Postmortem Digital Image Correlation and Finite Element Modeling Demonstrate Posterior Scleral Deformations during Optic Nerve Adduction Tethering.

Postmortem human eyes were subjected to optic nerve (ON) traction in adduction and elevated intraocular pressure (IOP) to investigate scleral surface deformations. We incrementally adducted 11 eyes (age 74.1 ± 9.3 years, standard deviation) from 26° to 32° under normal IOP, during imaging of the posterior globe, for analysis by three-dimensional digital image correlation (3D-DIC). In the same eyes, we performed uniaxial tensile testing in multiple regions of the sclera, ON, and ON sheath. Based on individual measurements, we analyzed eye-specific finite element models (FEMs) simulating adduction and IOP loading. Analysis of 3D-DIC showed that the nasal sclera up to 1 mm from the sheath border was significantly compressed during adduction. IOP elevation from 15 to 30 mmHg induced strains less than did adduction. Tensile testing demonstrated ON sheath stiffening above 3.4% strain, which was incorporated in FEMs of adduction tethering that was quantitatively consistent with changes in scleral deformation from 3D-DIC. Simulated IOP elevation to 30 mmHg did not induce scleral surface strains outside the ON sheath. ON tethering in incremental adduction from 26° to 32° compressed the nasal and stretched the temporal sclera adjacent to the ON sheath, more so than IOP elevation. The effect of ON tethering is influenced by strain stiffening of the ON sheath.

Biomechanics Explains Variability of Response of Small Hypertropia to Graded Vertical Rectus Tenotomy.

PURPOSE: Small angle hypertropia in sagging eye syndrome is conveniently treated by graded vertical rectus tenotomy, yet an adjustable technique under topical anesthesia has been recommended because of variability of effect. We performed graded tenotomy in an experimental model to elucidate the reason for variability of response to this surgical procedure. DESIGN: Experimental study. METHODS: Thirty-two fresh bovine rectus musculotendon specimens were prepared including continuity with insertional sclera, and extending for a total 40 mm length to the proximal muscle bellies, and trimmed to 16 mm width. Specimens were anchored by the clamps at the scleral insertion and muscle belly ends within a physiological chamber. After preconditioning and elongation to 10% strain was imposed by a linear motor, tensile force was allowed to stabilize at a plateau state. Then 25%, 50%, 75%, 90%, and 100% marginal tenotomies were performed progressively as remnant forces were measured. RESULTS: Tendon thickness averaged 0.29 ± 0.05 mm and width 19.71 ± 2.25 mm. On average, remnant force decreased linearly (R2 = 0.985) from 4.23 ± 1.34, 2.76 ± 0.88, 1.70 ± 0.73, 1.01 ± 0.49, 0.39 ± 0.10, and 0 N, at 0%, 25%, 50%, 75%, 90%, and 100% tenotomy. However, there was marked individual variability in effect among specimens, with coefficients of variation of 32%, 32%, 43%, 49%, and 27%, respectively. CONCLUSION: On average, there is a linear relationship between graded rectus tenotomy and percentage force reduction, but the effect among individual tendons is large, paralleling the reported variation in surgical effect. This explains and implies continued advisability of adjustable technique in this procedure.

Scanning Laser Ophthalmoscopy Demonstrates Pediatric Optic Disc and Peripapillary Strain During Horizontal Eye Rotation.

Purpose: We employed automated analysis of scanning laser ophthalmoscopy (SLO) to determine if mechanical strains imposed on disc, and retinal and choroidal vessels during horizontal duction in children differ from those of adults.Methods: Thirty-one children aged 11.3 ± 2.7 (standard deviation) years underwent SLO in central gaze, and 35° ab- and adduction. Automated registration with deep learning-based optical flow analysis quantified vessel deformations as horizontal, vertical, shear, and equivalent strains. Choroidal vessel displacements in lightly pigmented fundi, and central disc vessel displacements, were also observed.Results: As in adults, strain in vessels during horizontal duction was greatest at the disc and decreased with distance from it. Strain in the pediatric disc was similar to published values in young adults,1 but in the peripapillary region was greater and propagated significantly more peripherally to at least three disc radii from it. During adduction in children, the nasal disc was compressed and disc vessels distorted, but the temporal half experienced tensile strain, while peripapillary tissues were compressed. The pattern was similar but strains were less in abduction (p < .001). Choroidal vessels were visualized in 24 of the 62 eyes and shifted directionally opposite overlying retinal vessels.Conclusions: Horizontal duction deforms the normal pediatric optic disc, central retinal vessels, peripapillary retina, and choroid, shearing the inner retina over the choroid. These mechanical effects occur at the sites of remodeling of the disc, sclera, and choroid associated with typical adult features that later emerge later, including optic cup enlargement, temporal disc tilting, and peripapillary atrophy.

Empirical Quantification of Optic Nerve Strain Due to Horizontal Duction.

Magnetic resonance imaging (MRI) was used to measure in vivo local strains in the optic nerve (ON) associated with horizontal duction in humans. Axial and coronal MRI were collected in target-controlled gazes in 24 eyes of 12 normal adults (six males and six females, 59 ± 16 years) during large (~28°) and moderate (~24°) ductions. The ON, globe, and extraocular muscles were manually identified, and the pixels were converted to point-sets that were registered across different imaging planes and eye positions. Shape of the ON was parameterized based on point-sets. Displacements and strains were computed by comparing deformed with initial ON configurations. Displacements were the largest in the most anterior region. However, strains from adduction were uniform along the length of the ON, while those during abduction increased with distance from the globe and were maximal near the orbital apex. For large gaze angles, ON strain during abduction was primarily due to bending near the orbital apex that is less transmitted to the eye, but during adduction the ON undergoes uniform stretching that transmits much greater loading to the posterior eye, implied by greater strain on the ON.

Scanning Laser Ophthalmoscopy Demonstrates Disc and Peripapillary Strain During Horizontal Eye Rotation in Adults.

PURPOSE: We used automated image analysis of scanning laser ophthalmoscopy (SLO) to investigate mechanical strains imposed on disc, and retinal and choroidal vessels during horizontal duction in adults. DESIGN: Deep learning analysis of optical images. METHODS: The peripapillary region was imaged by SLO in central gaze, and 35° abduction and adduction, in younger and older healthy adults. Automated image registration was followed by deep learning-based optical flow analysis to track determine local tissue deformations quantified as horizontal, vertical, and shear strain maps relative to central gaze. Choroidal vessel displacements were observed when fundus pigment was light. RESULTS: Strains in the retina and disc could be quantified in 22 younger (mean ± SEM, 26 ± 5 years) and 19 older (64 ± 10 years) healthy volunteers. Strains were predominantly horizontal and greater for adduction than for abduction. During adduction, maximum horizontal strain was tensile in the nasal hemi-disc, and declined progressively with distance from it. Strain in the temporal hemi-retina during adduction was minimal, except for compressive strain on the disc of older subjects. In abduction, horizontal strains were less and largely confined to the disc, greater in older subjects, and generally tensile. Vertical and shear strains were small. Nasal to the disc, choroidal vessels shifted nasally relative to overlying peripapillary retinal vessels. CONCLUSIONS: Strain analysis during horizontal duction suggests that the optic nerve displaces the optic canal, choroid, and peripapillary sclera relative to the overlying disc and retina. This peripapillary shearing of the optic nerve relative to the choroid and sclera may be a driver of disc tilting and peripapillary atrophy.

Deep-Learning-Based Segmentation of Extraocular Muscles from Magnetic Resonance Images.

In this study, we investigated the performance of four deep learning frameworks of U-Net, U-NeXt, DeepLabV3+, and ConResNet in multi-class pixel-based segmentation of the extraocular muscles (EOMs) from coronal MRI. Performances of the four models were evaluated and compared with the standard F-measure-based metrics of intersection over union (IoU) and Dice, where the U-Net achieved the highest overall IoU and Dice scores of 0.77 and 0.85, respectively. Centroid distance offset between identified and ground truth EOM centroids was measured where U-Net and DeepLabV3+ achieved low offsets (p > 0.05) of 0.33 mm and 0.35 mm, respectively. Our results also demonstrated that segmentation accuracy varies in spatially different image planes. This study systematically compared factors that impact the variability of segmentation and morphometric accuracy of the deep learning models when applied to segmenting EOMs from MRI.

Linear viscoelasticity of human sclera and posterior ocular tissues during tensile creep.

PURPOSE: Despite presumed relevance to ocular diseases, the viscoelastic properties of the posterior human eye have not been evaluated in detail. We performed creep testing to characterize the viscoelastic properties of ocular regions, including the sclera, optic nerve (ON) and ON sheath. METHODS: We tested 10 pairs of postmortem human eyes of average age 77 ± 17 years, consisting of 5 males and 5 females. Except for the ON that was tested in native shape, tissues were trimmed into rectangles. With physiologic temperature and constant wetting, tissues were rapidly loaded to tensile stress that was maintained by servo feedback as length was monitored for 1,500 sec. Relaxation modulus was computed using Prony series, and Deborah numbers estimated for times scales of physiological eye movements. RESULTS: Correlation between creep rate and applied stress level was negligible for all tissues, permitting description as linear viscoelastic materials characterized by lumped parameter compliance equations for limiting behaviors. The ON was the most compliant, and anterior sclera least compliant, with similar intermediate values for posterior sclera and ON sheath. Sensitivity analysis demonstrated that linear behavior eventually become dominant after long time. For the range of typical pursuit tracking, all tissues exhibit Debora numbers less than 75, and should be regarded as viscoelastic. With a 6.7 Deborah number, this is especially so for the ON during pursuit and convergence. CONCLUSIONS: Posterior ocular tissues exhibit creep consistent with linear viscoelasticity necessary for describing biomechanical behavior of the ON, its sheath, and sclera during physiological eye movements and eccentric ocular fixations. Running Head: Tensile Creep of Human Ocular Tissues.

Optical Coherence Tomography Angiography Demonstrates Strain and Volume Effects on Optic Disk and Peripapillary Vasculature Caused by Horizontal Duction.

PURPOSE: The optic nerve mechanically loads the eye during ocular rotation, thus altering the configuration of the disk and peripapillary tissues. We used optical coherence tomography (OCT) angiography (OCTA) to investigate mechanical strains and volume changes in disk and peripapillary blood vessels during horizontal duction. METHODS: Structural OCT and OCTA were performed centered on optic disks; imaging was repeated in central gaze, and in 30° ab- and adduction. By an algorithm employing point-set registration of 3 D features, we developed a novel approach for measuring disk strains, and strains and volumes of the blood vessels associated with horizontal duction. Repeatability was demonstrated in each gaze position. RESULTS: 19 eyes of 10 healthy adults of average age 37 ± 15 (standard deviation, SD) years were imaged. The method was validated by demonstrating numerically consistent vascular volumes and strains for repeated imaging under identical conditions. Compared with central gaze, vascular volume increased by 5.2 ± 4.1% in adduction. Adduction and abduction caused strains of 3.0 ± 1.6% and 2.6 ± 1.8% in the optic disk, whereas blood vessels showed greater strains of 8.1 ± 1.3% and 8.2 ± 1.7%. Decomposition of strain components depending on directionality and regions demonstrated that adduction induces significant net tensile strains, suggesting traction exerted by the optic nerve. The decomposition also showed that nasotemporal compressive strains are larger in temporal hemidisks than nasal hemidisks. The Bruch's membrane opening was significantly compressed horizontally in adduction by 1.1% (p = .009). CONCLUSION: This novel analysis combining structural OCT and OCTA demonstrates that optic disk compression during adduction is associated with disk and vascular strains much larger than reported for intraocular pressure elevation and pulsatile perfusion, as well as compressing the disk and increasing peripapillary vascular volume. These changes may be relevant to the pathogenesis of optic nerve and retinal vascular disorders.

Three-dimensional pore network characterization of reconstructed extracellular matrix.

The extracellular matrix (ECM) has a fiber network that provides physical scaffolds to cells and plays important roles by regulating cellular functions. Some previous works characterized the mechanical and geometrical properties of the ECM fiber network using reconstituted collagen-I. However, the characterization of the porous structure of reconstituted collagen-I has been limited to the pore diameter measurement, and pore network extraction has not been applied to reconstituted collagen-I despite the importance of pore interconnectivity. Here, we aim to show the importance of characterizing the pore network of reconstituted collagen-I by comparing the pore networks of structures that have different fiber alignments. We show that the fiber alignment significantly changes the pore throat area but not the pore diameter. Also, we demonstrate that larger pore throats are directed in the direction of the fiber alignment, which may help in understanding the enhanced cell migration when fibers are aligned.

Emulating endothelial dysfunction by implementing an early atherosclerotic microenvironment within a microfluidic chip.

Recent studies on endothelial dysfunction in relation to vascular diseases including atherosclerosis have highlighted the key contribution of the microenvironment of endothelial cells (ECs). By mimicking the microenvironment of early atherosclerotic lesions, here, we replicate the pathophysiological phenotype and function of ECs within microchannels. Considering the elevated deposition of fibronectin (FN) in early atherosclerotic plaques and the close correlation between the vascular stiffness and the progression of atherosclerosis, we utilized FN coated hydrogels with increased stiffness for endothelial substrates within the microchannels. As a result, we demonstrated that endothelial integrity on FN coated microchannels is likely to be undermined exhibiting a random orientation in response to the applied fluid flow, notable disruption of vascular endothelial cadherins (VE-cadherins), and higher endothelial permeability as opposed to that on microchannels coated with collagen (CL), the atheroresistant vascular model.

Chemotaxis Model for Breast Cancer Cells Based on Signal/Noise Ratio.

Chemotaxis, a biased migration of cells under a chemical gradient, plays a significant role in diverse biological phenomena including cancer metastasis. Stromal cells release signaling proteins to induce chemotaxis, which leads to organ-specific metastasis. Epidermal growth factor (EGF) is an example of the chemical attractants, and its gradient stimulates metastasis of breast cancer cells. Hence, the interactions between EGF and breast cancer cells have long been a subject of interest for oncologists and clinicians. However, most current approaches do not systematically separate the effects of gradient and absolute concentration of EGF on chemotaxis of breast cancer cells. In this work, we develop a theoretical model based on signal/noise ratio to represent stochastic properties and report our microfluidic experiments to verify the analytical predictions from the model. The results demonstrate that even under the same EGF concentration gradients (0-50 or 0-150 ng/mL), breast cancer cells reveal a more evident chemotaxis pattern when the absolute EGF concentrations are low. Moreover, we found that reducing the number of EGF receptors (EGFRs) with addition of EGFR antibody (1 ng/mL) can promote chemotaxis at an EGF gradient of 0-1 ng/mL as shown by chemotaxis index (0.121 ± 0.037, reduced EGFRs vs. 0.003 ± 0.041, control). This counterintuitive finding suggests that EGFR-targeted therapy may stimulate metastasis of breast cancer because the partial suppression of the receptors makes the number of receptors close to the optimal one for chemotaxis. This analysis should be considered in anticancer drug design.

Vasculature-On-A-Chip for In Vitro Disease Models.

Vascularization, the formation of new blood vessels, is an essential biological process. As the vasculature is involved in various fundamental physiological phenomena and closely related to several human diseases, it is imperative that substantial research is conducted on characterizing the vasculature and its related diseases. A significant evolution has been made to describe the vascularization process so that in vitro recapitulation of vascularization is possible. The current microfluidic systems allow elaborative research on the effects of various cues for vascularization, and furthermore, in vitro technologies have a great potential for being applied to the vascular disease models for studying pathological events and developing drug screening platforms. Here, we review methods of fabrication for microfluidic assays and inducing factors for vascularization. We also discuss applications using engineered vasculature such as in vitro vascular disease models, vasculature in organ-on-chips and drug screening platforms.

System tolerance of all-optical sampling OFDM using AWG discrete Fourier transform.

The fundamental-mode arrayed waveguide grating (AWG) for all-optical discrete Fourier transformer (DFT) shows significant feasibility in the system tolerance of all-optical sampling orthogonal frequency division multiplexing (AOS-OFDM) systems. We discuss the system tolerance of AWG-based DFT designs for 100/160Gbps OFDM transmission system in comparison with coupler-based DFT designs.

Anaerobic organic acid production of food waste in once-a-day feeding and drawing-off bioreactor.

Acidogenesis of food waste was studied in a 2-L reactor with semi-continuous mode operation (once-a-day feeding and draw-off) for maximum 65 days to examine optimal volatile acid compositions for biological nitrogen removal (BNR) and enhanced biological phosphorus removal (ENPR). Various operational parameters of hydraulic retention time (HRT), organic loading rate (ORL), pH and temperature were investigated for soluble chemical oxygen demand (SCOD), volatile fatty acid composition, nitrogen and phosphate. The yields (gTVFA/g VS) and the volumetric productivity (gTVFA/d L) increased with HRT from 0.26-0.32, 1.25-1.50 (at 4 days) to 0.36-0.39, 1.71-1.83 (at 12 days). However, the acetate fraction (%) decreased with HRT from 35.7-37.5 at 4 days to 23.5-25 at 12 days. The yields decreased with increase of organic loading from 0.34-0.37 at 5 g/L d to 0.29-0.30 at 13 g/L d and the productivity increased from 1.63-1.65 to 3.61-3.75. The yield and productivity were highest at 35 degrees C among 25, 35 and 45 degrees C. The yield and productivity at pH 5.5 and 6.0 were best and very similar to each other. The condition of 35 degrees C, pH 6.0, HRT 8 days, ORL 9 g/L d resulted in TVFA, SCOD, acetate and butyrate of 25, 39.5, 12 and 5.25 g/L, respectively.