Developing a Lung Model in the Age of COVID-19: A Digital Image Correlation and Inverse Finite Element Analysis Framework.

Pulmonary diseases, driven by pollution, industrial farming, vaping, and the infamous COVID-19 pandemic, lead morbidity and mortality rates worldwide. Computational biomechanical models can enhance predictive capabilities to understand fundamental lung physiology; however, such investigations are hindered by the lung's complex and hierarchical structure, and the lack of mechanical experiments linking the load-bearing organ-level response to local behaviors. In this study we address these impedances by introducing a novel reduced-order surface model of the lung, combining the response of the intricate bronchial network, parenchymal tissue, and visceral pleura. The inverse finite element analysis (IFEA) framework is developed using 3-D digital image correlation (DIC) from experimentally measured non-contact strains and displacements from an ex-vivo porcine lung specimen for the first time. A custom-designed inflation device is employed to uniquely correlate the multiscale classical pressure-volume bulk breathing measures to local-level deformation topologies and principal expansion directions. Optimal material parameters are found by minimizing the error between experimental and simulation-based lung surface displacement values, using both classes of gradient-based and gradient-free optimization algorithms and by developing an adjoint formulation for efficiency. The heterogeneous and anisotropic characteristics of pulmonary breathing are represented using various hyperelastic continuum formulations to divulge compound material parameters and evaluate the best performing model. While accounting for tissue anisotropy with fibers assumed along medial-lateral direction did not benefit model calibration, allowing for regional material heterogeneity enabled accurate reconstruction of lung deformations when compared to the homogeneous model. The proof-of-concept framework established here can be readily applied to investigate the impact of assorted organ-level ventilation strategies on local pulmonary force and strain distributions, and to further explore how diseased states may alter the load-bearing material behavior of the lung. In the age of a respiratory pandemic, advancing our understanding of lung biomechanics is more pressing than ever before.

Intrafibrillar mineralization deficiency and osteogenesis imperfecta mouse bone fragility.

Osteogenesis imperfecta (OI), a brittle bone disease, is known to result in severe bone fragility. However, its ultrastructural origins are still poorly understood. In this study, we hypothesized that deficient intrafibrillar mineralization is a key contributor to the OI induced bone brittleness. To test this hypothesis, we explored the mechanical and ultrastructural changes in OI bone using the osteogenesis imperfecta murine (oim) model. Synchrotron X-ray scattering experiments indicated that oim bone had much less intrafibrillar mineralization than wild type bone, thus verifying that the loss of mineral crystals indeed primarily occurred in the intrafibrillar space of oim bone. It was also found that the mineral crystals were organized from preferentially in longitudinal axis in wild type bone to more randomly in oim bone. Moreover, it revealed that the deformation of mineral crystals was more coordinated with collagen fibrils in wild type than in oim bone, suggesting that the load transfer deteriorated between the two phases in oim bone. The micropillar test revealed that the compression work to fracture of oim bone (8.2 ± 0.9 MJ/m3) was significantly smaller (p < 0.05) than that of wild type bone (13.9 ± 2.7 MJ/m3), while the bone strength was not statistically different (p > 0.05) between the two genotype groups. In contrast, the uniaxial tensile test showed that the ultimate strength of wild type bone (50 ± 4.5 MPa) was significantly greater (p < 0.05) than that of oim bone (38 ± 5.3 MPa). Furthermore, the nanoscratch test showed that the toughness of oim bone was much less than that of wild type bone (6.6 ± 2.2 GJ/m3 vs. 12.6 ± 1.4 GJ/m3). Finally, in silico simulations using a finite element model of sub-lamellar bone confirmed the links between the reduced intrafibrillar mineralization and the observed changes in the mechanical behavior of OI bone. Taken together, these results provide important mechanistic insights into the underlying cause of poor mechanical quality of OI bone, thus pave the way toward future treatments of this brittle bone disease.

Novel Mechanical Strain Characterization of Ventilated ex vivo Porcine and Murine Lung using Digital Image Correlation.

Respiratory illnesses, such as bronchitis, emphysema, asthma, and COVID-19, substantially remodel lung tissue, deteriorate function, and culminate in a compromised breathing ability. Yet, the structural mechanics of the lung is significantly understudied. Classical pressure-volume air or saline inflation studies of the lung have attempted to characterize the organ's elasticity and compliance, measuring deviatory responses in diseased states; however, these investigations are exclusively limited to the bulk composite or global response of the entire lung and disregard local expansion and stretch phenomena within the lung lobes, overlooking potentially valuable physiological insights, as particularly related to mechanical ventilation. Here, we present a method to collect the first non-contact, full-field deformation measures of ex vivo porcine and murine lungs and interface with a pressure-volume ventilation system to investigate lung behavior in real time. We share preliminary observations of heterogeneous and anisotropic strain distributions of the parenchymal surface, associative pressure-volume-strain loading dependencies during continuous loading, and consider the influence of inflation rate and maximum volume. This study serves as a crucial basis for future works to comprehensively characterize the regional response of the lung across various species, link local strains to global lung mechanics, examine the effect of breathing frequencies and volumes, investigate deformation gradients and evolutionary behaviors during breathing, and contrast healthy and pathological states. Measurements collected in this framework ultimately aim to inform predictive computational models and enable the effective development of ventilators and early diagnostic strategies.

Computational investigation of the effect of water on the nanomechanical behavior of bone.

Previous experimental and computational studies have indicated that removing bound water in bone matrix makes bone stiffer, stronger, but more brittle at different length scales. However, a clear mechanistic explanation of the underlying mechanisms is lacking. Assuming that bound water mainly alters the mechanical behavior of collagen phase and the interfaces among bone constituents, this study investigated the effects of bound water on the mechanical properties of bone using a 2D cohesive finite element (FE) model representing the sub-lamellar hierarchy of the tissue. The model contained sufficient ultrastructural details of mineralized collagen fibrils (MCF), extrafibrillar matrix (EFM), and the interfaces among bone constituents. The mechanical behavior of the interfaces, and mineral/collagen phases, in the hydrated and dehydrated conditions was carefully selected based on the information available in the literature. The FE simulations indicated that hydration status induced changes at the interfaces played a key role in determining the mechanical behavior of bone. In tension, hydrated interfaces (weak but tough) in bone appeared to encourage multiple nanocrack formation, debonding between the MCF and EFM subunits, and crack bridging by MCFs. On the other hand, dehydrated (strong but brittle) interfaces made the tissue stiffer and stronger, but compromised the above energy dissipation mechanisms, thus leading to a brittle failure. In compression, hydrated interfaces resulted in sliding between the mineral crystals in EFM, debonding between EFM and MCF, and buckling of MCF, whereas dehydrated interfaces appeared to make the tissue stiffer and stronger and the energy dissipation mechanisms diminished. The outcome of this study provides new insights into the mechanisms underlying the effect of bound water on bone fragility at ultrastructural levels.

Computational investigation of ultrastructural behavior of bone using a cohesive finite element approach.

Bone ultrastructure at sub-lamellar length scale is a key structural unit in bone that bridges nano- and microscale hierarchies of the tissue. Despite its influence on bulk response of bone, the mechanical behavior of bone at ultrastructural level remains poorly understood. To fill this gap, in this study, a two-dimensional cohesive finite element model of bone at sub-lamellar level was proposed and analyzed under tensile and compressive loading conditions. In the model, ultrastructural bone was considered as a composite of mineralized collagen fibrils (MCFs) embedded in an extrafibrillar matrix (EFM) that is comprised of hydroxyapatite (HA) polycrystals bounded via thin organic interfaces of non-collagenous proteins (NCPs). The simulation results indicated that in compression, EFM dictated the pre-yield deformation of the model, then damage was initiated via relative sliding of HA polycrystals along the organic interfaces, and finally shear bands were formed followed by delamination between MCF and EFM and local buckling of MCF. In tension, EFM carried the most of load in pre-yield deformation, and then an array of opening-mode nano-cracks began to form within EFM after yielding, thus gradually transferring the load to MCF until failure, which acted as crack bridging filament. The failure modes, stress-strain curves, and in situ mineral strain of ultrastructural bone predicted by the model were in good agreement with the experimental observations reported in the literature, thus suggesting that this model can provide new insights into sub-microscale mechanical behavior of bone.