelectromechanical systems-based scanning device integrated with a fiber-optic probe to acquire high-resolution anatomic images of the subglottic epithelium and lamina propria. SETTING:All experiments were performed at the Beckman Laser Institute animal operating room. INTERVENTION OR EXPOSURE: Optical coherence tomography and endoscopy was performed with suspension laryngoscopy at 6 different time intervals and compared with conventional digital endoscopic images and histologic sections. Fifteen rabbits were killed at 3, 7, 14, 21, and 42 days after the induction of SGS. The laryngotracheal complexes were serially sectioned for histologic analysis. MAIN OUTCOME AND MEASURE:Histologic sections, endoscopic images, and OCT images were compared with one another to determine if OCT could accurately delineate the degree of SGS achieved. RESULTS:The rabbit model was able to reliably and reproducibly achieve grade I SGS. The real-time OCT imaging system was able to (1) identify multiple structures in the airway; (2) delineate different tissue planes, such as the epithelium, basement membrane, lamina propria, and cartilage; and (3) detect changes in each tissue plane produced by trauma. Optical coherence tomography was also able demonstrate a clear picture of airway injury that correlated with the endoscopic and histologic images. With subjective review, 3 patients had high correlation between OCT and histologic images, 10 demonstrated some correlation with histologic images, and 2 showed little to no correlation with histologic images. CONCLUSIONS AND RELEVANCE:Optical coherence tomography, coupled with a fiber-optic probe, identifies subglottic scarring and can detect tissue changes in the rabbit airway to a depth of 1 mm. This technology brings us 1 step closer to minimally invasive subglottic airway monitoring in the intubated neonate, with the ultimate goal of preventing SGS and better managing the airway. 10.1001/jamaoto.2013.2643
    Optical imaging of subacute airway remodeling and adipose stem cell engraftment after airway injury. Ahn Yeh-Chan,Kim Sung Won,Hwang Sang Seok,Chae Yu-Gyeong,Lee Andrew Sungwan,Jung Maan Hong,Chun Bong Kwon,Lee Sang Joon,Park Eun-Kee,Oak Chulho Biomedical optics express Acquired airway injury is frequently caused by endotracheal intubations, long-term tracheostomies, trauma, airway burns, and some systemic diseases. An effective and less invasive technique for both the early assessment and the early interventional treatment of acquired airway stenosis is therefore needed. Optical coherence tomography (OCT) has been proposed to have unique potential for early monitoring from the proliferative epithelium to the cartilage in acute airway injury. Additionally, stem cell therapy using adipose stem cells is being investigated as an option for early interventional treatment in airway and lung injury. Over the past decade, it has become possible to monitor the level of injury using OCT and to track the engraftment of stem cells using stem cell imaging in regenerative tissue. The purpose of this study was to assess the engraftment of exogenous adipose stem cells in injured tracheal epithelium with fluorescent microscopy and to detect and monitor the degree of airway injury in the same tracheal epithelium with OCT. OCT detected thickening of both the epithelium and basement membrane after tracheal scraping. The engraftment of adipose stem cells was successfully detected by fluorescent staining in the regenerative epithelium of injured tracheas. OCT has the potential to be a high-resolution imaging modality capable of detecting airway injury in combination with stem cell imaging in the same tracheal mucosa. 10.1364/BOE.5.000312
    In vivo detection of inhalation injury in large airway using three-dimensional long-range swept-source optical coherence tomography. Chou Lidek,Batchinsky Andriy,Belenkiy Slava,Jing Joseph,Ramalingam Tirunelveli,Brenner Matthew,Chen Zhongping Journal of biomedical optics We report on the feasibility of using long-range swept-source optical coherence tomography (OCT) to detect airway changes following smoke inhalation in a sheep model. The long-range OCT system (with axial imaging range of 25 mm) and probe are capable of rapidly obtaining a series of high-resolution full cross-sectional images and three-dimensional reconstructions covering 20-cm length of tracheal and bronchial airways with airway diameter up to 25 mm, regardless of the position of the probe within the airway lumen. Measurements of airway thickness were performed at baseline and postinjury to show mucosal thickness changes following smoke inhalation. 10.1117/1.JBO.19.3.036018
    Validation of airway wall measurements by optical coherence tomography in porcine airways. Lee Anthony M D,Kirby Miranda,Ohtani Keishi,Candido Tara,Shalansky Rebecca,MacAulay Calum,English John,Finley Richard,Lam Stephen,Coxson Harvey O,Lane Pierre PloS one Examining and quantifying changes in airway morphology is critical for studying longitudinal pathogenesis and interventions in diseases such as chronic obstructive pulmonary disease and asthma. Here we present fiber-optic optical coherence tomography (OCT) as a nondestructive technique to precisely and accurately measure the 2-dimensional cross-sectional areas of airway wall substructure divided into the mucosa (WAmuc), submucosa (WAsub), cartilage (WAcart), and the airway total wall area (WAt). Porcine lung airway specimens were dissected from freshly resected lung lobes (N = 10). Three-dimensional OCT imaging using a fiber-optic rotary-pullback probe was performed immediately on airways greater than 0.9 mm in diameter on the fresh airway specimens and subsequently on the same specimens post-formalin-fixation. The fixed specimens were serially sectioned and stained with H&E. OCT images carefully matched to selected sections stained with Movat's pentachrome demonstrated that OCT effectively identifies airway epithelium, lamina propria, and cartilage. Selected H&E sections were digitally scanned and airway total wall areas were measured. Traced measurements of WAmuc, WAsub, WAcart, and WAt from OCT images of fresh specimens by two independent observers found there were no significant differences (p>0.05) between the observer's measurements. The same wall area measurements from OCT images of formalin-fixed specimens found no significant differences for WAsub, WAcart and WAt, and a small but significant difference for WAmuc. Bland-Altman analysis indicated there were negligible biases between the observers for OCT wall area measurements in both fresh and formalin-fixed specimens. Bland-Altman analysis also indicated there was negligible bias between histology and OCT wall area measurements for both fresh and formalin-fixed specimens. We believe this study sets the groundwork for quantitatively monitoring pathogenesis and interventions in the airways using OCT. 10.1371/journal.pone.0100145
    Spatiotemporal correlation of optical coherence tomography in-vivo images of rabbit airway for the diagnosis of edema. Kang DongYel,Wang Alex,Volgger Veronika,Chen Zhongping,Wong Brian J F Journal of biomedical optics Detection of an early stage of subglottic edema is vital for airway management and prevention of stenosis, a life-threatening condition in critically ill neonates. As an observer for the task of diagnosing edema in vivo, we investigated spatiotemporal correlation (STC) of full-range optical coherence tomography (OCT) images acquired in the rabbit airway with experimentally simulated edema. Operating the STC observer on OCT images generates STC coefficients as test statistics for the statistical decision task. Resulting from this, the receiver operating characteristic (ROC) curves for the diagnosis of airway edema with full-range OCT in-vivo images were extracted and areas under ROC curves were calculated. These statistically quantified results demonstrated the potential clinical feasibility of the STC method as a means to identify early airway edema. 10.1117/1.JBO.20.7.076015
    Reproducibility of optical coherence tomography airway imaging. Kirby Miranda,Ohtani Keishi,Nickens Taylor,Lisbona Rosa Maria Lopez,Lee Anthony M D,Shaipanich Tawimas,Lane Pierre,MacAulay Calum,Lam Stephen,Coxson Harvey O Biomedical optics express Optical coherence tomography (OCT) is a promising imaging technique to evaluate small airway remodeling. However, the short-term insertion-reinsertion reproducibility of OCT for evaluating the same bronchial pathway has yet to be established. We evaluated 74 OCT data sets from 38 current or former smokers twice within a single imaging session. Although the overall insertion-reinsertion airway wall thickness (WT) measurement coefficient of variation (CV) was moderate at 12%, much of the variability between repeat imaging was attributed to the observer; CV for repeated measurements of the same airway (intra-observer CV) was 9%. Therefore, reproducibility may be improved by introduction of automated analysis approaches suggesting that OCT has potential to be an in-vivo method for evaluating airway remodeling in future longitudinal and intervention studies. 10.1364/BOE.6.004365
    Validation of human small airway measurements using endobronchial optical coherence tomography. Chen Yu,Ding Ming,Guan Wei-jie,Wang Wei,Luo Wei-zhan,Zhong Chang-hao,Jiang Mei,Jiang Ju-hong,Gu Ying-ying,Li Shi-yue,Zhong Nan-shan Respiratory medicine BACKGROUND:Small airway remodeling is the cardinal feature underlying chronic airway diseases. There is no modality which identifies small airway pathological changes, which is crucial for early diagnosis, efficacy and prognostic assessment. OBJECTIVE:To evaluate the usefulness of endobronchial optical coherence tomography (EB-OCT) in assessing small airways morphology in vivo. METHODS:Twelve patients with pulmonary nodules scheduled for lung resection underwent spirometry, multi-detector computed tomography (MDCT) and EB-OCT. We measured D(mean) (mean luminal diameter), Ai (inner luminal area), Aw (airway wall area) and Aw% [Aw/(Ai + Aw) × 100%] from the 3rd to 5th generation bronchi of RB9 segment by MDCT. D(mean), Ai, Aw and Aw% from the 3rd to 9th generation bronchi of RB9 segment were measured by EB-OCT and histology. Correlations of these parameters, measured by three different methods, were evaluated. We recruited 4 COPD patients to determine if EB-OCT could identify peripheral airway remodeling. RESULTS:The 4 parameters, measured by CT and EB-OCT, correlated significantly [D(mean) (r = 0.991), Ai (r = 0.997), Aw (r = 0.997), Aw% (r = 0.991), all P < 0.01]. Significant correlation were found for these parameters, measured by histology and EB-OCT, from the 3rd to 5th generation bronchi [D(mean) (r = 0.989), Ai (r = 0.997), Aw (r = 0.999), Aw% (r = 0.988), all P < 0.01], and from the 6th to 9th generation bronchi [D(mean) (r = 0.979), Ai (r = 0.997), Aw (r = 0.994) and Aw% (r = 0.988), all P < 0.01]. Significant small airways morphological abnormalities were observed in COPD patients. CONCLUSIONS:EB-OCT, a minimally invasive imaging modality with high-resolution, is useful and clinically practical for assessing proximal and distal airways of human compared with CT and histology. 10.1016/j.rmed.2015.09.006
    Long-Range Optical Coherence Tomography of the Neonatal Upper Airway for Early Diagnosis of Intubation-related Subglottic Injury. Sharma Giriraj K,Ahuja Gurpreet S,Wiedmann Maximilian,Osann Kathryn E,Su Erica,Heidari Andrew E,Jing Joseph C,Qu Yueqiao,Lazarow Frances,Wang Alex,Chou Lidek,Uy Cherry C,Dhar Vijay,Cleary John P,Pham Nguyen,Huoh Kevin,Chen Zhongping,Wong Brian J-F American journal of respiratory and critical care medicine RATIONALE:Subglottic edema and acquired subglottic stenosis are potentially airway-compromising sequelae in neonates following endotracheal intubation. At present, no imaging modality is capable of in vivo diagnosis of subepithelial airway wall pathology as signs of intubation-related injury. OBJECTIVES:To use Fourier domain long-range optical coherence tomography (LR-OCT) to acquire micrometer-resolution images of the airway wall of intubated neonates in a neonatal intensive care unit setting and to analyze images for histopathology and airway wall thickness. METHODS:LR-OCT of the neonatal laryngotracheal airway was performed a total of 94 times on 72 subjects (age, 1-175 d; total intubation, 1-104 d). LR-OCT images of the airway wall were analyzed in MATLAB. Medical records were reviewed retrospectively for extubation outcome. MEASUREMENTS AND MAIN RESULTS:Backward stepwise regression analysis demonstrated a statistically significant association between log(duration of intubation) and both laryngeal (P < 0.001; multiple r(2) = 0.44) and subglottic (P < 0.001; multiple r(2) = 0.55) airway wall thickness. Subjects with positive histopathology on LR-OCT images had a higher likelihood of extubation failure (odds ratio, 5.9; P = 0.007). Longer intubation time was found to be significantly associated with extubation failure. CONCLUSIONS:LR-OCT allows for high-resolution evaluation and measurement of the airway wall in intubated neonates. Our data demonstrate a positive correlation between laryngeal and subglottic wall thickness and duration of intubation, suggestive of progressive soft tissue injury. LR-OCT may ultimately aid in the early diagnosis of postintubation subglottic injury and help reduce the incidences of failed extubation caused by subglottic edema or acquired subglottic stenosis in neonates. Clinical trial registered with www.clinicaltrials.gov (NCT 00544427). 10.1164/rccm.201501-0053OC
    Automatic airway wall segmentation and thickness measurement for long-range optical coherence tomography images. Qi Li,Huang Shenghai,Heidari Andrew E,Dai Cuixia,Zhu Jiang,Zhang Xuping,Chen Zhongping Optics express We present an automatic segmentation method for the delineation and quantitative thickness measurement of multiple layers in endoscopic airway optical coherence tomography (OCT) images. The boundaries of the mucosa and the sub-mucosa layers are accurately extracted using a graph-theory-based dynamic programming algorithm. The algorithm was tested with sheep airway OCT images. Quantitative thicknesses of the mucosal layers are obtained automatically for smoke inhalation injury experiments. 10.1364/OE.23.033992
    Measuring Airway Remodeling in Patients With Different COPD Staging Using Endobronchial Optical Coherence Tomography. Ding Ming,Chen Yu,Guan Wei-Jie,Zhong Chang-Hao,Jiang Mei,Luo Wei-Zhan,Chen Xiao-Bo,Tang Chun-Li,Tang Yan,Jian Qi-Ming,Wang Wei,Li Shi-Yue,Zhong Nan-Shan Chest BACKGROUND:Although FEV remains the gold standard for staging COPD, the association between airway remodeling and airflow limitation remains unclear. Endobronchial optical coherence tomography (EB-OCT) was performed to assess the association between disorders of large and medium to small airways and COPD staging. We also evaluated small airway architecture in heavy smokers with normal FEV (S) and healthy never-smokers. METHODS:We recruited 48 patients with COPD (stage I, n = 14; stage II, n = 15; stage, III-IV, n = 19), 21 S, and 17 healthy never-smokers. A smoking history inquiry, as well as spirometry, chest CT, bronchoscopy, and EB-OCT were performed. Mean luminal diameter (D), inner luminal area (Ai), and airway wall area (Aw) of third- to ninth-generation bronchi were measured using EB-OCT. RESULTS:Patients with more advanced COPD demonstrated greater abnormality of airway architecture in both large and medium to small airways, followed by S and never-smokers. Abnormality of airway architecture and EB-OCT parameters in S were comparable to those in stage I COPD. FEV% predicted correlated with D and Ai of seventh- to ninth-generation bronchi in COPD; however, neither D nor Ai of third- to sixth-generation bronchi correlated with FEV% in stage I and stage II COPD and in S. CONCLUSIONS:FEV-based COPD staging partially correlates with small airway disorders in stage II-IV COPD. Small airway abnormalities detected by EB-OCT correlate with FEV-based staging in COPD and identify early pathologic changes in healthy heavy smokers. 10.1016/j.chest.2016.07.033
    Diagnosis of subglottic stenosis in a rabbit model using long-range optical coherence tomography. Ajose-Popoola Olubunmi,Su Erica,Hamamoto Ashley,Wang Alex,Jing Joseph C,Nguyen Tony D,Chen Jason J,Osann Kathryn E,Chen Zhongping,Ahuja Gurpreet S,Wong Brian J F The Laryngoscope OBJECTIVES/HYPOTHESIS:Current imaging modalities lack the necessary resolution to diagnose subglottic stenosis. The aim of this study was to use optical coherence tomography (OCT) to evaluate nascent subglottic mucosal injury and characterize mucosal thickness and structural changes using texture analysis in a simulated intubation rabbit model. STUDY DESIGN:Prospective animal study in rabbits. METHODS:Three-centimeter-long sections of endotracheal tubes (ETT) were endoscopically placed in the subglottis and proximal trachea of New Zealand White rabbits (n = 10) and secured via suture. OCT imaging and conventional endoscopic video was performed just prior to ETT segment placement (day 0), immediately after tube removal (day 7), and 1 week later (day 14). OCT images were analyzed for airway wall thickness and textural properties. RESULTS:Endoscopy and histology of intubated rabbits showed a range of normal to edematous tissue, which correlated with OCT images. The mean airway mucosal wall thickness measured using OCT was 336.4 μm (day 0), 391.3 μm (day 7), and 420.4 μm (day 14), with significant differences between day 0 and day 14 (P = .002). Significance was found for correlation and homogeneity texture features across all time points (P < .05). CONCLUSIONS:OCT is a minimally invasive endoscopic imaging modality capable of monitoring progression of subglottic mucosal injury. This study is the first to evaluate mucosal injury during simulated intubation using serial OCT imaging and texture analysis. OCT and texture analysis have the potential for early detection of subglottic mucosal injury, which could lead to better management of the neonatal airway and limit the progression to stenosis. LEVEL OF EVIDENCE:NA Laryngoscope, 127:64-69, 2017. 10.1002/lary.26241
    Airway compliance measured by anatomic optical coherence tomography. Bu Ruofei,Balakrishnan Santosh,Iftimia Nicusor,Price Hillel,Zdanski Carlton,Oldenburg Amy L Biomedical optics express Quantification of airway compliance can aid in the diagnosis and treatment of obstructive airway disorders by detecting regions vulnerable to collapse. Here we evaluate the ability of a swept-source anatomic optical coherence tomography (SSaOCT) system to quantify airway cross-sectional compliance (CC) by measuring changes in the luminal cross-sectional area (CSA) under physiologically relevant pressures of 10-40 cmHO. The accuracy and precision of CC measurements are determined using simulations of non-uniform rotation distortion (NURD) endemic to endoscopic scanning, and experiments performed in a simplified tube phantom and porcine tracheas. NURD simulations show that CC measurements are typically more accurate than that of the CSAs from which they are derived. Phantom measurements of CSA versus pressure exhibit high linearity (>0.99), validating the dynamic range of the SSaOCT system. Tracheas also exhibited high linearity ( = 0.98) suggestive of linear elasticity, while CC measurements were obtained with typically ± 12% standard error. 10.1364/BOE.8.002195
    Optical coherence tomography for identification and quantification of human airway wall layers. d'Hooghe Julia N S,Goorsenberg Annika W M,de Bruin Daniel M,Roelofs Joris J T H,Annema Jouke T,Bonta Peter I PloS one BACKGROUND:High-resolution computed tomography has limitations in the assessment of airway wall layers and related remodeling in obstructive lung diseases. Near infrared-based optical coherence tomography (OCT) is a novel imaging technique that combined with bronchoscopy generates highly detailed images of the airway wall. The aim of this study is to identify and quantify human airway wall layers both ex-vivo and in-vivo by OCT and correlate these to histology. METHODS:Patients with lung cancer, prior to lobectomy, underwent bronchoscopy including in-vivo OCT imaging. Ex-vivo OCT imaging was performed in the resected lung lobe after needle insertion for matching with histology. Airway wall layer perimeters and their corresponding areas were assessed by two independent observers. Airway wall layer areas (total wall area, mucosal layer area and submucosal muscular layer area) were calculated. RESULTS:13 airways of 5 patients were imaged by OCT. Histology was matched with 51 ex-vivo OCT images and 39 in-vivo OCT images. A significant correlation was found between ex-vivo OCT imaging and histology, in-vivo OCT imaging and histology and ex-vivo OCT imaging and in-vivo OCT imaging for all measurements (p < 0.0001 all comparisons). A minimal bias was seen in Bland-Altman analysis. High inter-observer reproducibility with intra-class correlation coefficients all above 0.90 were detected. CONCLUSIONS:OCT is an accurate and reproducible imaging technique for identification and quantification of airway wall layers and can be considered as a promising minimal-invasive imaging technique to identify and quantify airway remodeling in obstructive lung diseases. 10.1371/journal.pone.0184145
    Significances of spirometry and impulse oscillometry for detecting small airway disorders assessed with endobronchial optical coherence tomography in COPD. Su Zhu-Quan,Guan Wei-Jie,Li Shi-Yue,Ding Ming,Chen Yu,Jiang Mei,Chen Xiao-Bo,Zhong Chang-Hao,Tang Chun-Li,Zhong Nan-Shan International journal of chronic obstructive pulmonary disease Background:Spirometry confers limited value for identifying small-airway disorders (SADs) in early-stage COPD, which can be detected with impulse oscillometry (IOS) and endobronchial optical coherence tomography (EB-OCT). Whether IOS is useful for reflecting small-airway morphological abnormalities in COPD remains unclear. Objectives:To compare the diagnostic value of spirometry and IOS for identifying SADs in heavy-smokers and COPD based on the objective assessment with EB-OCT. Methods:We recruited 59 COPD patients (stage I, n=17; stage II, n=18; stage III-IV, n=24), 26 heavy-smokers and 21 never-smokers. Assessments of clinical characteristics, spirometry, IOS and EB-OCT were performed. Receiver operation characteristic curve was employed to demonstrate the diagnostic value of IOS and spirometric parameters. Results:More advanced staging of COPD was associated with greater abnormality of IOS and spirometric parameters. Resonant frequency (Fres) and peripheral airway resistance (R-R) conferred greater diagnostic values than forced expiratory volume in one second (FEV%) and maximal (mid-)expiratory flow (MMEF%) predicted in discriminating SADs in never-smokers from heavy-smokers (area under curve [AUC]: 0.771 and 0.753 vs 0.570 and 0.558, respectively), and heavy-smokers from patients with stage I COPD (AUC: 0.726 and 0.633 vs 0.548 and 0.567, respectively). The combination of IOS (Fres and R-R) and spirometric parameters (FEV% and MMEF% predicted) contributed to a further increase in the diagnostic value for identifying SADs in early-stage COPD. Small airway wall area percentage (Aw% 7-9), an EB-OCT parameter, correlated significantly with Fres and R-R in COPD and heavy-smokers, whereas EB-OCT parameters correlated with FEV% and MMEF% in advanced, rather than early-stage, COPD. Conclusions:IOS parameters correlated with the degree of morphologic abnormalities of small airways assessed with EB-OCT in COPD and heavy-smokers. Fres and R-R might be sensitive parameters that reliably reflect SADs in heavy-smokers and early-stage COPD. 10.2147/COPD.S172639
    Combined anatomical optical coherence tomography and intraluminal pressure reveal viscoelasticity of the in vivo airway. Balakrishnan Santosh,Bu Ruofei,Iftimia Nicusor,Price Hillel,Zdanski Carlton,Oldenburg Amy L Journal of biomedical optics It is hypothesized that the local, viscoelastic (time-dependent) properties of the airway are important to accurately model and ultimately predict dynamic airway collapse in airway obstruction. Toward this end, we present a portable, endoscopic, swept-source anatomical optical coherence tomography (aOCT) system combined with a pressure catheter to capture local airway dynamics in vivo during respiration. aOCT scans were performed in the airways of a mechanically ventilated pig under paralysis with dynamic and static ventilation protocols. Validation of dynamic aOCT luminal cross-sectional area (CSA) measurements against Cine CT, obtained during the same exam, showed an aggregate difference of 15  %    ±  3  %  . aOCT-derived CSA obtained in the in vivo trachea also exhibited hysteresis as a function of pressure, depicting the viscoelastic nature of the airway wall. The volumetric imaging capabilities were validated by comparing aOCT- and CT-derived geometries of the porcine airway spanning nine generations from the trachea to the bronchioles. The ability to delineate regional differences in airway viscoelastic properties, by measuring airway deformation using aOCT combined with intraluminal pressure, paves the way to patient-specific models of dynamic airway collapse. 10.1117/1.JBO.23.10.100501
    Localized compliance measurement of the airway wall using anatomic optical coherence elastography. Bu Ruofei,Balakrishnan Santosh,Price Hillel,Zdanski Carlton,Mitran Sorin,Oldenburg Amy L Optics express We describe an elastographic method to circumferentially-resolve airway wall compliance using endoscopic, anatomic optical coherence tomography (aOCT) combined with an intraluminal pressure catheter. The method was first demonstrated on notched silicone phantoms of known elastic modulus under respiratory ventilation, where localized compliance measurements were validated against those predicted by finite element modeling. Then, ex vivo porcine tracheas were scanned, and the pattern of compliance was found to be consistent with histological identification of the locations of (stiff) cartilage and (soft) muscle. This quantitative method may aid in diagnosis and monitoring of collapsible airway wall tissues in obstructive respiratory disorders. 10.1364/OE.27.016751
    Advances in Optical Coherence Tomography and Confocal Laser Endomicroscopy in Pulmonary Diseases. Goorsenberg Annika,Kalverda Kirsten A,Annema Jouke,Bonta Peter Respiration; international review of thoracic diseases Diagnosing and monitoring pulmonary diseases is highly dependent on imaging, physiological function tests and tissue sampling. Optical coherence tomography (OCT) and confocal laser endomicroscopy (CLE) are novel imaging techniques with near-microscopic resolution that can be easily and safely combined with conventional bronchoscopy. Disease-related pulmonary anatomical compartments can be visualized, real time, using these techniques. In obstructive lung diseases, airway wall layers and related structural remodelling can be identified and quantified. In malignant lung disease, normal and malignant areas of the central airways, lung parenchyma, lymph nodes and pleura can be discriminated. A growing number of interstitial lung diseases (ILDs) have been visualized using OCT or CLE. Several ILD-associated structural changes can be imaged: fibrosis, cellular infiltration, bronchi(ol)ectasis, cysts and microscopic honeycombing. Although not yet implemented in clinical practice, OCT and CLE have the potential to improve detection and monitoring pulmonary diseases and can contribute in unravelling the pathophysiology of disease and mechanism of action of novel treatments. Indeed, assessment of the airway wall layers with OCT might be helpful when evaluating treatments targeting airway remodelling. By visualizing individual malignant cells, CLE has the potential as a real-time lung cancer detection tool. In the future, both techniques could be combined with laser-enhanced fluorescent-labelled tracer detection. This review discusses the value of OCT and CLE in pulmonary medicine by summarizing the current evidence and elaborating on future perspectives. 10.1159/000503261
    Evaluation of the Normal Airway Morphology Using Optical Coherence Tomography. Su Zhu-Quan,Guan Wei-Jie,Li Shi-Yue,Feng Jia-Xin,Zhou Zi-Qing,Chen Yu,Zhong Ming-Lu,Zhong Nan-Shan Chest BACKGROUND:The anatomic location of small airways, the distribution of airway cartilage, and their correlation with ageing have not been well elucidated. The objective of this article was to explore the morphologic characteristics of small airways in vivo, and how airway structural changes correlate with age using endobronchial optical coherence tomography (EB-OCT). METHODS:We recruited 112 subjects with peripheral pulmonary nodules. Participants underwent CT scan, spirometry, and EB-OCT measurements. We measured the airway internal diameter, the inner area (Ai), the airway wall area percentage (Aw%), and the thickness of airway cartilage. EB-OCT airway structural characteristics at different age intervals were analyzed, and the association between airway morphology and age was evaluated. RESULTS:Of the small airways, 47.3% originated from the seventh generation of bronchi. Cartilage was uniformly present in the third to sixth generation of bronchi, despite a decreasing proportion of cartilage from the seventh to ninth generation of bronchi (92.4%, 54.5%, and 26.8%, respectively). The thickness of airway cartilage progressively decreased with older age. In subjects 40 to 54 years of age, Ai from the third to sixth generation correlated positively with age (r = 0.577, P < .001). Both Ai from the third to sixth generation and Ai from the seventh to ninth generation correlated negatively with age in subjects 55 to 69 years of age (r = -0.374, P = .021 and r = -0.410, P = .011). Aw% from the third to sixth generation and Aw% from the seventh to ninth generation did not correlate significantly with age. CONCLUSIONS:Small airways are mainly located at the seventh generation, where cartilaginous structures are present despite reduced distribution in more distal airways, and the thickness decreased in older age. Reduction in luminal area of medium-to-small airways might be the morphologic changes associated with ageing (ie, > 55 years of age). 10.1016/j.chest.2019.06.009
    Seeing beyond the bronchoscope to increase the diagnostic yield of bronchoscopic biopsy. Hariri Lida P,Villiger Martin,Applegate Matthew B,Mino-Kenudson Mari,Mark Eugene J,Bouma Brett E,Suter Melissa J American journal of respiratory and critical care medicine 10.1164/rccm.201208-1483OE
    Sex Differences in Airway Remodeling in a Mouse Model of Chronic Obstructive Pulmonary Disease. Tam Anthony,Churg Andrew,Wright Joanne L,Zhou Steven,Kirby Miranda,Coxson Harvey O,Lam Stephen,Man S F Paul,Sin Don D American journal of respiratory and critical care medicine RATIONALE:After adjustment for the amount of smoking, women have a 50% increased risk of chronic obstructive pulmonary disease (COPD) compared with men. The anatomic basis and/or mechanism(s) of these sex-related differences in COPD are unknown. OBJECTIVES:To characterize the impact of female sex hormones on chronic cigarette smoke-induced airway remodeling and emphysema in a mouse model of COPD. METHODS:Airway remodeling and emphysema were determined morphometrically in male, female, and ovariectomized mice exposed to 6 months of cigarette smoke. Antioxidant- and transforming growth factor (TGF)-β-related genes were profiled in airway tissues. The selective estrogen receptor modulator tamoxifen was also administered during smoke exposure in a short-term model. Airway wall thickness of male and female human smokers at risk of or with mild COPD was measured using optical coherence tomography. MEASUREMENTS AND MAIN RESULTS:Small airway wall remodeling was increased in female but not male or ovariectomized mice and was associated with increased distal airway resistance, down-regulation of antioxidant genes, increased oxidative stress, and activation of TGF-β1. These effects were prevented by ovariectomy. Use of tamoxifen as a therapeutic intervention mitigated smoke-induced increase in oxidative stress in female mice. Compared with male human smokers, female human smokers had significantly thicker airway walls. CONCLUSIONS:The excess risk of small airway disease in female mice after chronic smoke exposure was associated with increased oxidative stress and TGF-β1 signaling and also was related to the effects of female sex hormones. Estrogen receptor antagonism might be of value in reducing oxidative stress in female smokers. 10.1164/rccm.201503-0487OC
    Birefringence microscopy platform for assessing airway smooth muscle structure and function in vivo. Adams David C,Hariri Lida P,Miller Alyssa J,Wang Yan,Cho Josalyn L,Villiger Martin,Holz Jasmin A,Szabari Margit V,Hamilos Daniel L,Scott Harris R,Griffith Jason W,Bouma Brett E,Luster Andrew D,Medoff Benjamin D,Suter Melissa J Science translational medicine The inability to visualize airway smooth muscle (ASM) cells in vivo is a major obstacle in understanding their role in normal physiology and diseases. At present, there is no imaging modality available to assess ASM in vivo. Confocal endomicroscopy lacks the penetration depth and field of view, and conventional optical coherence tomography (OCT) does not have sufficient contrast to differentiate ASM from surrounding tissues. We have developed a birefringence microscopy platform that leverages the micro-organization of tissue to add further dimension to traditional OCT. We have used this technology to validate ASM measurements in ex vivo swine and canine studies, visualize and characterize volumetric representations of ASM in vivo, and quantify and predict ASM contractile force as a function of optical retardation. We provide in vivo images and volumetric assessments of ASM in living humans and document structural disease variations in subjects with mild asthma. The opportunity to link inflammatory responses to ASM responses and to link ASM responses to clinical responses and outcomes could lead to an increased understanding of diseases of the airway and, ultimately, to improved patient outcomes. 10.1126/scitranslmed.aag1424
    Measuring airway dimensions during bronchoscopy using anatomical optical coherence tomography. Williamson J P,Armstrong J J,McLaughlin R A,Noble P B,West A R,Becker S,Curatolo A,Noffsinger W J,Mitchell H W,Phillips M J,Sampson D D,Hillman D R,Eastwood P R The European respiratory journal Airway dimensions are difficult to quantify bronchoscopically because of optical distortion and a limited ability to gauge depth. Anatomical optical coherence tomography (aOCT), a novel imaging technique, may overcome these limitations. This study evaluated the accuracy of aOCT against existing techniques in phantom, excised pig and in vivo human airways. Three comparative studies were performed: 1) micrometer-derived area measurements in 10 plastic tubes were compared with aOCT-derived area; 2) aOCT-derived airway compliance curves from excised pig airways were compared with curves derived using an endoscopic technique; and 3) airway dimensions from the trachea to subsegmental bronchi were measured using aOCT in four anaesthetised patients during bronchoscopy and compared with computed tomography (CT) measurements. Measurements in plastic tubes revealed aOCT to be accurate and reliable. In pig airways, aOCT-derived compliance measurements compared closely with endoscopic data. In human airways, dimensions measured with aOCT and CT correlated closely. Bland-Altman plots showed that aOCT diameter and area measurements were higher than CT measurements by 7.6% and 15.1%, respectively. Airway measurements using aOCT are accurate, reliable and compare favourably with existing imaging techniques. Using aOCT with conventional bronchoscopy allows real-time measurement of airway dimensions and could be useful clinically in settings where knowledge of airway calibre is required. 10.1183/09031936.00041809
    Elastic properties of the central airways in obstructive lung diseases measured using anatomical optical coherence tomography. Williamson Jonathan P,McLaughlin Robert A,Noffsinger William J,James Alan L,Baker Vanessa A,Curatolo Andrea,Armstrong Julian J,Regli Adrian,Shepherd Kelly L,Marks Guy B,Sampson David D,Hillman David R,Eastwood Peter R American journal of respiratory and critical care medicine RATIONALE:Our understanding of how airway remodeling affects regional airway elastic properties is limited due to technical difficulties in quantitatively measuring dynamic, in vivo airway dimensions. Such knowledge could help elucidate mechanisms of excessive airway narrowing. OBJECTIVES:To use anatomical optical coherence tomography (aOCT) to compare central airway elastic properties in control subjects and those with obstructive lung diseases. METHODS:After bronchodilation, airway lumen area (Ai) was measured using aOCT during bronchoscopy in control subjects (n = 10) and those with asthma (n = 16), chronic obstructive pulmonary disease (COPD) (n = 9), and bronchiectasis (n = 8). Ai was measured in each of generations 0 to 5 while airway pressure was increased from -10 to 20 cm H(2)O. Airway compliance (Caw) and specific compliance (sCaw) were derived from the transpulmonary pressure (Pl) versus Ai curves. MEASUREMENTS AND MAIN RESULTS:Caw decreased progressively as airway generation increased, but sCaw did not differ appreciably across the generations. In subjects with asthma and bronchiectasis, Caw and sCaw were similar to control subjects and the Pl-Ai curves were left-shifted. No significant differences were observed between control and COPD groups. CONCLUSIONS:Proximal airway elastic properties are altered in obstructive lung diseases. Although central airway compliance does not differ from control subjects in asthma, bronchiectasis, or COPD, Ai is lower in asthma and the Pl-Ai relationship is left-shifted in both asthma and bronchiectasis, suggesting that airways are maximally distended at lower inflating pressures. Such changes reflect alteration in the balance between airway wall distensibility and radial traction exerted on airways by surrounding lung parenchyma favoring airway narrowing. Clinical trial registered with Australian New Zealand Clinical Trials Registry (ACTRN12607000624482). 10.1164/rccm.201002-0178OC
    Quantitative upper airway imaging with anatomic optical coherence tomography. Armstrong Julian J,Leigh Matthew S,Sampson David D,Walsh Jennifer H,Hillman David R,Eastwood Peter R American journal of respiratory and critical care medicine BACKGROUND:Measurements of upper airway size and shape are important in investigating the pathophysiology of obstructive sleep apnea (OSA) and in devising, applying, and determining the effectiveness of treatment modalities. We describe an endoscopic optical technique (anatomic optical coherence tomography, aOCT) that provides quantitative real-time imaging of the internal anatomy of the human upper airway. METHODS:Validation studies were performed by comparing aOCT- and computed tomography (CT)-derived measurements of cross-sectional area (CSA) in (1) conduits in a wax phantom and (2) the velo-, oro-, and hypopharynx during wakefulness in five volunteers. aOCT scanning was performed during sleep in one subject with OSA. RESULTS:aOCT generated images of pharyngeal shape and measurements of CSA and internal dimensions that were comparable to radiographic CT images. The mean difference between aOCT- and CT-derived measurements of CSA in (1) the wax phantom was 2.1 mm(2) with limits of agreement (2 SD) from -13.2 to 17.4 mm(2) and intraclass correlation coefficient of 0.99 (p < 0.001) and (2) the pharyngeal airway was 14.1 mm(2) with limits of agreement from -43.7 to 57.8 mm(2) and intraclass correlation coefficient of 0.89 (p < 0.001). aOCT generated quantitative images of changes in upper airway size and shape before, during, and after an apneic event in an individual with OSA. CONCLUSIONS:aOCT generates quantitative, real-time measurements of upper airway size and shape with minimal invasiveness, allowing study over lengthy periods during both sleep and wakefulness. These features should make it useful for study of upper airway behavior to investigate OSA pathophysiology and aid clinical management. 10.1164/rccm.200507-1148OC
    High resolution imaging of the upper respiratory tract with optical coherence tomography: a feasibility study. Pitris C,Brezinski M E,Bouma B E,Tearney G J,Southern J F,Fujimoto J G American journal of respiratory and critical care medicine A need exists in respiratory medicine for a technology capable of identifying airway pathology on a micron scale. This study has demonstrated the feasibility of optical coherence tomography (OCT) for ultrahigh resolution imaging of the upper respiratory tract by in vitro studies of human tissue. OCT is a relatively new technique that can be used to noninvasively collect tomographic images of tissue microstructure with micron-scale resolution. OCT is analogous to ultrasound, measuring the intensity of infrared light rather than acoustical waves. Samples throughout the upper respiratory tract, from the epiglottis to the secondary bronchi, were imaged. The resulting images were compared with histopathology and verified the ability of OCT to delineate relevant structures such as the epithelium, mucosa, cartilage and its sublayers, and glands at a resolution higher than any clinical imaging technology. The ability of OCT to generate image resolution in the range close to that of histopathology in real time, as well as easy integration with small, relatively inexpensive endoscopes, low cost, and lack of a need for a transducing medium, supports the hypothesis that this optical technology could become a powerful modality in the diagnosis and management of a wide range of clinical respiratory pathology. 10.1164/ajrccm.157.5.9707075
    Airway wall thickness assessed using computed tomography and optical coherence tomography. Coxson Harvey O,Quiney Brendan,Sin Don D,Xing Li,McWilliams Annette M,Mayo John R,Lam Stephen American journal of respiratory and critical care medicine RATIONALE:Computed tomography (CT) has been shown to reliably measure the airway wall dimensions of medium to large airways. Optical coherence tomography (OCT) is a promising new micron-scale resolution imaging technique that can image small airways 2 mm in diameter or less. OBJECTIVES:To correlate OCT measurements of airway dimensions with measurements assessed using CT scans and lung function. METHODS:Forty-four current and former smokers received spirometry, CT scans, and OCT imaging at the time of bronchoscopy. Specific bronchial segments were identified and measured using the OCT images and three-dimensional reconstructions of the bronchial tree using CT. MEASUREMENTS AND MAIN RESULTS:There was a strong correlation between CT and OCT measurements of lumen and wall area (r = 0.84, P < 0.001, and r = 0.89, P < 0.001, respectively). Compared with CT, OCT measurements were lower for both lumen and wall area by 31 and 66%, respectively. The correlation between FEV(1)% predicted and CT and OCT measured wall area (as percentage of the total area) of fifth-generation airways was very strong (r = -0.79, r = -0.75), but the slope of the relationship was much steeper using OCT than using CT (y = -0.33x + 82, y = -0.1x + 78), indicating greater sensitivity of OCT in detecting changes in wall measurements that relate to FEV(1). CONCLUSIONS:OCT can be used to measure airway wall dimensions. OCT may be more sensitive at detecting small airway wall changes that lead to FEV(1) changes in individuals with obstructive airway disease. 10.1164/rccm.200712-1776OC