Optical coherence tomography (OCT) is an emerging medical imaging technology that can generate high resolution, cross-sectional images of tissue in situ and in real time. Although endoscopic OCT has been used successfully to identify certain pathologies in the gastrointestinal tract, the resolution of current endoscopic OCT systems has been limited to 10–15 µm for in vivo studies. In this study, in vivo imaging of the rabbit gastrointestinal tract is demonstrated at a three-fold higher resolution (<5 µm), using a broadband Cr4+:Forsterite laser as the optical light source. Images acquired from the esophagus, trachea, and colon reveal high-resolution details of tissue architecture. Definitive correlation of architectural features in OCT images and histological sections is shown. The ability of ultrahigh resolution endoscopic OCT to image tissue morphology at an unprecedented resolution in vivo advances the development of OCT as a potential imaging tool for the early detection of neoplastic changes in biological tissue.
©2004 Optical Society of America
Optical coherence tomography (OCT) is an imaging modality that can perform high resolution cross-sectional imaging of biological tissues in situ and in real time . One application where high resolution OCT imaging could have a significant impact on the detection and diagnosis of disease is endoscopic imaging. Gastrointestinal (GI) endoscopy has received increased attention over the past several years due to the prevalence of esophageal, stomach, and colonic cancers . In the early stages of development, these cancers manifest as cellular and architectural changes in the epithelium or mucosal layers located inside the wall of the gastrointestinal tract. In contrast to conventional video endoscopy, which can only visualize surface alterations, OCT can detect changes in tissue morphology beneath the tissue surface. Therefore endoscopic imaging with high-resolution OCT has the potential to improve the detection, visualization, and diagnosis of gastrointestinal diseases.
Since OCT can be employed using single-mode optical fibers, it is possible to develop small diameter catheter probes for minimally invasive OCT imaging [3, 4]. The potential of endoscopic OCT imaging has been explored in early in vitro [5, 6] and in vivo studies in animals  and in humans . Improvements in imaging performance have included the use of high-speed delay lines [8, 9], linear scanning catheters , and optimal interferometer designs [11, 12]. New techniques such as endoscopic Doppler imaging have also been demonstrated . Several clinical studies of endoscopic OCT have been performed in the upper as well as lower GI tracts [14–22]. The resolution of standard OCT systems is typically 10–15 µm. While high performance OCT systems can achieve axial resolutions of 1–2 µm by employing broadband optical light sources , almost all clinical studies to date have been performed by using standard OCT with 10–15 µm resolution. Higher resolution imaging systems may provide a critical advance that will enable identification of early neoplastic changes in gastrointestinal tissue. Although excisional biopsy and histopathology are the gold standards for assessing pathology, they often suffer from sampling errors. Biopsy is an error-prone sampling process, since only small areas of tissue are removed and processed for examination. If the biopsy site misses the area of pathology, then a false negative result can occur. A real-time imaging modality such as OCT could enable image guidance of excisional biopsy. This would improve the sensitivity of biopsy by reducing sampling errors and has the advantage that clinical diagnoses could be made using the well accepted standard of biopsy and histopathology.
In this paper, we report in vivo endoscopic OCT imaging in an animal model with the highest axial resolution achieved in endoscopic OCT systems to date (5 µm in air, or 3.7 µm in tissue). The OCT system architecture, catheter design, light source, and experimental procedure are discussed. In vivo OCT imaging results of the upper and lower gastrointestinal tracts, as well as the upper respiratory tract, are presented with corresponding histology. Several scan protocols are demonstrated to visualize tissue structure in multiple cross-sectional imaging planes.
2. Materials and methods
Figure 1 shows a schematic of the OCT imaging system. Light was coupled into a broadband optical circulator and a 90/10 fiber optic coupler, which transmitted 90% of the incident light to the sample. A rapid scanning delay line in the reference arm provided real-time imaging at up to 3125 axial scans per second. Imaging was performed at a frame rate of 4 Hz which corresponded to a transverse pixel image density of up to 780 axial scans per image. The OCT beam was scanned in both longitudinal and rotational directions to generate cross-sectional images of tissue structure in orthogonal imaging planes. To match optical dispersion within the system, SFL6 and LaKN22 dispersion-compensating glasses were inserted in the reference arm to compensate for the catheter focusing optics in the sample arm, and an air gap coupling was used in the sample arm to compensate for the air path in the reference arm from the collimator to the scanning delay mirror. The use of the dispersion-compensating glass and air gap coupling allowed precise dispersion compensation for ultrahigh resolution imaging performance. The backcoupled OCT signal was divided into two orthogonal polarization channels by a polarizing beam splitter, and the two detector outputs were digitally demodulated using a DSP board. A polarization diversity signal was obtained from the square root of the sum of the squared signal intensities from the two polarization channels.
A compact, broadband Cr4+:Forsterite laser combined with a nonlinear fiber was used to generate a spectral bandwidth greater than 200 nm at a center wavelength of 1250 nm. An output power of 50 mW was coupled into a single-mode fiber. The Cr4+:Forsterite laser was somewhat similar to one previously demonstrated [24, 25]; however, it used broadband double-chirped mirrors  to compensate intra-cavity dispersion and achieve a compact, prismless laser design. A compact Yb fiber laser was used as the pump source. Figure 2(a) shows the optical spectrum generated by the Cr4+:Forsterite laser and nonlinear fiber. The bandwidth is 210 nm FWHM. Due to bandwidth limitations in the optical circulator, shorter wavelengths were attenuated and the transmitted spectrum was reduced to 150 nm bandwidth (also shown). The measured axial point spread function shown in Fig. 2(b) has a resolution of 5 µm in air, close to the calculated theoretical value of 4.6 µm for the transmitted bandwidth. This corresponds to an axial resolution of ~3.7 µm in tissue, assuming an index of refraction of ~1.37, and is a three-fold improvement in resolution when compared to previous endoscopic OCT systems. It is expected that, with improvements in bandwidth of the optical interferometer components, better axial resolutions can be achieved. The system detection sensitivity was measured to be 102 dB with 10 mW of power on the sample.
The OCT beam was delivered through a 1.5 mm outer diameter imaging catheter with a focal spot size of 15 µm (2ωo) and a focal distance of 0.5 mm from the outer wall of the catheter sheath. The design of the optical catheter was similar to previously reported designs [3, 4]. The catheter used a single-mode optical fiber with a graded index lens and a microprism encased inside a transparent plastic sheath. An index matching fluid was used between the fiber assembly and the sheath to reduce reflections from the sheath wall. For linear scan imaging in a push-pull mode, the fiber optics of the catheter were driven along the axis of the catheter by a magnetic actuator to create a linear cross-sectional imaging plane. It was possible to adjust the scan length by modifying the input control voltages on the magnetic actuator. The physical position of the OCT beam was synchronized with both image acquisition software and timing signals to generate the OCT image. Rotational imaging was also performed by using rotary-scan actuation of the catheter optics. The fiber optics of the catheter were connected to a rotary free space optical coupler and actuated on the proximal end by using a variable-speed motor. Images were formed by rotating the optical fiber within the catheter sheath, resulting in a radar-like scan of the beam to acquire an image in the plane orthogonal to the catheter.
OCT imaging of the upper and lower gastrointestinal tracts, as well as the respiratory tract, of New Zealand White rabbit was performed. All imaging procedures were performed at MIT facilities with protocol approval by the MIT Committee on Animal Care. The rabbits were initially sedated and anesthesia was administered during the procedure via a marginal ear vein. The OCT catheter was manually introduced into the upper gastrointestinal tract (esophagus) through the oral pharynx. Imaging was performed from the proximal esophagus to the proximal stomach, with particular emphasis placed on imaging the distal esophagus and the gastroesophageal junction. In human subjects, these sites are of primary interest for the evaluation of Barrett’s esophagus, which occurs near the gastroesophageal junction . Barrett’s esophagus is a metaplastic condition associated with chronic gastroesophageal reflux disease, and patients with this condition have elevated risk for esophageal adenocarcinoma . If endoscopic OCT could detect dysplastic changes which occur as a precursor to adenocarcinoma, OCT guidance of excisional biopsy could be performed resulting in improved sensitivity and reduced sampling errors.
For imaging of the lower gastrointestinal tract, the OCT imaging catheter was introduced through the rectum. To minimize animal discomfort and to reduce the risk of damaging the colonic mucosa, a 5.0-French introducer and sterile bacteriostatic lubricant were used during catheter insertion. Imaging was performed from the distal colon to the rectum in both rotational and linear scanning modes. The respiratory tract was also imaged to assess the ability of OCT to delineate tissues inside the pulmonary tract. A midline transverse incision was made in the skin and supportive tissue of the anterior neck, just below the hyoid bone, and a small puncture was made in the cricothyroid membrane. After disinfection, the catheter was introduced through the opening. OCT imaging was done while the catheter was advanced through the trachea until the tracheal bifurcation was reached. After in vivo endoscopic imaging was complete, the animal was euthanized with sodium pentobarbital administered intravenously. Tissues from the esophagus, colon, and trachea were resected for tissue harvest and histological processing. Tissue samples were placed in 10% buffered formalin and stained with hematoxylin and eosin, as well as trichrome stain.
OCT imaging was conducted using both linear and rotary scanning protocols. Figure 3(a) shows an in vivo OCT image of the esophagus taken with the linear scanning catheter. The corresponding histology is shown in Fig. 3(b). The layered structure of the esophagus is clearly delineated, with good definition of the squamous epithelium (e), lamina propria (lp), muscularis mucosa (mm), submucosa (sm), and the inner (im) and outer muscular (om) layers. The OCT image correlated well with the histology in both the order of layers and the layer thickness. This result was also in agreement with previous OCT imaging studies of the esophagus in the rabbit . Changes in the orientation of muscular fiber bundles in the inner and outer muscular layers correlated with different scattering patterns in the corresponding layers seen in the OCT image. Epithelial folds evident in the histology resulted from artifacts introduced by the histological processing. The esophagus contracted when excised, thereby producing a roughened appearance of the epithelium. Since the linear catheter was placed in contact with the esophageal surface to allow for high image contrast, the epithelial layer in the OCT images appeared smooth. Finally, we note a gap under submucosa that was present in the histology but not in the OCT image. This was likely the result of a histological processing artifact. In general, there can be significant changes in tissue dimensions produced by the excision, fixation, and microtoming processes used in histology. Therefore OCT images may provide a more accurate representation of the dimensions of different tissue structures in vivo.
Figure 4(a) shows an in vivo OCT image of the esophagus and trachea. The tracheal hyaline cartilage (hc) is visible through the esophageal wall, thus demonstrating the ability of the endoscopic OCT system to image deeply within the tissue. In addition, the structural details of the tracheal mucosa and trachealis muscle are visible. The vacuous region below the tracheal wall located at the bottom of the image is the tracheal airway. The corresponding histology section in Fig. 4(b) shows very good correlation with the architecture seen in the OCT image. Trichrome staining was used in the histological section to enhance delineation of cartilage rings in the trachea.
With the high speed of the OCT system used for this study, it was possible to image large regions within the gastrointestinal tract while maintaining high axial and transverse image resolutions. Figure 5 shows a composite image of five OCT linear scans acquired sequentially as the catheter was withdrawn during imaging. Images were acquired over a 12 mm scanning range from the epiglottis to the inner esophagus. This image illustrates the capability to visualize continuous morphology over a large field of view at ultrahigh resolution, a method that permits suspect regions to be rapidly surveyed.
Figure 6(a) shows a large-field OCT image of rabbit esophagus, gastroesophageal (GE) junction, and gastric mucosa (stomach) acquired in vivo. The transition region between the esophagus and stomach can be clearly visualized. This region is important in humans because it is the site of metaplastic changes associated with Barrett’s esophagus. Architectural changes from the laminar esophageal mucosa to the gastric mucosa are well differentiated with good correlation to the histological cross section shown in Fig. 6(b). Reduced penetration was observed within the stomach due to high scattering of the gastric mucosa and is consistent with observations in previous OCT studies in humans [16, 17].
In Fig. 7, an in vivo OCT image and corresponding histology of the rabbit colon are shown. The OCT image shows a highly scattering and multi-structured layer at the surface that correlates with the upper colonic mucosa. Individual crypts of Lieberkuhn can be seen in the OCT image and they correlate well with the histological cross section. Increased detail of crypts and features within the colon are visualized in the 2x magnification images on the right of Fig. 7. Crypt boundaries within the lamina exhibit high scattering intensity in the OCT image, thereby increasing the contrast between individual crypts. This allows the colonic crypt structure to be visualized clearly. The capability to resolve crypt features within the colon is important in the clinical diagnosis of conditions such as inflammatory bowel disease and colon cancer. The submucosa appears as a highly scattering layer that separates the muscularis mucosa from the muscularis externa. Sets of cylindrical fiber bundles, which are oriented transverse to the OCT catheter beam, are also visible within the OCT image (arrows).
In addition to lateral scanning, rotational scanning within the esophagus and colon was also performed. Figure 8 shows cross-sectional images of the rabbit esophagus and stomach generated by rotational scanning at 4 frames per second. The lamina layers are well defined in the esophagus, and the epithelial, mucosal, and submucosal regions can be readily distinguished. The rotational image in the stomach of the rabbit (Fig. 8(b)) shows the characteristic, highly scattering behavior of gastric mucosa as seen in the longitudinal images. Figure 9 illustrates a pullback imaging technique that is useful for surveying luminal structures. To generate this image, the optical fiber assembly was pulled back within the catheter sheath at a constant rate of 0.5 mm/sec, while imaging in a rotational scan mode at 4 rotations per second. Maintaining the external catheter sheath stationary during the pullback scan minimized any motion artifacts or image distortions that would have been caused by movement of the outer sheath surface sheath relative to the colonic wall. Figure 9(a) shows one rotational scan in the pullback sequence. The location of this scan is indicated by the solid line in the full pullback cross section (Fig. 9(b)). The full cross-sectional image of the colon over a 35 mm scan range was acquired in 70 seconds. The orientation of the cross-sectional imaging plane is seen on the rotational scan image (Fig. 9(a)) as the dashed line in the figure. The rotational and cross-sectional pullback images allow simultaneous views of the colon from two aspects. The longitudinal scan format can be valuable in cases where the extent and dimensions of atypical tissue structures must be identified. With the ultrahigh resolution capability of the system, delineation of the colonic mucosa and muscularis was possible. Pullback imaging of the esophagus was also performed with similar performance (data not shown). The full rotational scan data sets acquired from both the colon and esophagus provided sufficient information for reconstruction of three-dimensional images of the gastrointestinal tract. At this imaging speed, the separation of the successive image planes and corresponding pixel spacing is 125 µm in the pullback direction. With increased imaging speeds, higher pixel density, three-dimensional image reconstruction will be possible.
In recent years there has been a substantial increase in the number of endoscopic procedures aimed at the early detection and diagnosis of gastrointestinal diseases. While video endoscopy is the most established clinical technique, its diagnostic utility is limited by its inability to image below the tissue surface. Although endoscopic ultrasound allows sub-surface imaging within the GI tract, its resolution is limited to features with dimensions larger than 100 µm. OCT is emerging as a new and powerful technique in endoscopic imaging that can image at resolutions 10–20 times greater than conventional ultrasound or MRI, and it has the potential to detect changes in tissue structure associated with disease pathogenesis. Clinical studies have been performed in humans on both the upper and lower gastrointestinal tracts and they indicate that OCT can differentiate normal from diseased tissue states, such as specialized intestinal metaplasia in Barrett’s esophagus and adenocarcinoma.
While standard resolution OCT systems have demonstrated the ability to visualize architectural changes associated with Barrett’s esophagus, ultrahigh resolution OCT could significantly increase the ability to visualize morphological changes characteristic of dysplasia. In particular, the ability to visualize high grade dysplasia would enable endoscopic OCT to guide excisional biopsy, thereby reducing sampling errors and improving sensitivity.
To obtain ultrahigh resolution OCT images, axial resolution can be increased through the use of broadband optical light sources. Standard OCT systems and most previous studies have used superluminescent diodes. The optical bandwidths of these superluminescent diodes are typically 30–60 nm at a central wavelength of 1300 nm, which corresponds to 10–20 µm axial resolution in tissue. In this study, a broadband, high-power Cr4+:Forsterite laser was used to image at ultrahigh resolution. The optical bandwidth of the laser delivered on the sample was 150 nm, which resulted in a 5 µm axial resolution measured in air, corresponding to a resolution of 3.7 µm in tissue. The higher axial resolution achieved with this system provided enhanced visualization of tissue morphology. Broader bandwidths also improve image quality by reducing speckle noise in images. In addition, the excellent correspondence between the OCT images and histopathology suggests the capability of OCT as an imaging technique that can visualize tissue morphology in situ and in real time. The results from this animal model suggest the potential of ultrahigh resolution endoscopic OCT imaging of gastrointestinal pathologies. Improvement of image resolution in OCT may enhance the capability to detect early neoplastic changes in gastrointestinal tissue.
The studies demonstrated here achieved ultrahigh resolution in the axial direction by using broadband light sources. However, the resolution in the transverse direction is determined by the numerical aperture of the focused spot size. Smaller spot sizes can be achieved by higher numerical aperture focusing, but the depth of focus will be reduced. Improving transverse resolutions remains challenging and will likely require special catheter designs for focus tracking.
The OCT scan format also has an important influence on image quality. For luminal structures, the most common format used for OCT is a radial scan performed by rotating the fiber optic catheter along its central axis. A benefit of this scan format is that the OCT catheter can be pulled back during the rotational motion to obtain a scan over a large tissue volume. By using rotational scanning with catheter pullback in this study, it was possible to obtain a spiral OCT scan over a large tissue volume. This is a powerful technique to identify regions of interest within a gastrointestinal lumen for subsequent diagnosis or identification of biopsy sites. It is also possible to use this scanning method to form three-dimensional images of the lumen by volume reconstruction methods.
In the linear scanning mode, the catheter was moved in a push-pull manner to create a line scan along a section of the lumen. With linear scanning, the cross-sectional image can have a higher pixel density and better transverse image resolution than radial scanning. This is because, in a radial scan format, pixel density is decreased at more distant radial positions in the scan. A linear scanning method does not suffer from this effect; however, it usually requires a more complex scanning mechanism for actuation and is more prone to non-uniform motion. In this study, a magnetic voice coil actuator was used to achieve precise linear actuation over the OCT scan range. It is also challenging to orient the radial direction of the optical beam while the catheter is scanning in a linear mode. Design modifications were implemented in the catheter construction and mounting configuration to allow the operator to simultaneously rotate the catheter orientation while scanning in a linear mode.
Pullback imaging was demonstrated here in the rabbit esophagus and colon, but successful pullback imaging of larger lumens such as the human esophagus may require special catheter designs. A novel balloon catheter design for intraluminal catheter stabilization was previously suggested . The balloon acts to insufflate the esophagus to a uniform diameter while stabilizing the radial-scanning catheter near the center of the lumen. OCT imaging can then be performed by radial scanning the beam during the pullback in a manner similar to spiral computed tomography. With improvements in OCT imaging speed, surveys of large areas can be performed in the future.
In this study ultrahigh resolution OCT images were obtained of the rabbit esophagus, trachea, and colon with minimally invasive catheter devices. Using a broadband Cr4+:Forsterite laser, endoscopic OCT imaging in vivo was demonstrated with ~3.7 µm axial image resolution in tissue. To the best of our knowledge, this is the highest endoscopic resolution demonstrated to date. Linear and rotary scanning catheters were used to generate high pixel density images at a real-time imaging rate of 4 frames per second. Histological cross sections were obtained from in vivo imaging sites and excellent correspondence of architectural detail was seen between histopathology and OCT scans. Identification of clinically relevant tissue morphology was possible at ultrahigh resolution and was in agreement with histological findings. By imaging in real time it was possible to construct large-field, ultrahigh resolution OCT images from consecutive lateral scans. High image penetration in tissue was realized and enabled imaging through the complete esophagus and tracheal walls in the rabbit. Visualization of individual colonic crypts was also achieved at ultrahigh resolution. These results demonstrate the feasibility of using ultrahigh resolution endoscopic OCT to identify architectural features within the gastrointestinal tract. Ongoing advances in the development of turn-key and commercial broadband optical light sources promise to give investigators wider access to ultrahigh resolution OCT imaging capability. Further clinical studies will be pursued to establish the performance of ultrahigh resolution OCT in human subjects.
We thank K. Schneider, P. Hsiung, K. Madden, and Prof. F. Kaertner for their technical assistance and helpful discussions. This research was sponsored in part by the National Institutes of Health R01-CA75289-06 and R01-EY11289-18, the National Science Foundation ECS-01-19452 and BES-0119494, the Air Force Office of Scientific Research Medical Free Electron Laser Program F49620-01-1-0186 and F49620-01-01-0084, the Poduska Family Foundation Fund for Innovative Research in Cancer, and through the philanthropy of Mr. Gerhard Andlinger.
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