Optical techniques in pulmonary medicine

Abstract

There is ongoing interest in the emerging field of pulmonary photonic-based diagnostics. Potential clinical need areas that are being actively investigated at this time include airway and peripheral lung cancer diagnostics, pulmonary parenchymal and interstitial disorders, alveolar structure function, inhalation injury, ciliary function analysis, asthma and obstructive lung diseases.

Pulmonary diseases can involve different parts of the bronchial tree, pleura and/or lung parenchyma. For example, squamous cell carcinoma of the lung is found mainly in the central airways while adenocarcinoma arises in smaller, peripheral airways and the lung parenchyma. Clinically, autofluorescence bronchoscopy is a sensitive method to detect preinvasive bronchial cancers. Narrow-band imaging has higher specificity, but its role compared with high-definition white light examination with a megapixel-charged couple device bronchoscope is not yet defined. Optical coherence tomography (OCT) is more sensitive than endoscopic ultrasound to detect tumor invasion through the basement membrane and it may be useful for guiding treatment decisions [1]. For diagnosis of peripheral tumors, theoretically, OCT has higher resolution than endoscopic ultrasound with a miniature radial probe, but both suffer the same disadvantages of having to couple with another method to navigate the probe to the airway leading to the tumor, and need to change from detector to biopsy catheters to obtain samples once the target has been located [1]. OCT image of tumors can be fairly structureless, making it difficult to differentiate malignant tumors from other benign pathology [2]. Doppler or speckle variance OCT may improve the discrimination between benign and malignant tissue [3,4]. In chronic obstructive pulmonary disease, narrowing and disappearance of small conducting airways occurs before the onset of emphysematous destruction. The changes can explain the increased peripheral airway resistance reported in chronic obstructive pulmonary disease. The resolution of computed tomography is not adequate to image critical events that begin at the seventh branching generation, nor can it measure morphological changes in different layers of the airway wall. On the other hand, the airway remodeling process can be studied in vivo by OCT, confocal microendoscopy and Raman spectroscopy [1,5]. Two studies highlight the importance of correlating airway wall structure measurement with pathology [3,6]. Smooth muscle in the airway wall is currently not well visualized by volumetric optical frequency domain imaging. Further refinement of the technology is needed.

The use of OCT to understand normal and diseased alveolar structure and dynamics is an area of active research. Subpleural OCT has been performed using noncontact 2D scanners [7] or using novel lightweight probes that rest on the pleural surface [8]. Both techniques allow for dynamic assessment of changes in alveolar volume during ventilation to a depth of two to three alveoli. Accurate interpretation of individual alveolar structures from the OCT images can be challenging due to changes in the refractive index of air, tissue and mucous. This refractive index mismatch results in distortion of the 3D alveolar shape and in the appearance of double- and triple-walled alveoli. To mitigate this distortion, investigators are exploring methods including imaging during liquid ventilation to eliminate the air–tissue interface [7], and by developing ray-tracing models to correct for the image distortion using postprocessing algorithms [9]. Novel multimodality OCT and two-photon microscopy techniques are being developed to provide synergistic information regarding alveolar structure using OCT, and elastin density and distribution using two-photon microscopy [10].

Recent technology developments are making strides in increasing the utility of pulmonary optical imaging techniques. Advancements include improvements in the spatial and temporal resolution of imaging systems [11,12], and in the development of novel endobronchial [13] and needle probe catheter designs [14,15]. Ultra-thin 30-gauge rigid OCT catheters have been developed to assess the peripheral lung while reducing the likelihood of pneumothorax [15], and flexible OCT catheters that are compatible with standard 22-gauge transbronchial needles have been developed for the assessment of peripheral nodules [14]. Optical imaging of the lung has been traditionally restricted to endobronchial- or pleural-based imaging. The development of needle probe catheters now facilitates optical assessment of the lung beyond these boundaries.

Efforts are also underway in the development of in vitro and in vivo models of human lung disease for photonics-based research. In vivo cilia-driven microfluidic mixing models have been described and modeled [16,17]. Functional anatomic imaging using micro-optical OCT has demonstrated autoregulatory mechanisms governing ciliary feedback and mucociliary transport in mammalian respiratory ciliated cell systems and primary human cultures [12]. Innovative large animal models of 3D optical frequency domain dynamic responses in large animal models of asthma using the methacholine challenge test demonstrate the potential for investigation of reactive airways disease [18,19]. Marked changes in airway diameter and airway wall were seen in response to methacholine-induced bronchoconstriction [18]. Temporal investigation of smoke inhalation-induced changes in early airway injury have been demonstrated in sheep and rabbit models [1]. Significant changes in airway wall structure, mucosal sloughing and evidence of acute injury were demonstrated using high-resolution OCT very early following smoke exposure in vivo[20]. How these changes will correlate with long-term outcomes can now be investigated to help determine the value of airway imaging for assessment of injury extent, prognostics, and the potential to alter needed therapeutic intervention decisions. Correlation between pulmonary gas exchange and optical measures of anaerobic metabolism were investigated using diffuse optical spectroscopy rabbit models. These model systems have broad-reaching potential for future applications in diseases such as cystic fibrosis, asthma, chronic obstructive pulmonary disease/emphysema, inhalation exposure injuries for diagnostics, as well as therapeutic treatment development programs.

Summary

There is exciting, ongoing research addressing inherent limitations of the clinical application of photonic diagnostics to pulmonary medicine, including:

• • Large size and volume of lungs (with only 10% of airways visible by standard endoscopic approaches);

• • Limited penetration of photons into tissue;

• • High refractive index differences between air and tissue;

• • Limitations of allowable source power;

• • Access to specific lung regions;

• • Ability to localize to targets of interest;

• • Potential for pneumothorax with transthoracic needle approaches, numerous generations of branching airways;

• • Peripheral nature of many lung nodules;

• • High incidence of benign nodules that are hard to distinguish from malignancy;

• • High lethality of lung cancer and need for highly sensitive and specific diagnoses;

• • Respiratory and cardiac motion;

• • The underlying problem of how representative small sampling regions are in systemic lung processes, as well as how to process and evaluate larger data sets as acquisition increases.

These issues are the focus of active research. The ability to overcome these hurdles will ultimately define the role of photonics imaging in pulmonary medicine and will likely involve multimodality approaches in the future.

Conference chairs

MJ Suter (Massachusetts General Hospital, MA, USA); S Lam (The BC Cancer Agency Research Center, BC, Canada); M Brenner (University of California, CA, USA).

Financial & competing interests disclosure

MJ Suter receives research support from NinePoint Medical. NinePoint Medical has a licensing arrangement with Massachusetts General Hospital. MJ Suter has the right to receive royalty payments from NinePoint Medical. M Brenner is a co-investigator on an SBIR Phase II Grant with OCT Medical, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.