Two-Dimensional Cochlear Micromechanics Measured In Vivo Demonstrate Radial Tuning within the Mouse Organ of Corti.

UNLABELLED: The exquisite sensitivity and frequency discrimination of mammalian hearing underlie the ability to understand complex speech in noise. This requires force generation by cochlear outer hair cells (OHCs) to amplify the basilar membrane traveling wave; however, it is unclear how amplification is achieved with sharp frequency tuning. Here we investigated the origin of tuning by measuring sound-induced 2-D vibrations within the mouse organ of Corti in vivo Our goal was to determine the transfer function relating the radial shear between the structures that deflect the OHC bundle, the tectorial membrane and reticular lamina, to the transverse motion of the basilar membrane. We found that, after normalizing their responses to the vibration of the basilar membrane, the radial vibrations of the tectorial membrane and reticular lamina were tuned. The radial tuning peaked at a higher frequency than transverse basilar membrane tuning in the passive, postmortem condition. The radial tuning was similar in dead mice, indicating that this reflected passive, not active, mechanics. These findings were exaggerated in Tecta(C1509G/C1509G) mice, where the tectorial membrane is detached from OHC stereocilia, arguing that the tuning of radial vibrations within the hair cell epithelium is distinct from tectorial membrane tuning. Together, these results reveal a passive, frequency-dependent contribution to cochlear filtering that is independent of basilar membrane filtering. These data argue that passive mechanics within the organ of Corti sharpen frequency selectivity by defining which OHCs enhance the vibration of the basilar membrane, thereby tuning the gain of cochlear amplification. SIGNIFICANCE STATEMENT: Outer hair cells amplify the traveling wave within the mammalian cochlea. The resultant gain and frequency sharpening are necessary for speech discrimination, particularly in the presence of background noise. Here we measured the 2-D motion of the organ of Corti in mice and found that the structures that stimulate the outer hair cell stereocilia, the tectorial membrane and reticular lamina, were sharply tuned in the radial direction. Radial tuning was similar in dead mice and in mice lacking a tectorial membrane. This suggests that radial tuning comes from passive mechanics within the hair cell epithelium, and that these mechanics, at least in part, may tune the gain of cochlear amplification.

Iterative re-weighted approach to high-resolution optical coherence tomography with narrow-band sources.

Optical coherence tomography (OCT) is a non-invasive optical imaging modality capable of high resolution imaging of internal tissue structures. It is widely believed that the high axial resolution in OCT systems requires a wide-bandwidth light source. As a result, often the potential advantages of narrow-bandwidth sources (in terms of cost and/or imaging speed) are understood to come at the cost of significant reduction in imaging resolution. In this paper, we argue that this trade-off between resolution and speed is a shortcoming imposed by the-state-of-the-art A-scan reconstruction algorithm, Fast Fourier Transform, and can be circumvented through use of alternative processing methods. In particular, we investigate the shortcomings of the FFT as well as previously proposed alternatives and demonstrate the first application of an iterative regularized re-weighted l(2) norm method to improve the axial resolution of fast scan rate OCT systems in the narrow-bandwidth imaging conditions. We validate our claims via experimental results generated from a home-built OCT system used to image layered phantom and in vivo data. Our results rely on new, sophisticated signal processing algorithms to generate higher precision (i.e., higher resolution) OCT images at correspondingly fast scan rates. In other words, our work demonstrates the feasibility of simultaneously more reliable and more comfortable medical imaging systems for patients by reducing the overall scan time, without sacrificing image quality.

Enhanced depolarization contrast in polarization-sensitive optical coherence tomography.

We demonstrate the first application of the differential depolarization index (DDI) for depolarization imaging in polarization-sensitive optical coherence tomography (PS-OCT). Unlike the widely used degree of polarization uniformity (DOPU), the DDI is independent of the incident polarization state and, therefore, more robust to varying system and sample parameters. Moreover, it can be applied to single-input-polarization-state PS-OCT systems, and it overcomes several limitations of the emerging depolarization index used in multiple-input-polarization-state systems. Our results on tissue phantoms and human skin prove that DDI yields significant depolarization contrast improvements compared to DOPU, which highlights its potential for depolarization imaging in PS-OCT.

3D reconstruction of cystoscopy videos for comprehensive bladder records.

White light endoscopy is widely used for diagnostic imaging of the interior of organs and body cavities, but the inability to correlate individual 2D images with 3D organ morphology limits its utility for quantitative or longitudinal studies of disease physiology or cancer surveillance. As a result, most endoscopy videos, which carry enormous data potential, are used only for real-time guidance and are discarded after collection. We present a computational method to reconstruct and visualize a 3D model of organs from an endoscopic video that captures the shape and surface appearance of the organ. A key aspect of our strategy is the use of advanced computer vision techniques and unmodified, clinical-grade endoscopy hardware with few constraints on the image acquisition protocol, which presents a low barrier to clinical translation. We validate the accuracy and robustness of our reconstruction and co-registration method using cystoscopy videos from tissue-mimicking bladder phantoms and show clinical utility during cystoscopy in the operating room for bladder cancer evaluation. As our method can powerfully augment the visual medical record of the appearance of internal organs, it is broadly applicable to endoscopy and represents a significant advance in cancer surveillance opportunities for big-data cancer research.

Endothelial pattern formation in hybrid constructs of additive manufactured porous rigid scaffolds and cell-laden hydrogels for orthopedic applications.

Vascularization of tissue engineering constructs (TECs) in vitro is of critical importance for ensuring effective and satisfactory clinical outcomes upon implantation of TECs. Biomechanical properties of TECs have remarkable influence on the in vitro vascularization of TECs. This work utilized in vitro experiments and finite element analysis to investigate endothelial patterns in hybrid constructs of soft collagen gels and rigid macroporous poly(ε-caprolactone)-ß-tricalcium phosphate (PCL-ß-TCP) scaffold seeded/embedded with human umbilical vein endothelial cells (HUVECs) for bone tissue engineering applications. We first fabricated and characterized well-defined porous PCL-ß-TCP scaffolds with identical pore size (500µm) but different strut sizes (200 and 400µm) using additive manufacturing (AM) technology, and then assessed the HUVEC׳s proliferation and morphogenesis within collagen, PCL-ß-TCP scaffold, and the collagen-scaffold hybrid construct. Results showed that, in the hybrid construct, the cell population in the collagen component dropped by day 7 but then increased by day 14. Also, cells migrated onto the struts of the scaffold component, proliferated over time, and formed networks on the thinner struts (i.e., 200µm). Also, the thinner struts resulted in formation of long linear cellular cords structures within the pores. Finite element simulation demonstrated principal stress patterns similar to the observed cell-network pattern. It is probable that the scaffold component modulated patterns of principal stresses in the collagen component as biomechanical cues for reorganization of cell network patterns. Also, the scaffold component significantly improved the mechanical integrity of hydrogel component in the hybrid construct for weight-bearing applications. These results have collectively indicated that the manipulation of micro-architecture of scaffold could be an effective means to further regulate and guide desired cellular response in hybrid constructs.

Multimodal 3D cancer-mimicking optical phantom.

Three-dimensional (3D) organ-mimicking phantoms provide realistic imaging environments for testing various aspects of optical systems, including for evaluating new probe designs, characterizing the diagnostic potential of new technologies, and assessing novel image processing algorithms prior to validation in real tissue. We introduce and characterize the use of a new material, Dragon Skin (Smooth-On Inc.), and fabrication technique, air-brushing, for fabrication of a 3D phantom that mimics the appearance of a real organ under multiple imaging modalities. We demonstrate the utility of the material and technique by fabricating the first 3D, hollow bladder phantom with realistic normal and multi-stage pathology features suitable for endoscopic detection using the gold standard imaging technique, white light cystoscopy (WLC), as well as the complementary imaging modalities of optical coherence tomography and blue light cystoscopy, which are aimed at improving the sensitivity and specificity of WLC to bladder cancer detection. The flexibility of the material and technique used for phantom construction allowed for the representation of a wide range of diseased tissue states, ranging from inflammation (benign) to high-grade cancerous lesions. Such phantoms can serve as important tools for trainee education and evaluation of new endoscopic instrumentation.

Registration of free-hand OCT daughter endoscopy to 3D organ reconstruction.

Despite the trend to pair white light endoscopy with secondary image modalities for in vivo characterization of suspicious lesions, challenges remain to co-register such data. We present an algorithm to co-register two different optical imaging modalities as a mother-daughter endoscopy pair. Using white light cystoscopy (mother) and optical coherence tomography (OCT) (daughter) as an example, we developed the first forward-viewing OCT endoscope that fits in the working channel of flexible cystoscopes and demonstrated our algorithm's performance with optical phantom and clinical imaging data. The ability to register multimodal data opens opportunities for advanced analysis in cancer imaging applications.

Classification of basal cell carcinoma in human skin using machine learning and quantitative features captured by polarization sensitive optical coherence tomography.

We report the first fully automated detection of basal cell carcinoma (BCC), the most commonly occurring type of skin cancer, in human skin using polarization-sensitive optical coherence tomography (PS-OCT). Our proposed automated procedure entails building a machine-learning based classifier by extracting image features from the two complementary image contrasts offered by PS-OCT, intensity and phase retardation (PR), and selecting a subset of features that yields a classifier with the highest accuracy. Our classifier achieved 95.4% sensitivity and specificity, validated by leave-one-patient-out cross validation (LOPOCV), in detecting BCC in human skin samples collected from 42 patients. Moreover, we show the superiority of our classifier over the best possible classifier based on features extracted from intensity-only data, which demonstrates the significance of PR data in detecting BCC.

Robust dipstick urinalysis using a low-cost, micro-volume slipping manifold and mobile phone platform.

We introduce a novel manifold and companion software for dipstick urinalysis that eliminate many of the aspects that are traditionally plagued by user error: precise sample delivery, accurate readout timing, and controlled lighting conditions. The proposed all-acrylic slipping manifold is reusable, reliable, and low in cost. A simple timing mechanism ensures results are read out at the appropriate time. Results are obtained by capturing videos using a mobile phone and by analyzing them using custom-designed software. We show that the results obtained with the proposed device are as accurate and consistent as a properly executed dip-and-wipe method, the industry gold-standard, suggesting the potential for this strategy to enable confident urinalysis testing in home environments.

Metal-insulator-metal waveguides for particle trapping and separation.

Optical particle trapping and separation are essential techniques in the fields of biology and chemistry. In many applications, it is important to identify passive separation techniques that only rely on intrinsic forces in a system with a fixed device geometry. We present a dual-waveguide sorter that utilizes the loss of metal-insulator-metal (MIM) waveguides for completely passive particle trapping and separation and is created using a unique angle sidewall deposition process. Our experiments show that an inner Au-Si3N4-Au waveguide is able to trap particles within the propagation distance of its dominant modes and release the particles into an outer Au-H2O-Au waveguide. The outer waveguide then propels the particles and separates them by size. The separation results are accurately modeled by a first-principles, analytical model.