Recent Advances in Optical Coherence Tomography for the Diagnoses of Lung Disorders

Randy Hou; Tho Le; Septimiu D Murgu; Zhongping Chen; Matt Brenner

Disclosures

Expert Rev Resp Med. 2011;5(5):711-724. 

In This Article

Future Directions

New Pulmonary Applications

Airway Compliance Airway compliance is a key factor in peripheral and central obstructive lung diseases such as asthma, COPD and tracheobronchomalacia, respectively. New research is being developed using OCT to analyze strains during breathing and provides estimates of the elastic properties of the airway. In experimental models, these techniques were used to assess the compliance of rabbit trachea in vivo, in its normal state as well as in a wound-healing model.[42] This information could be clinically useful for identifying the collapsible airway segments that limit airflow (also known as 'choke points') in patients with dynamic central airway obstruction who may require stabilizing procedures such as stent insertion or tracheoplasty.[43,44]

Doppler OCT The interaction between the lungs and the pulmonary vasculature is extremely dynamic, with disorder in the lung significantly affecting the structure and function of the vasculature. Doppler OCT is being investigated as a means to provide imaging of the pulmonary vessels, and has been shown to be able to visualize even small bronchial vasculature in vivo.[45] The basic principle of Doppler OCT is that the broadband laser signals will be Doppler shifted when reflecting off of moving surfaces, resulting in shifts in the interference pattern. These shifts provide the information on highly specific, spatially localized velocities of the target tissues involved. This information is potentially useful for calculating resistance indices in the mediastinal lymph nodes thus potentially facilitating differentiation between benign and malignant lymphadenopathy as has already been suggested by application of color Doppler ultrasonography.[46]

Alveolar Imaging The dynamics of the alveoli are insufficiently studied since there has been no previous method able to provide real time dynamic imaging of such a minute structure. New research has been able to provide 3D images of in vivo murine subpleural alveoli during the inspiratory phase utilizing a triggered SS-OCT system. The ability to capture alveoli dynamics can provide valuable insight into the pathophysiology of lung injury states such as ventilator-associated lung injury, acute lung injury and acute respiratory distress syndrome, and inspire new therapeutic options for an illness that carries a very high mortality rate.[47] There are several limitations of alveolar OCT studies at this time and, therefore, it is unlikely that this technology will be clinically valuable in the very near future. Owing to the major changes in refractive index between air filled alveoli and alveolar walls/interstitium, only a few alveolar layers can be visualized. In addition, these tend to be adjacent to the probe (or window to lung surface). Thus, questions remain over sampling error bias, and potential differences between function of surface or probe adjacent alveolar function compared with other alveolar sites. Use of index matching fluid filling has been described to improve depths of penetration for OCT, but the additional penetration benefits are modest and effects on alveolar properties from fluid filling must be considered.

Needle-based OCT Although OCT excels in providing high resolution images at very high speeds, a major limitation of OCT is its depth of penetration, which in most cases does not exceed 2–4 mm. One way to overcome this barrier, which is currently being investigated is the use of needle-based OCT platforms. A frequency-domain OCT probe was miniaturized and placed inside a 23-gauge hypodermic needle. Fresh, ex vivo sheep lungs were analyzed using this needle probe, and 3D images of individual alveoli and small respiratory bronchioles several centimeters below the surface were captured using this approach.[48]

Sampling of lymph nodes can sometimes prove difficult, depending on the location and size and often requires invasive methods, which carry significant morbidity risks. In an ex vivo animal model, tumor cells were injected into the lymphatic system, and excised popliteal lymph nodes were examined with OCT. OCT was able to capture images of the capsule, precortical regions, follicles and germinal centers. The findings were compared with OCT images of normal lymph nodes, as well as histopathological preparations of the same lymph nodes. OCT images correlated well with the histologic findings in showing the inflammatory and immunologic changes of the malignant lymph nodes.[49] In a different study, OCT imaging of the ex vivo lymph node specimens demonstrated a clear correlation with histology. OCT was shown to enable differentiation of lymph node tissue from surrounding adipose tissue, reveal nodal structures such as germinal centers and intranodal vessels, and show both diffuse and well circumscribed patterns of metastatic node involvement.[50] The potential to image metastatic deposits using OCT opens the possibility of new in vivo techniques for the assessment of lymph node involvement. While biopsy may still be necessary, OCT can be used as a guide to aim for the intranodal areas involved with tumor, thus increasing the yield of the procedure. Therefore, needle-based OCT holds potential to be utilized in combination with many other modalities to guide needle biopsies. While a true 'optical biopsy' in clinical practice may be years away from becoming a reality (if ever) owing to the inability to provide vital information from special stains, immunohistochemical assays, culture, sensitivity and genotyping information, OCT-guided needle biopsies have the potential to become integrated into clinical practice in the relatively near future.

Another aspect of the airway that has not been well studied in vivo is the ciliary system, which serves to clear excess mucus and other foreign bodies out of the airway. No previous method has been able to capture ciliary motion and its changes in response to mucus in vivo and in 3D. In a novel research endeavor, OCT was used to visualize active cilia, and characterize the beating motion into resting, recovery and effective phases. OCT was also able to monitor ciliary motion in response to a heavy mucus load. The ciliary system was seen to both recruit more cilia, and increase the beat frequency by up to 50% in response to increased mucus. This new insight into ciliary mechanisms can potentially be utilized in the clinical application of various diseases such as cystic fibrosis, bronchiectasis of other etiologies, and diseases such as Kartagener's syndrome.[51]

Advancing OCT Technology

Many optical and bioengineering groups are currently developing novel systems that are performing OCT with faster and better results. These systems are scanning at much higher speeds and producing images with much higher spatial resolution than before. Some groups are reporting four-times the scanning speed of any prior system (approaching MHz axial scanning rates), and spatial resolutions of 6 µm to as low as 2.1 µm have been reported as well. These are accomplished through a variety of new systems such as polarization-sensitive OCT, the use of new and modified light sources, and novel contrast agents such as gold nanoparticles and glucose clearance.[52–57] Although some of these research projects are performed on in vivo lung tissue, many of these research projects use ex vivo tissue or ophthalmologic animal models as, intuitively, these mediums are easier to access with no space restriction. Further validation studies for clinical application of these novel systems, as well as technological advancements to miniaturize these systems, will be needed before these advancements can be applied to in vivo pulmonary medicine.

Multimodality Imaging

Alongside OCT, there are a number of other novel imaging techniques that have their advantages and limitations. One way to capitalize on the best aspects of each technology is to use multiple complementary techniques concurrently in the same clinical application. This multimodality approach using OCT is an area of active research.

With the advent of OCT needle probes, it is feasible to envision a multimodal approach to sampling of mediastinal and hilar lymph nodes with the combination of WLB EBUS[58] and needle-based OCT.[48] In this regard, OCT has been shown in previous studies to effectively image the lymph node and may be able to distinguish the changes characteristic for malignancy that correlate well with histology.[49] This multimodal approach may further improve the diagnostic yield of EBUS-transbronchial needle aspiration by guiding the needle to areas of lymph node tissue that are highly suspicious for malignancy or other abnormality. In addition, OCT may also provide a higher index of suspicion for malignancy if the OCT images are consistent with cancer but the biopsy is negative, providing further justification for proceeding with a more definitive diagnostic procedure such as a mediastinoscopy.

Electromagnetic navigation bronchoscopy (ENB) is a bronchoscopic technique that uses an electromagnetic field and a 3D CT reconstruction of a patient's airways to guide a catheter through the small airways and direct it to a peripheral nodule for sampling. The locating catheter has a sheath around it that is left in place while the catheter is retrieved and a needle or biopsy forceps is inserted through the sheath.[59] It would be relatively seamless to utilize an OCT needle probe instead of a standard biopsy needle. Similar to the current needle EBUS systems for this purpose, OCT could then be used to confirm that the needle is indeed in the lesion of interest; in addition OCT could potentially provide information on its likelihood of being malignant or benign. In the future, if an OCT needle probe could be designed so that the probe could be removed while the needle is left in (or concurrently with the probe OCT fiber in place), then an aspiration of tissue could be obtained without removal of the needle, which would further simplify the procedure and likely lead to increased diagnostic yield.

Confocal endoscopy, based on CFM principles, provides image of a thin section within a biological sample, where the microscope's objective is replaced by a flexible fiberoptic miniprobe and provides images of nuclear and cellular morphology: en face section, parallel to surface with a lateral resolution of 0.2–2 µm; and section thickness of 1–5 µm. Compared with the other optical technologies, CFM has the highest resolution (1 µm), but shallow depth of penetration and covers a small area. For the lung, the commercially available system is currently provided by Manu Kea from France, the Cellvizio system. The respiratory probes are devoid of distal optics and have a depth of focus of 0–50 µm, lateral resolution of 3 µm for a field of view of 600 × 600 µm with a 9–12-frames/s image acquisition. Two wavelengths are available: 488 (for autofluorescence) and 660 nm (for exogenous fluorophores). This system has been used for in vivo autofluorescence of the proximal bronchial wall; the probe is placed over the mucosa, the basement membrane is clearly visualized. The pattern is that of large fibers oriented along the longitudinal axis of the airway with cross-linked small fibers; and large opening of 100–200 µm, corresponding to the openings of the mucosal glands. It can provide near-histologic level images of the mucosal surface, with a depth of penetration of less than 1 mm.[60] Its obvious limitation is the shallow penetration. New probes have been developed that combine confocal microscopy and OCT together for concurrent use in the same clinical application. One study utilized this multimodal approach in analyzing the morphological changes and compliance of alveoli in an ex vivo acute lung injury model. Another group modified a fluorescence confocal microendoscope to accommodate a spectral-domain OCT fiber, thus creating a device capable of simultaneous confocal and OCT imaging.[61,62]

Photoacoustic tomography (PAT) is another new imaging modality that combines optical, thermal and ultrasonic properties of tissue to produce high-resolution images. Essentially, tissue is irradiated with a short-pulsed laser beam, which causes a small rise in temperature, resulting in thermal expansion of the tissue, creating a rise in pressure. This pressure is propagated as an ultrasonic wave, which is the information medium that is collected and processed to produce a photoacoustic image. PAT provides information not available through OCT, including an increased depth range (3–30 mm), as well as functional, molecular and genetic imaging. Endogenous contrast is used to image physiologic changes tissue/organ systems. Molecular imaging uses exogenous contrast to stain biomarkers and provide information on processes occurring at the molecular level. For example, molecular imaging probes can be designed to specifically target biomarkers on tumor cell surfaces. Genetic imaging can be based on fusion of a reporter gene to another segment of interest. This leads to protein expression that can either be imaged directly or is involved in enzymatic reactions that lead to imageable substrates.[63] Current research endeavors are combining OCT and PAT in a multimodal system that can provide advantages of both technologies in one application. One such study utilized OCT as a guidance system in correlation with PAT as the main imaging modality in an ophthalmological study. The increased depth range as well as the capability to provide functional imaging could be useful in pulmonary application in a variety of settings, including imaging of mediastinal structures and lung parenchymal lesions that are not in close proximity to either the airways or the visceral pleura,[64] as well as a clear high resolution visualization of the layers of the entire airway. To our knowledge, there are no reports of the use of this technology for pulmonary application. While PAT can be an excellent addition to the multimodal airway imaging armamentarium, miniaturization of the probes is necessary for bronchoscopic applications.

Positron detection has been utilized in cancer detection, most widely in the technique of PET scanning. In one study, a novel probe was designed that could detect positron emissions as well as produce OCT images. Normal, precancer, and malignant ovarian tissues were analyzed ex vivo using this combined positron–OCT probe. Positron counts in malignant tissue were 3–30-fold higher than in normal tissues. OCT images were able to distinguish changes consistent with malignancy that correlated well with histology preparations. This technique is unique in that it enables both functional and morphologic detection of malignancy.[65] Although this study used ex vivo ovarian cancer as the model, this combination probe could feasibly be used in pulmonary application as well. If the probe was sufficiently small enough to be passed through the working channel of a flexible bronchoscope, it could be used to further confirm areas of malignancy within the thoracic lymph node system when used in conjunction with EBUS, or in the lung parenchyma when used in conjunction with ENB. Its application would be even more powerful if the probe could be miniaturized into a needle-based system.

Identification of Tumor Boundaries Optical coherence tomography may have a role in identification of tumor boundaries in the mucosa and submucosa of airways. Multimodality bronchoscopic imaging including EBUS, OCT and WLB was used in recurrent respiratory papillomatosis. Determining the exact extent of the lesion requires precise delineation of the proximal and distal boundaries of airway involvement. This is an important step in determining operability, extent of resection and resection margins.[66]

Because thermal injury disrupts the normal optical properties of tissues, OCT is capable of visualizing architectural features of the airway wall. It is well suited to defining therapeutic target volumes in situ and to monitoring tissue coagulation, cutting and ablation intraoperatively. This may result in subsequent reduction in iatrogenic collateral airway wall injury which is well described in experimental studies. Furthermore, the use of targeted laser energy to induce localized zones of thermal coagulation and necrosis has been investigated ex vivo and in vivo in animal studies. The effects of laser assisted mechanical dilation in tracheal stenosis were recently investigated and it was noticed that there were clear differences in the OCT imaging at the level of stenosis, in comparison with the normal airway wall structures, and that the charred tissue absorbs the light, the penetration is reduced and the OCT imaging is compromised (Figure 3).[41] If these findings are validated in larger studies, then real time OCT imaging feedback during laser application could soon become applicable in clinical practice.

Figure 3.

Optical coherence tomography findings before and after laser treatment of tracheal stenosis. (A) Optical coherence tomography (OCT) probe overlying the normal tracheal wall. (B) OCT probe at the laser incision site before laser ablation. (C) Laser incision site shows charring. (D) OCT tomogram reveals the normal airway wall layers: mucosa has enhanced reflectivity compared with the underlying submucosa; the extracellular matrix of cartilage decreases scattering of incident light and reflects as a dark region on the OCT image. (E) OCT imaging of the left incision site before laser: the homogeneous light backscattering layer and resultant loss of layer structures is visible. (F) OCT of the charred fibrotic tissue post laser shows a high backscattering layer; the carbonized layer at the surface absorbs and scatters the incident OCT beam resulting in reduced OCT imaging penetration. OCT image size is 2 mm horizontal and 2.2 mm vertical. OCT was performed using a commercial 2D, time-domain system (Niris® Imaging system, Imalux Corp, Cleveland, OH, USA).

Fiber optic reflectance spectroscopy may improve the identification of malignant regions in lymph nodes and improve sampling selection and decrease the false negative rates seen with the current endobronchial ultrasound needle aspiration techniques.[67] In one study, this was accomplished by extending the probe through the sampling needle. When a lesion is identified, the needle is deployed and a sample taken. Normal and metastatic lymph nodes were differentiated by analysis of the single fiber reflectance spectra. Microvascular hemoglobin oxygen saturation and blood volume fraction were found to be lower in metastatic nodes in comparison with normal lymph nodes. As tumor burden worsened, the vasculature inside the node may be destroyed or replaced by tumor cells as well as necrosis and keratinization within the node. Using OCT, one may be able to image lymph nodes and discern surrounding structures and aid in sampling choices in vivo.[67]

Optical coherence tomography can also be used to monitor real time effects and treatment efficacy. One such novel treatment for severely asthmatic patients that has just been approved by the US FDA is bronchial thermoplasty. Asthma is a chronic inflammatory disease that may lead to remodeling, with changes in the airway smooth muscle bundle, cellular hyperplasia and hypertrophy.[68] Hyperplasia and hypertrophy of certain cells/tissues including the airway smooth muscle can lead to decreased airway compliance, changes to the extra and cartilage can decrease elasticity causing flaccidity and malacia. As described before, using aOCT, the elastic properties such as luminal area, airway compliance and specific compliance have been measured and derived.[19] Bronchial thermoplasty is a novel technique designed to reduce the number of airway smooth muscle bundles for patients with chronic severe asthma, thus decreasing the contractility. Using a specially designed bronchial catheter and radiofrequency generator, the airway wall is heated with radiofrequency energy using a flexible bronchoscopic approach.[69] Although this treatment has recently been approved in the USA, there is no method for real time assessment of anatomic effects or dosimetry. OCT could potentially address this need but clinical studies would be required to assess such feasibility in asthmatic patients.

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