Tethered capsule endomicroscopy (TCE) is a recently developed form of in vivo microscopy based on optical coherence tomography (OCT). With TCE, a small tethered pill is swallowed, procuring high resolution microscopic images of the esophageal wall. TCE does not require sedation and is thus a more rapid and convenient procedure comparing to traditional endoscopic examination. Our group and others have successfully conducted OCT-TCE in pilot, single-center studies that demonstrated the potential of this technology for upper GI tract diagnosis. Here, we demonstrate and evaluate the feasibility and safety of a next generation OCT-TCE system and device in patients with Barrett’s esophagus (BE) and report the initial longitudinal analysis of the natural history of BE.
Celiac disease (CD) is an autoimmune disease that damages the small intestine's villi upon gluten ingestion. Intestinal biopsy via esophagogastroduodenoscopy is the current diagnostic gold standard for CD, but this procedure requires sedation and suffers from sampling error. Here, we conducted a clinical study to test whether image biomarkers derived from duodenal OCT tethered capsule endomicroscopy (TCE) can be used to diagnose CD. Results showed a statistically significant difference in OCT image metrics (villus height & width, contrast, and homogeneity with p<0.0001) among active CD, inactive CD and healthy subjects, demonstrating the potential of TCE for the diagnosis of CD.
For OCT-tethered capsule endomicroscopy (TCE) to be a useful minimally invasive tool for evaluating Crohn’s disease, the capsule must be able to be localized within the terminal ileum where the disease often manifests. Here, we developed a machine learning algorithm to assign OCT images of the small intestine into their corresponding anatomical regions. We selected a convolutional neural network and trained it on a set of 2108 cross-sectional images obtained from four swine ex vivo imaging studies to classify images into duodenum, jejunum, or terminal ileum. The model achieved 93±1.72% (95% confidence interval) accuracy on a separate test set of 846 images. These results suggest machine learning may be used to automatically determine when the capsule is in the terminal ileum, enabling microscopic evaluation of this anatomical segment that exhibits pathology in Crohn’s disease.
KEYWORDS: Optical coherence tomography, Luminescence, Imaging systems, Tissues, Process control, Near infrared, Visualization, Standards development, Lens design, Control systems
We present our next generation clinical dual-modality OCT and near infrared autofluorescence/fluorescence (NIRAF/NIRF) imaging platform. This platform allows combined tissue microstructure visualization (OCT) and obtaining molecular information either by intrinsic tissue near infrared autofluorescence (NIRAF) or by exogenous near infrared fluorescence contrast agents (NIRF). Components of this platform, OCT-NIRAF/NIRF imaging system, rotary junction and catheters, were developed using an industry standard design control processes to enable quality clinical translation. We have identified sources of image degradation in dual-modality catheter-based imaging (e.g. core-cladding crosstalk in OCT, background noise in fluorescence) and present methods to mitigate their effects. We also show catheter fabrication and validation, as well as automated fluorescence sensitivity and distance calibration methods that ensure robust and repeatable system performance.
Environmental enteric dysfunction (EED) is a pathological condition of the small intestine that is endemic to low- and middle-income countries (LMICs). EED is thought to interfere with nutrient absorption and enteropathogen exclusion, resulting in altered immune response, increased infection, and limited neurological and physical development. Biopsy of the small intestine is the current diagnostic gold standard for diagnosis yet is untenable due to lack of availability in these countries. Endoscopic biopsy is further problematic since EED-related stunting can only be reversed if diagnosed in the first two years of life when endoscopy must be conducted under anesthesia in advanced medical care settings. Thus, there is an unmet need for a minimally invasive technology for obtaining small intestinal biopsies in unsedated infants in LMICs. To address this need, we have developed an OCT image-guided trans-nasal cryobiopsy device. The device comprises a dual-lumen 1.2 mm outer diameter (OD) probe, terminated by a metal tip, through which Freon is injected. The device is introduced through the lumen of a novel liquid-metal transnasal imaging tube that passively transits to the small intestine. M-mode OCT image guidance is used to determine when the metal tip is in contact with the mucosa so that cryobiopsies may be efficiently acquired. We have conducted feasibility experiments using this device in 10 swine in vivo, demonstrating residual bleeding that is comparable to conventional excisional biopsy, tissue sampling volumes that are greater than or equal to those of conventional biopsy, and high-quality histopathology. These results suggest that this transnasal cryobiopsy technique may be suitable for infants in low-resource settings where EED is prevalent, due to its simplicity and its ability to be used in unsedated subjects.
Upper endoscopy is a standard technique for imaging, sampling, and treating gastrointestinal tissue. Endoscopy is frequently requiring the subjects who undergo the procedure be consciously sedated. Sedation necessitates that the endoscopy procedure be conducted in a specialized setting to mitigate complications should they arise. Endoscopy is further problematic for infants and young children (aged 0-24 months) who sometimes need to be anesthetized. These issues motivate alternative methods for upper gastrointestinal tract visualization and biopsy that do not require conscious sedation/anesthesia. To address this need, we have developed a double lumen 6.5 Fr transnasal introduction catheter (TNIC). During transnasal insertion, real-time OCT imaging provides confirmation of the anatomical location of the device. Once in the stomach, a safe and high-density liquid metal fills a balloon at the distal tip of the TNIC, allowing it to passively transit through stomach into the small intestine. Once properly positioned, OCT-guided instruments for imaging and biopsy can be inserted through main lumen of the TNIC, performing many of the functions of conventional endoscopy and advanced endomicroscopy. To test the feasibility of the TNIC, we conducted a clinical study using the first version of the device in 4 unsedated normal volunteers. Results showed detailed OCT endomicroscopy images of the esophagi and duodena. These results suggest that TNIC may be an effective, less invasive method for the diagnosis of upper GI tract conditions.
KEYWORDS: Optical coherence tomography, Endomicroscopy, Intestine, Endoscopy, Inflammation, Biopsy, 3D image processing, Visualization, Control systems
Environmental Enteric Dysfunction (EED) is a poorly understood condition of the small intestine that is prevalent in regions of the world with inadequate sanitation and hygiene. EED affects 25% of all children globally and causes over a million deaths each year. The condition is associated with increased intestinal permeability, bacterial translocation, inflammation and villous blunting. The loss of absorptive area and intestinal function leads to nutrient malabsorption, with long term outcomes characterized by stunted growth and neurocognitive development. Currently, the only way to directly evaluate the morphology of the intestine is endoscopy with mucosal biopsy. Yet because EED is endemic in low and middle-income countries, endoscopy is untenable for studying EED. As a result, the diagnosis of EED and the assessment of the efficacy of EED interventions is hampered by an inability to evaluate the intestinal mucosa.
Our lab has previously developed a technology termed tethered capsule OCT endomicroscopy (TCE). The method involves swallowing an optomechanically-engineered pill that generates 3D images of the GI tract as it traverses the lumen of the organ via peristalsis, assisted by gravity. In order to study the potential of using TCE to investigate EED, we initiated and conducted a TCE study in adolescents at Aga Khan Medical Center in Pakistan. To make swallowing easier, the tethered capsule’s size was reduced from 11x25 mm to 8x22 mm. Villous morphologic visualization was enhanced by building a notch (x mm deep, y mm wide) in the capsule’s imaging window. To date, 26 Pakistani subjects with ages ranging from 14 to 18 y/o (16.4 +/- 1.0) have been enrolled and imaged. A total of 19 subjects were able to swallow the capsule. Of those, 9 successfully passed through the pylorus, allowing successful microscopic imaging of the entire duodenum. There were no adverse events in any of the cases. Maximum villous height and width were measured from 3 randomly chosen, representative frames from each Pakistan subject as well as a matching number from US controls. Preliminary results, comparing Pakistani vs US villous morphology, indicated that subjects from Pakistan have shorter (628.6 +/- 22.0 um and 492.3 +/- 13.2 um, respectively, p< 0.0001) and wider duodenal villi (244.9 +/- 8.8 um and 293.4 +/- 13.2 um, respectively, p< 0.0001). These findings suggest that OCT TCE of the duodenum may be a useful tool for evaluating villous morphology in EED.
Tethered capsule endomicroscopy (TCE) is a new method for performing comprehensive microstructural OCT imaging of gastrointestinal (GI) tract in unsedated patients in a well-tolerated and cost-effective manner. These features of TCE bestow it with significant potential to improve the screening, surveillance and management of various upper gastrointestinal diseases. To achieve clinical adoption of this imaging technique, it is important to validate it with co-registered histology, the current diagnostic gold standard. One such method for co-registering OCT images with histology is laser cautery marking, previously demonstrated using a balloon-centering OCT catheter that operates in conjunction with sedated endoscopy. With laser marking, an OCT area of interest is identified on the screen and this target is marked in the patient by exposing adjacent tissue to laser light that is absorbed by water, creating superficial, visible marks on the mucosal surface. Endoscopy can then be performed after the device is removed and biopsies taken from the marks. In this talk, we will present the design of a tethered capsule laser marking device that uses a distal stepper motor to perform high precision (< 0.5 mm accuracy) laser targeting and high quality OCT imaging. Ex vivo animal tissue tests and pilot human clinical studies using this technology will be presented.
Environmental enteric dysfunction (EED) is a poorly understood condition of the small intestine prevalent in low and middle income countries. This disease is believed to cause nutrient malabsorption and poor oral vaccine uptake, resulting in arrested neurological development and growth stunting in children that persists as they grow into adulthood. Optical coherence tomography (OCT) imaging of the small intestine can potentially capture some of the microstructural changes, such as villous blunting, in the small gut that accompany EED, and hence could potentially improve the understanding of EED and help in determining and monitoring the effectiveness of EED interventions. Notably, EED must be studied and diagnosed in infants, aged 0-24 months as this is the only window in which interventional strategies can reverse the disease. In order to address this need, we propose a trans-nasal OCT imaging technique for imaging the small intestine that may be suitable for low-resource settings owing to its simplicity, ease of administration, and implementation in unsedated infants. To demonstrate the potential of transnasal OCT intestinal imaging, we have created a 10 Fr transnasal OCT imaging probe and have submitted an IRB application for a first-in-human study using this probe to image the adult small intestine. We anticipate that the results from this pilot study will justify the development of a transnasal OCT intestinal imaging device for infants.
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