Iris stromal cell nuclei deform to more elongated shapes during pharmacologically-induced miosis and mydriasis.

Nuclear shape alteration in ocular tissues, which can be used as a metric for overall cell deformation, may also lead to changes in gene expression and protein synthesis that could affect the biomechanics of the tissue extracellular matrix. The biomechanics of iris tissue is of particular interest in the study of primary angle-closure glaucoma. As the first step towards understanding the mutual role of the biomechanics and deformation of the iris on the activity of its constituent stromal cells, we conducted an ex-vivo study in freshly excised porcine eyes. Iris deformation was achieved by activating the constituent smooth muscles of the iris. Pupillary responses were initiated by inducing miosis and mydriasis, and the irides were placed in a fixative, bisected, and sliced into thin sections in a nasal and temporal horizontal orientation. The tissue sections were stained with DAPI for nucleus, and z-stacks were acquired using confocal microscopy. Images were analyzed to determine the nuclear aspect ratio (NAR) using both three-dimensional (3D) reconstructions of the nuclear surfaces as well as projections of the same 3D reconstruction into flat two-dimensional (2D) shapes. We observed that regardless of the calculation method (i.e., one that employed 3D surface reconstructions versus one that employed 2D projected images) the NAR increased in both the miosis group and the mydriasis group. Three-dimensional quantifications showed that NAR increased from 2.52 ± 0.96 in control group to 2.80 ± 0.81 and 2.74 ± 0.94 in the mydriasis and miosis groups, respectively. Notwithstanding the relative convenience in calculating the NAR using the 2D projected images, the 3D reconstructions were found to generate more physiologically realistic values and, thus, can be used in the development of future computational models to study primary angle-closure glaucoma. Since the iris undergoes large deformations in response to ambient light, this study suggests that the iris stromal cells are subjected to a biomechanically active micro-environment during their in-vivo physiological function.

Appropriate Objective Functions for Quantifying Iris Mechanical Properties Using Inverse Finite Element Modeling.

Quantifying the mechanical properties of the iris is important, as it provides insight into the pathophysiology of glaucoma. Recent ex vivo studies have shown that the mechanical properties of the iris are different in glaucomatous eyes as compared to normal ones. Notwithstanding the importance of the ex vivo studies, such measurements are severely limited for diagnosis and preclude development of treatment strategies. With the advent of detailed imaging modalities, it is possible to determine the in vivo mechanical properties using inverse finite element (FE) modeling. An inverse modeling approach requires an appropriate objective function for reliable estimation of parameters. In the case of the iris, numerous measurements such as iris chord length (CL) and iris concavity (CV) are made routinely in clinical practice. In this study, we have evaluated five different objective functions chosen based on the iris biometrics (in the presence and absence of clinical measurement errors) to determine the appropriate criterion for inverse modeling. Our results showed that in the absence of experimental measurement error, a combination of iris CL and CV can be used as the objective function. However, with the addition of measurement errors, the objective functions that employ a large number of local displacement values provide more reliable outcomes.

Quantification of Material Constants for a Phenomenological Constitutive Model of Porcine Tricuspid Valve Leaflets for Simulation Applications.

The tricuspid valve is a one-way valve on the pulmonary side of the heart, which prevents backflow of blood during ventricular contractions. Development of computational models of the tricuspid valve is important both in understanding the normal valvular function and in the development/improvement of surgical procedures and medical devices. A key step in the development of such models is quantification of the mechanical properties of the tricuspid valve leaflets. In this study, after examining previously measured five-loading-protocol biaxial stress-strain response of porcine tricuspid valves, a phenomenological constitutive framework was chosen to represent this response. The material constants were quantified for all three leaflets, which were shown to be highly anisotropic with average anisotropy indices of less than 0.5 (an anisotropy index value of 1 indicates a perfectly isotropic response, whereas a smaller value of the anisotropy index indicates an anisotropic response). To obtain mean values of material constants, stress-strain responses of the leaflet samples were averaged and then fitted to the constitutive model (average R2 over 0.9). Since the sample thicknesses were not hugely different, averaging the data using the same tension levels and stress levels produced similar average material constants for each leaflet.

In silicomodeling of tibial fatigue life in physically active males and females during different exercise protocols.

Preventing bone stress injuries (BSI) requires a deep understanding of the condition's underlying causes and risk factors. Subject-specific computer modeling studies of gait mechanics, including the effect of changes in running speed, stride length, and landing patterns on tibial stress injury formation can provide essential insights into BSI prevention. This study aimed to computationally examine the effect of different exercise protocols on tibial fatigue life in male and female runners during prolonged walking and running at three different speeds. To achieve these aims, we combined subject-specific magnetic resonance imaging (MRI), gait data, finite element analysis, and a fatigue life prediction algorithm, including repair and adaptation's influence. The algorithm predicted a steep increase in the likelihood of developing a BSI within the first 40 days of activity. In five of the six subjects simulated, faster running speeds corresponded with higher tibial strains and higher probability of failure. Our simulations also showed that female subjects had a higher mean peak probability of failure in all four gait conditions than the male subjects studied. The approach used in this study could lay the groundwork for studies in larger populations and patient-specific clinical tools and decision support systems to reduce BSIs in athletes, military personnel, and other active individuals.

Towards a multi-scale computer modeling workflow for simulation of pulmonary ventilation in advanced COVID-19.

Physics-based multi-scale in silico models offer an excellent opportunity to study the effects of heterogeneous tissue damage on airflow and pressure distributions in COVID-19-afflicted lungs. The main objective of this study is to develop a computational modeling workflow, coupling airflow and tissue mechanics as the first step towards a virtual hypothesis-testing platform for studying injury mechanics of COVID-19-afflicted lungs. We developed a CT-based modeling approach to simulate the regional changes in lung dynamics associated with heterogeneous subject-specific COVID-19-induced damage patterns in the parenchyma. Furthermore, we investigated the effect of various levels of inflammation in a meso-scale acinar mechanics model on global lung dynamics. Our simulation results showed that as the severity of damage in the patient's right lower, left lower, and to some extent in the right upper lobe increased, ventilation was redistributed to the least injured right middle and left upper lobes. Furthermore, our multi-scale model reasonably simulated a decrease in overall tidal volume as the level of tissue injury and surfactant loss in the meso-scale acinar mechanics model was increased. This study presents a major step towards multi-scale computational modeling workflows capable of simulating the effect of subject-specific heterogenous COVID-19-induced lung damage on ventilation dynamics.

Integration of mechanics and biology in computer simulation of bone remodeling.

Bone remodeling is a complex physiological process that spans across multiple spatial and temporal scales and is regulated by both mechanical and hormonal cues. An imbalance between bone resorption and bone formation in the process of bone remodeling may lead to various bone pathologies. One powerful and non-invasive approach to gain new insights into mechano-adaptive bone remodeling is computer modeling and simulation. Recent findings in bone physiology and advances in computer modeling have provided a unique opportunity to study the integration of mechanics and biology in bone remodeling. Our objective in this review is to critically appraise recent advances and developments and discuss future research opportunities in computational bone remodeling approaches that enable integration of mechanics and cellular and molecular pathways. Based on the critical appraisal of the relevant recent published literature, we conclude that multiscale in silico integration of personalized bone mechanics and mechanobiology combined with data science and analytics techniques offer the potential to deepen our knowledge of bone remodeling and provide ample opportunities for future research.

Fluorinated Methacrylamide Chitosan Hydrogel Dressings Improve Regenerated Wound Tissue Quality in Diabetic Wound Healing.

Objective: Oxygen therapy has shown promising results for treating diabetic wounds. However, clinically used oxygen therapies are cumbersome and expensive. Thus, there is a need to develop a localized oxygenating treatment that is easy to use and inexpensive. Approach: In this study, we tested a previously developed hydrogel sheet wound dressing based on fluorinated methacrylamide chitosan (MACF) for enhanced oxygenation and compared it with a commercial sheet hydrogel dressing, AquaDerm™, and no treatment controls in a splinted transgenic diabetic mouse wound model. Results: AquaDerm exhibited poor wound closure response compared with the MACF oxygenating hydrogel sheet dressing (MACF+O2) and no treatment. Histological analysis revealed enhanced collagen synthesis and neovascularization upon MACF+O2 treatment as indicated by higher collagen content and number of blood vessels/capillaries compared with AquaDerm and no treatment. MACF+O2 also improved wound collagen fiber alignment, thus demonstrating improved skin tissue maturation. Nuclear magnetic resonance spectroscopy-based biodistribution analysis revealed that the degradation products of the MACF-based dressing did not accumulate in lung, liver, and kidney tissues of the treated animals after 14 days of treatment. Innovation: This study presents the first application of a unique oxygenating biomaterial (MACF) made into a moist hydrogel wound dressing for treating diabetic wounds. Conclusion: The results of this study confirm the benefits of this novel biomaterial approach for improving regenerated tissue structure in diabetic wound healing.

Increased Iris Stiffness in Patients With a History of Angle-Closure Glaucoma: An Image-Based Inverse Modeling Analysis.

Purpose: Previous studies have shown that iris mechanical properties may play a role in the pathophysiology of primary angle-closure glaucoma (PACG). Such studies, however, were not conducted in vivo and as such were limited in application and scope, especially for the development of diagnostic methods or new treatment options. The purpose of this study was to quantify in vivo iris mechanical properties both in patients with a history of angle-closure glaucoma and in healthy volunteers. Methods: We acquired optical coherence tomography scans of anterior segments under standard and dim light conditions. Using a combination of finite element simulation and an inverse fitting algorithm, we quantified the stiffness of the iris. Results: The irides in the eyes of patients with a history of PACG were significantly stiffer when compared with healthy control irides, a result consistent with ex vivo studies. This result was independent of the compressibility assumption (incompressible: 0.97 ± 0.14 vs. 2.72 ± 0.71, P = 0.02; compressible: 0.89 ± 0.13 vs. 2.57 ± 0.69, P = 0.02) when comparing the normalized elastic modulus of the iris between patients with PACG and healthy controls. Conclusions: Our noninvasive, in vivo quantification is free of numerous ethical issues and potential limitations involved with ex vivo examinations. If further studies confirm that the iris stiffness is an omnipresent PACG risk factor and a mechanistic role between increased iris stiffness and angle-closure glaucoma does exist, treatment methods such as lowering the iris stiffness can be developed.

Pressure-induced microstructural changes in porcine tricuspid valve leaflets.

Quantifying mechanically-induced changes in the tricuspid valve extracellular matrix (ECM) structural components, e.g. collagen fiber spread and distribution, is important as it determines the overall macro-scale tissue responses and subsequently its function/malfunction in physiological/pathophysiological states. For example, functional tricuspid regurgitation, a common tricuspid valve disorder, could be caused by elevated right ventricular pressure due to pulmonary hypertension. In such patients, the geometry and the normal function of valve leaflets alter due to chronic pressure overload, which could cause remodeling responses in the ECM and change its structural components. To understand such a relation, we developed an experimental setup and measured alteration of leaflet microstructure in response to pressure increase in porcine tricuspid valves using the small angle light scattering technique. The anisotropy index, a measure of the fiber spread and distribution, was obtained and averaged for each region of the anterior, posterior, and septal leaflet using four averaging methods. The average anisotropy indices (mean ±â€¯standard error) in the belly region of the anterior, posterior, and septal leaflets of non-pressurized valves were found to be 12 ±â€¯2%, 21 ±â€¯3% and 12 ±â€¯1%, respectively. For the pressurized valve, the average values of the anisotropy index in the belly region of the anterior, posterior, and septal leaflets were 56 ±â€¯5%, 39 ±â€¯7% and 32 ±â€¯5%, respectively. Overall, the average anisotropy index was found to be higher for all leaflets in the pressurized valves as compared to the non-pressurized valves, indicating that the ECM fibers became more aligned in response to an increased ventricular pressure. STATEMENT OF SIGNIFICANCE: Mechanics plays a critical role in development, regeneration, and remodeling of tissues. In the current study, we have conducted experiments to examine how increasing the ventricular pressure leads to realignment of protein fibers comprising the extracellular matrix (ECM) of the tricuspid valve leaflets. Like many other tissues, in cardiac valves, cell-matrix interactions and gene expressions are heavily influenced by changes in the mechanical microenvironment at the ECM/cellular level. We believe that our study will help us better understand how abnormal increases in the right ventricular pressure (due to pulmonary hypertension) could change the structural architecture of tricuspid valve leaflets and subsequently the mechanical microenvironment at the ECM/cellular level.

An imaged-based inverse finite element method to determine in-vivo mechanical properties of the human trabecular meshwork.

AIM: Previous studies have shown that the trabecular meshwork (TM) is mechanically stiffer in glaucomatous eyes as compared to normal eyes. It is believed that elevated TM stiffness increases resistance to the aqueous humor outflow, producing increased intraocular pressure (IOP). It would be advantageous to measure TM mechanical properties in vivo, as these properties are believed to play an important role in the pathophysiology of glaucoma and could be useful for identifying potential risk factors. The purpose of this study was to develop a method to estimate in-vivo TM mechanical properties using clinically available exams and computer simulations. DESIGN: Inverse finite element simulation. METHODS: A finite element model of the TM was constructed from optical coherence tomography (OCT) images of a healthy volunteer before and during IOP elevation. An axisymmetric model of the TM was then constructed. Images of the TM at a baseline IOP level of 11, and elevated level of 23 mmHg were treated as the undeformed and deformed configurations, respectively. An inverse modeling technique was subsequently used to estimate the TM shear modulus (G). An optimization technique was used to find the shear modulus that minimized the difference between Schlemm's canal area in the in-vivo images and simulations. RESULTS: Upon completion of inverse finite element modeling, the simulated area of the Schlemm's canal changed from 8,889 µm2 to 2,088 µm2, similar to the experimentally measured areal change of the canal (from 8,889 µm2 to 2,100 µm2). The calculated value of shear modulus was found to be 1.93 kPa, (implying an approximate Young's modulus of 5.75 kPa), which is consistent with previous ex-vivo measurements. CONCLUSION: The combined imaging and computational simulation technique provides a unique approach to calculate the mechanical properties of the TM in vivo without any surgical intervention. Quantification of such mechanical properties will help us examine the mechanistic role of TM biomechanics in the regulation of IOP in healthy and glaucomatous eyes.