Magnetic and Plasmonic Contrast Agents in Optical Coherence Tomography

Optical coherence tomography (OCT) has gained widespread application for many biomedical applications, yet the traditional array of contrast agents used in incoherent imaging modalities do not provide contrast in OCT. Owing to the high biocompatibility of iron oxides and noble metals, magnetic and plasmonic nanoparticles, respectively, have been developed as OCT contrast agents to enable a range of biological and pre-clinical studies. Here we provide a review of these developments within the past decade, including an overview of the physical contrast mechanisms and classes of OCT system hardware addons needed for magnetic and plasmonic nanoparticle contrast. A comparison of the wide variety of nanoparticle systems is also presented, where the figures of merit depend strongly upon the choice of biological application

Resonant acoustic spectroscopy of soft tissues using embedded magnetomotive nanotransducers and optical coherence tomography

We present a new method for performing dynamic elastography of soft tissue samples. By sensing nanoscale displacements with optical coherence tomography, a chirped, modulated force is applied to acquire the mechanical spectrum of a tissue sample within a few seconds. This modulated force is applied via magnetic nanoparticles, named ‘nanotransducers’, which are diffused into the tissue, and which contribute negligible inertia to the soft tissue mechanical system. Using this novel system, we observed that excised tissues exhibit mechanical resonance modes which are well described by a linear damped harmonic oscillator. Results are validated by using cylindrical tissue phantoms of agarose in which resonant frequencies (30–400 Hz) are consistent with longitudinal modes and the sample boundary conditions. We furthermore show that the Young’s modulus can be computed from their measured resonance frequencies, analogous to resonant ultrasound spectroscopy for stiff material analysis. Using this new technique, named magnetomotive resonant acoustic spectroscopy (MRAS), we monitored the relative stiffening of an excised rat liver during a chemical fixation process

A portable blood plasma clot micro-elastometry device based on resonant acoustic spectroscopy

Abnormal blood clot stiffness is an important indicator of coagulation disorders arising from a variety of cardiovascular diseases and drug treatments. Here, we present a portable instrument for elastometry of microliter volume blood samples based upon the principle of resonant acoustic spectroscopy, where a sample of well-defined dimensions exhibits a fundamental longitudinal resonance mode proportional to the square root of the Young’s modulus. In contrast to commercial thromboelastography, the resonant acoustic method offers improved repeatability and accuracy due to the high signal-to-noise ratio of the resonant vibration. We review the measurement principles and the design of a magnetically actuated microbead force transducer applying between 23 pN and 6.7 nN, providing a wide dynamic range of elastic moduli (3 Pa–27 kPa) appropriate for measurement of clot elastic modulus (CEM). An automated and portable device, the CEMport, is introduced and implemented using a 2 nm resolution displacement sensor with demonstrated accuracy and precision of 3% and 2%, respectively, of CEM in biogels. Importantly, the small strains (<0.13%) and low strain rates (<1/s) employed by the CEMport maintain a linear stress-to-strain relationship which provides a perturbative measurement of the Young’s modulus. Measurements of blood plasma CEM versus heparin concentration show that CEMport is sensitive to heparin levels below 0.050 U/ml, which suggests future applications in sensing heparin levels of post-surgical cardiopulmonary bypass patients. The portability, high accuracy, and high precision of this device enable new clinical and animal studies for associating CEM with blood coagulation disorders, potentially leading to improved diagnostics and therapeutic monitoring

Airway compliance measured by anatomic optical coherence tomography

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 cmH2O. 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 ex vivo 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 (R2>0.99), validating the dynamic range of the SSaOCT system. Tracheas also exhibited high linearity (R2 = 0.98) suggestive of linear elasticity, while CC measurements were obtained with typically ± 12% standard error

Fractal analysis for classification of breast carcinoma in optical coherence tomography

The accurate and rapid assessment of tumor margins during breast cancer resection using optical coherence tomography (OCT) has the potential to reduce patient risk. However, it is difficult to subjectively distinguish cancer from normal fibroglandular stromal tissues in OCT images, and an objective measure is needed. In this initial study, we investigate the potential of a one-dimensional fractal box-counting method for cancer classification in OCT. We computed the fractal dimension, a measure of the self-similarity of an object, along the depth axis of 44 ultrahigh-resolution OCT images of human breast tissues obtained from 4 cancer patients. Correlative histology was employed to identify distinct regions of adipose, stroma, and cancer in the OCT images. We report that the fractal dimension of stroma is significantly higher than that of cancer (P < 10(-5), t-test). Furthermore, by adjusting the cutoff values of fractal dimension between cancer, stroma, and adipose tissues, sensitivities and specificities of either 82.4% and 88.9%, or 88.2% and 81.5%, are obtained, respectively, for cancer classification. The use of fractal analysis with OCT could potentially provide automated identification of tumor margins during breast-sparing surgery

Imaging Extracellular Matrix Remodeling In Vitro by Diffusion-Sensitive Optical Coherence Tomography

The mammary gland extracellular matrix (ECM) is comprised of biopolymers, primarily collagen I, that are created and maintained by stromal fibroblasts. ECM remodeling by fibroblasts results in changes in ECM fiber spacing (pores) that have been shown to play a critical role in the aggressiveness of breast cancer. However, minimally invasive methods to measure the spatial distribution of ECM pore areas within tissues and in vitro 3D culture models are currently lacking. We introduce diffusion-sensitive optical coherence tomography (DS-OCT) to image the nanoscale porosity of ECM by sensing weakly constrained diffusion of gold nanorods (GNRs). DS-OCT combines the principles of low-coherence interferometry and heterodyne dynamic light scattering. By collecting co- and cross-polarized light backscattered from GNRs within tissue culture, the ensemble-averaged translational self-diffusion rate, DT, of GNRs is resolved within ∼3 coherence volumes (10 × 5 μm, x × z). As GNRs are slowed by intermittent collisions with ECM fibers, DT is sensitive to ECM porosity on the size scale of their hydrodynamic diameter (∼46 nm). Here, we validate the utility of DS-OCT using pure collagen I gels and 3D mammary fibroblast cultures seeded in collagen/Matrigel, and associate differences in artificial ECM pore areas with gel concentration and cell seed density. Across all samples, DT was highly correlated with pore area obtained by scanning electron microscopy (R2 = 0.968). We also demonstrate that DS-OCT can accurately map the spatial heterogeneity of layered samples. Importantly, DS-OCT of 3D mammary fibroblast cultures revealed the impact of fibroblast remodeling, where the spatial heterogeneity of matrix porosity was found to increase with cell density. This provides an unprecedented view into nanoscale changes in artificial ECM porosity over effective pore diameters ranging from ∼43 to 360 nm using a micron-scale optical imaging technique. In combination with the topical deposition of GNRs, the minimally invasive nature of DS-OCT makes this a promising technology for studying tissue remodeling processes

Monitoring airway mucus flow and ciliary activity with optical coherence tomography

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)

Photothermal optical coherence tomography in ex vivo human breast tissues using gold nanoshells

We demonstrate photothermal optical coherence tomography (OCT) imaging in highly scattering human breast tissue ex vivo. A 120 kHz axial scan rate, swept-source phase-sensitive OCT system at 1300 nm was used to detect phase changes induced by 830 nm photothermal excitation of gold nanoshells. Localized phase modulation was observed 300–600 μm deep in scattering tissue using an excitation power of only 22 mW at modulation frequencies up to 20 kHz. This technique enables integrated structural and molecular-targeted imaging for cancer markers using nanoshells.National Institutes of Health (U.S.) (Grant Number R01- CA75289-13)United States. Air Force Office of Scientific Research (Contract Number FA9550-07-1-0014)MFELP (Contract Number FA9550-07-1-0101)Natural Sciences and Engineering Research Council of Canada (NSERC) Heritage Scholarship FundCenter for Integration of Medicine and Innovative TechnologyNational Science council of Taiwan. Taiwan Merit Scholarshi

Quantitative upper airway endoscopy with swept-source anatomical optical coherence tomography

Minimally invasive imaging of upper airway obstructions in children and adults is needed to improve clinical decision-making. Toward this goal, we demonstrate an anatomical optical coherence tomography (aOCT) system delivered via a small-bore, flexible endoscope to quantify the upper airway lumen geometry. Helical scans were obtained from a proximally-scanned fiber-optic catheter of 820 μm outer diameter and >2 mm focal length. Coupled with a long coherence length wavelength-swept light source, the system exhibited an SNR roll-off of < 10 dB over a 10 mm range. Operating at 10 rotations/s, the average accuracy of segmented cross-sectional areas was found to be −1.4 ± 1.0%. To demonstrate the capability of this system, aOCT was performed on a pediatric airway phantom and on ex vivo swine trachea. The ability for quantitative endoscopy afforded by this system can aid in diagnosis, medical and surgical decision making, and predictive modeling of upper airway obstructive disorders