Biomechanical Correlations Between the Cornea and the Optic Nerve Head.

Purpose: A thin cornea is a potent risk factor for glaucoma. The underlying mechanisms remain unexplained. It has been postulated that central corneal thickness (CCT) may be a surrogate for biomechanical parameters of the posterior eye. In this study, we aimed to explore correlations of biomechanical responses between the cornea and the optic nerve head (ONH) and the peripapillary sclera (PPS) to elevated intraocular pressure (IOP), the primary risk factor of glaucoma. Methods: Inflation tests were performed in nine pairs of human donor globes. One eye of each pair was randomly assigned for cornea or posterior eye inflation. IOP was raised from 5 to 30 millimeters of mercury (mmHg) at 0.5 mmHg steps in the whole globe and the cornea or the ONH/PPS was imaged using a 50 MHz ultrasound probe. Correlation-based ultrasound speckle tracking was used to calculate tissue displacements and strains. Associations of radial, tangential, and shear strains at 30 mmHg between the cornea and the ONH or PPS were evaluated. Results: Corneal shear strain was significantly correlated with ONH shear strain (R = 0.857, P = 0.003) and PPS shear strain (R = 0.724, P = 0.028). CCT was not correlated with any strains in the cornea, ONH, or PPS. Conclusions: Our results suggested that an eye that experiences a larger shear strain in the cornea would likely experience a larger shear strain in its ONH and PPS at IOP elevations. The strong correlation between the cornea's and the ONH's shear response to IOP provides new insights and suggests a plausible explanation of the cornea's connection to glaucoma risk.

Three-Dimensional Ultrasound Elastography Detects Age-Related Increase in Anterior Peripapillary Sclera and Optic Nerve Head Compression During IOP Elevation.

Purpose: High-frequency ultrasound elastography offers a tool to resolve the complex and heterogeneous deformation through the full thickness of the optic nerve head (ONH) and peripapillary sclera (PPS). Using this tool, we quantified the three-dimensional deformation of the ONH and PPS in human donor eyes and evaluated age-associated changes. Methods: The ONH and PPS in 15 human donor globes were imaged with a 50-MHz ultrasound probe while increasing intraocular pressure (IOP) from 15 to 30 mm Hg. Tissue displacements were obtained using correlation-based ultrasound speckle tracking. Three-dimensional spherical strains (radial, circumferential, meridional, and respective shear strains) were calculated for the ONH and PPS volumes segmented from three-dimensional ultrasound images. Age-related trends of different strains in each region of interest were explored. Results: The dominant form of IOP-induced deformation in the ONH and PPS was radial compression. High-magnitude localized out-of-plane shear strains were also observed in both regions. Most strains were concentrated in the anterior one-half of the ONH and PPS. The magnitude of radial and volumetric strains increased with age in the anterior ONH and anterior PPS, indicating greater radial compression and volume loss during IOP elevation in older age. Conclusions: The age-associated increase of radial compression, the predominant form of IOP-induced deformation in anterior ONH and PPS, may underlie age-associated glaucoma risk. High-frequency ultrasound elastography offers a useful tool to quantify all types of deformation comprehensively in all regions of ONH and PPS, which may improve our understanding of the biomechanical factors contributing to glaucoma risk.

Escaping the Laboratory: An Escape Room to Reinforce Biomedical Engineering Skills.

Commercial escape rooms have grown in popularity as an enjoyable experience that also doubles as an exercise in communication and collaboration. Educators can take advantage of these natural qualities to engage and support students in a low-stress learning environment. The primary goal of this study is to share the development and application of an educational escape room as a tool to provide biomedical engineering (BME) students with an immersive and practical experience. A BME laboratory course-specific escape room was developed and beta-tested on an initial group of BME students. The first set of feedback enabled improvements to the design and difficulty of the escape room, which was followed by the final release of the activity for the intended undergraduate BME course. Across an academic year, 74 participants agreed to provide survey feedback for this study. Despite a moderate escape rate (29%), students reported high satisfaction and enthusiasm for the activity. Student survey responses indicated that participants were engaged and empowered to successfully escape even without external motivators. Responses supported the effectiveness of the escape room as a BME learning environment, allowing students to practice and retain course-related knowledge in a challenging but low-risk activity. The foundational structure of escape rooms offers a beneficial environment for experiential knowledge application. We conclude that educational escape rooms show promise as a pedagogical tool in promoting enhanced knowledge retention through immersive, game-based learning. Supplementary Information: The online version contains supplementary material available at 10.1007/s43683-022-00089-w.

High-frequency ultrasound detects biomechanical weakening in keratoconus with lower stiffness at higher grade.

In vivo biomechanical characterization of the cornea remains a challenge. We have developed a high-frequency ultrasound elastography method, the ocular pulse elastography (OPE), to measure corneal axial displacement (CAD) induced by the ocular pulse. Here we compared CAD and a stiffness index derived from CAD between keratoconus patients and normal controls. We also explored the trend of these parameters with keratoconus grade. Twenty normal subjects and twenty keratoconus patients were recruited in this study. Corneal topography, tomography, intraocular pressure (IOP) and ocular pulse amplitude (OPA) were obtained in each measured eye. The cornea's heartbeat-induced cyclic axial displacements were measured by high-frequency (50 MHz) ultrasound. A corneal stiffness index (CSI) was derived from CAD normalized against OPA. CAD and CSI were compared between normal and keratoconus groups, and across keratoconus grades. Keratoconus corneas had significantly greater CAD and lower CSI than normal controls (p's<0.01). Both parameters correlated strongly with grade, in which CAD increased significantly (p = 0.002) and CSI decreased significantly (p = 0.011) with grade. These results suggested a biomechanical weakening in keratoconus which worsens at higher disease severity. This study also demonstrated the ability of high-frequency ultrasound elastography to provide a safe, quick, and accurate evaluation of the cornea's biomechanical condition in vivo. The OPE-measured biomechanical metrics, when integrated with existing diagnostic criteria, may aid the decision-making in the early and definitive diagnosis and staging of keratoconus.

Mechanical Deformation of Peripapillary Retina in Response to Acute Intraocular Pressure Elevation.

Elevated intraocular pressure (IOP) may cause mechanical injuries to the optic nerve head (ONH) and the peripapillary tissues in glaucoma. Previous studies have reported the mechanical deformation of the ONH and the peripapillary sclera (PPS) at elevated IOP. The deformation of the peripapillary retina (PPR) has not been well-characterized. Here we applied high-frequency ultrasound elastography to map and quantify PPR deformation, and compared PPR, PPS and ONH deformation in the same eye. Whole globe inflation was performed in ten human donor eyes. High-frequency ultrasound scans of the posterior eye were acquired while IOP was raised from 5 to 30 mmHg. A correlation-based ultrasound speckle tracking algorithm was used to compute pressure-induced displacements within the scanned tissue cross sections. Radial, tangential, and shear strains were calculated for the PPR, PPS, and ONH regions. In PPR, shear was significantly larger in magnitude than radial and tangential strains. Strain maps showed localized high shear and high tangential strains in PPR. In comparison to PPS and ONH, PPR had greater shear and a similar level of tangential strain. Surprisingly, PPR radial compression was minimal and significantly smaller than that in PPS. These results provide new insights into PPR deformation in response of IOP elevation, suggesting that shear rather than compression was likely the primary mode of IOP-induced mechanical insult in PPR. High shear, especially localized high shear, may contribute to the mechanical damage of this tissue in glaucoma.

Regional variation of corneal stromal deformation measured by high-frequency ultrasound elastography.

The cornea's mechanical response to intraocular pressure elevations may alter in ectatic diseases such as keratoconus. Regional variations of mechanical deformation in normal and keratoconus eyes during intraocular pressure elevation have not been well-characterized. We applied a high-frequency ultrasound elastography technique to characterize the regional deformation of normal and keratoconus human corneas through the full thickness of corneal stroma. A cross-section centered at the corneal apex in 11 normal and 2 keratoconus human donor eyes was imaged with high-frequency ultrasound during whole globe inflation from 5 to 30 mmHg. An ultrasound speckle tracking algorithm was used to compute local tissue displacements. Radial, tangential, and shear strains were mapped across the imaged cross-section. Strains in the central (1 mm surrounding apex) and paracentral (1 to 4 mm from apex) regions were analyzed in both normal and keratoconus eyes. Additional regional analysis was performed in the eye with severe keratoconus presenting significant thinning and scarring. Our results showed that in normal corneas, the central region had significantly smaller tangential stretch than the paracentral region, and that within the central region, the magnitudes of radial and shear strains were significantly larger than that of tangential strain. The eye with mild keratoconus had similar shear strain but substantially larger radial strains than normal corneas, while the eye with severe keratoconus had similar overall strains as in normal eyes but marked regional heterogeneity and large strains in the cone region. These findings suggested regional variation of mechanical responses to intraocular pressure elevation in both normal and keratoconus corneas, and keratoconus appeared to be associated with mechanical weakening in the cone region, especially in resisting radial compression. Comprehensive characterization of radial, tangential, and shear strains through corneal stroma may provide new insights to understand the biomechanical alterations in keratoconus.

IOP-induced regional displacements in the optic nerve head and correlation with peripapillary sclera thickness.

Mechanical insult induced by intraocular pressure (IOP) is likely a driving force in the disease process of glaucoma. This study aimed to evaluate regional displacements in human optic nerve head (ONH) and peripapillary tissue (PPT) in response to acute IOP elevations, and their correlations with morphological characteristics of the posterior eye. Cross-sectional (2D) images of the ONH and PPT in 14 globes of 14 human donors were acquired with high-frequency ultrasound during whole globe inflation from 5 to 30 mm Hg. High-frequency ultrasound has a spatial resolution of tens of micrometers and is capable of imaging through the ONH and PPT thickness. Tissue displacements were calculated using a correlation-based speckle tracking algorithm for a dense matrix of kernels covering the 2D imaging plane. The ONH was manually segmented in the ultrasound B-mode images acquired at 5 mmHg based on echogenicity. The lamina cribrosa (LC) boundaries were visible in eight of the fourteen eyes and the LC region was segmented using a semi-automated superpixel-based method. The ONH had larger radial displacement than the PPT in all tested eyes and the difference increased with increasing IOP. A significant negative correlation was found between ONH-PPT displacement difference and PPT thickness (p < 0.05), while no significant correlations were found between ONH-PPT displacement difference and other morphological parameters including PPT radius of curvature, scleral canal size, LC thickness and anterior LC surface depth. Within the ONH, the radial displacement decreased in the region anterior to and across LC but not in the region posterior to LC. Finite element models using simplified geometry and material properties confirmed the role of LC in reducing the overall ONH radial displacements, but did not predict the displacement gradient change observed experimentally. These results suggested that a thinner PPT may be associated with a larger relative posterior motion of the ONH with respect to the surrounding PPT and the LC may play a major role in preventing excessive posterior displacement of ONH during acute IOP elevations.

Heartbeat-Induced Corneal Axial Displacement and Strain Measured by High Frequency Ultrasound Elastography in Human Volunteers.

Purpose: The purpose of this study was to establish in vivo data acquisition and processing protocols for repeatable measurements of heartbeat-induced corneal displacements and strains in human eyes, using a high-frequency ultrasound elastography method, termed ocular pulse elastography (OPE). Methods: Twenty-four volunteers with no known ocular diseases were recruited for this study. Intraocular pressure (IOP) and ocular pulse amplitude (OPA) were measured using a PASCAL Dynamic Contour Tonometer (DCT). An in vivo OPE protocol was developed to measure heartbeat-induced corneal displacements. Videos of the central 5.7 mm of the cornea were acquired using a 50-MHz ultrasound probe at 128 frames per second. The radiofrequency data of 1000 frames were analyzed using an ultrasound speckle tracking algorithm to calculate corneal displacements and quantify spectral and temporal characteristics. The intrasession and intersession repeatability of OPE- and DCT-measured parameters were also analyzed. Results: The in vivo OPE protocol and setup were successful in tracking heartbeat-induced corneal motion using high-frequency ultrasound. Corneal axial displacements showed a strong cardiac rhythm, with good intrasession and intersession repeatability, and high interocular symmetry. Corneal strain was calculated in two eyes of two subjects, showing substantially different responses. Conclusions: We demonstrated the feasibility of high-frequency ultrasound elastography for noninvasive in vivo measurement of the cornea's biomechanical responses to the intrinsic ocular pulse. The high intrasession and intersession repeatability suggested a robust implementation of this technique to the in vivo setting. Translational Relevance: OPE may offer a useful tool for clinical biomechanical evaluation of the cornea by quantifying its response to the intrinsic pulsation.

Three-Dimensional Inflation Response of Porcine Optic Nerve Head Using High-Frequency Ultrasound Elastography.

Characterization of the biomechanical behavior of the optic nerve head (ONH) in response to intraocular pressure (IOP) elevation is important for understanding glaucoma susceptibility. In this study, we aimed to develop and validate a three-dimensional (3D) ultrasound elastographic technique to obtain mapping and visualization of the 3D distributive displacements and strains of the ONH and surrounding peripapillary tissue (PPT) during whole globe inflation from 15 to 30 mmHg. 3D scans of the posterior eye around the ONH were acquired through full tissue thickness with a high-frequency ultrasound system (50 MHz). A 3D cross-correlation-based speckle-tracking algorithm was used to compute tissue displacements at ∼30,000 kernels distributed within the region of interest (ROI), and the components of the strain tensors were calculated at each kernel by using least square estimation of the displacement gradients. The accuracy of displacement calculation was evaluated using simulated rigid-body translation on ultrasound radiofrequency (RF) data obtained from a porcine posterior eye. The accuracy of strain calculation was evaluated using finite element (FE) models. Three porcine eyes were tested showing that ONH deformation was heterogeneous with localized high strains. Substantial radial (i.e., through-thickness) compression was observed in the anterior ONH and out-of-plane (i.e., perpendicular to the surface of the shell) shear was shown to concentrate in the vicinity of ONH/PPT border. These preliminary results demonstrated the feasibility of this technique to achieve comprehensive 3D evaluation of the mechanical responses of the posterior eye, which may provide mechanistic insights into the regional susceptibility in glaucoma.

Mechanical Deformation of Human Optic Nerve Head and Peripapillary Tissue in Response to Acute IOP Elevation.

Purpose: To measure the deformation of the human optic nerve head (ONH) and peripapillary tissue (PPT) in response to acute intraocular pressure (IOP) elevation. Methods: The ONH and PPT of 14 human donor globes were imaged with high-frequency ultrasonography during inflation testing from 5 to 30 mm Hg. A correlation-based speckle tracking algorithm was used to compute tissue displacements, and the through-thickness, in-plane, and shear strains were calculated by using least-squares strain estimation methods. The ONH and PPT were segmented along the anterior-posterior direction and the nasal-temporal direction. Regional displacements and strains were analyzed and compared. Results: The ONH displaced more posteriorly than the PPT in response to an acute IOP increase. Scleral canal expansion was minimal but correlated with ONH posterior displacement at all IOP levels. Through-thickness compression was concentrated in the anterior of both the ONH and the PPT. Shear was concentrated in the vicinity of the canal with higher shear in the peripheral ONH than the central ONH and higher shear in the PPT near the scleral canal than that further away from the canal. Conclusions: High-resolution ultrasound speckle tracking showed a displacement mismatch between the ONH and the PPT, larger compressive strains in the direction of IOP loading in the anterior ONH and PPT, and higher shear strains in the periphery of ONH in response to acute IOP elevation in the human eye. These findings delineate the deformation patterns within and around the ONH and may help understand IOP-associated optic nerve damage.

Lipid Microbubbles as Ultrasound-Stimulated Oxygen Carriers for Controllable Oxygen Release for Tumor Reoxygenation.

Microbubbles are proposed as a potentially novel method for oxygen delivery in vivo in initial studies. The lack of commercial microbubbles for oxygen delivery in preclinical research prompted us to fabricate an oxygen-loaded lipid microbubble. We aimed to extend the innovative strategy to modulate the tumor hypoxic microenvironment, using microbubbles intravenously as an oxygen carrier for the controllable tumor-specific delivery of oxygen by ultrasound (US). In our experiment, an oxygen-loaded lipid-coated microbubble (OLM) with mixed gas (O2/C3 F8, 5:1 v/v) was fabricated and exhibited a higher rate of oxygen release to a desaturated solution through burst by US than that in the absence of US. Although in in vivo studies, OLMs could be imaged and triggered by US to elevate the pO2 level in the breast VX2 tumor dramatically within a matter of minutes. The added presence of US-activated OLMs elicited a nearly six-fold increase in pO2 levels within 1 min compared with that of the pre-injection. Owing to the high oxygen payload, great acoustic stability and acoustic properties, OLMs may be proposed as an ideal radio-sensitizer. We conclude that oxygen release mediated by ultrasound-targeted microbubble destruction is feasible and shows potential in image-guided, site-specific cancer radiotherapy.

Hemocompatibility of nitrogen-doped, hydrogen-free diamond-like carbon prepared by nitrogen plasma immersion ion implantation-deposition.

Amorphous hydrogenated carbon (a-C:H) has been shown to be a potential material in biomedical devices such as artificial heart valves, bone implants, and so on because of its chemical inertness, low coefficient of friction, high wear resistance, and good biocompatibility. However, the biomedical characteristics such as blood compatibility of doped hydrogen-free diamond-like carbon (DLC) have not been investigated in details. We recently began to investigate the potential use of nitrogen-doped, hydrogen-free DLC in artificial heart valves. In our experiments, a series of hydrogen-free DLC films doped with nitrogen were synthesized by plasma immersion ion implantation-deposition (PIII-D) utilizing a pulsed vacuum arc plasma source and different N to Ar (FN/FAr) gas mixtures in the plasma chamber. The structures and properties of the film were evaluated by Raman spectroscopy, Rutherford backscattering spectrometry (RBS), and X-ray photoelectron spectroscopy (XPS). To assess the blood compatibility of the films and the impact on the blood compatibility by the presence of nitrogen, platelet adhesion tests were conducted. Our results indicate that the blood compatibility of both hydrogen-free carbon films (a-C) and amorphous carbon nitride films are better than that of low-temperature isotropic pyrolytic carbon (LTIC). The experimental results are consistent with the relative theory of interfacial energy and surface tension including both dispersion and polar components. Our results also indicate that an optimal fraction of sp2 bonding is desirable, but an excessively high nitrogen concentration degrades the properties to an extent that the biocompatibility can be worse than that of LTIC.