Biology subjects

Elahi, S. A.

Publications and source records attributed to Elahi, S. A..

3 recordsLinked to original sources

bioRxiv2024

Joint and tissue mechanics in post-traumatic osteoarthritis: insights from the rat model

ObjectiveAltered mechanical loading is a known risk factor for osteoarthritis. Destabilization of the medial meniscus (DMM) is a preclinical gold standard model for post-traumatic osteoarthritis and is thought to induce instability and locally increased loading. However, the joint- and tissue-level mechanical environment underlying cartilage degeneration remains poorly documented. DesignUsing a custom multiscale modeling approach, we assessed joint and tissue biomechanics in rats undergoing sham surgery and DMM. High-fidelity experimental gait data were collected in a setup combining biplanar fluoroscopy and a ground reaction force plate. Knee poses and joint-level loading were estimated through musculoskeletal modeling, using bony landmarks, semi-automatically tracked via deep learning on fluoroscopic images, and ground reaction forces. A musculoskeletal model of the rat hindlimb was adapted to represent knee flexion-extension, valgus-varus, and internal-external rotation. The tissue-level cartilage mechanical environment was then spatially estimated, using the musculoskeletal modeling parameters as inputs into a dedicated finite element (FE) model of the rat knee, comprising cartilage and meniscal tissues. Experimental gait data and modeling workflows, including musculoskeletal models and FE meshes, are openly shared through a data repository. ResultsIn rats with DMM, the frontal plane knee pose was altered, yet there was no indication of joint-level overloading. Tissue-level mechanical cues typically linked with cartilage degeneration were not increased in the medial tibial cartilage, despite evidence of tissue structural changes. ConclusionDMM did not increase joint and tissue mechanical responses in the knee medial compartment, suggesting that mechanical loading alone does not explain the observed osteoarthritis-like structural changes.

bioengineering↗

bioRxiv2024

Mechanical Drivers of Glycosaminoglycan Content Changes in Intact and Damaged Human Cartilage

Articular cartilage undergoes significant degeneration during osteoarthritis, currently lacking effective treatments. This study explores mechanical influences on cartilage health using a novel finite element-based mechanoregulatory model, predicting combined degenerative and regenerative responses to mechanical loading. Calibrated and validated through one-week longitudinal ex vivo experiments on intact and damaged cartilage samples, the model underscores the roles of maximum shear strain, fluid velocity, and dissipated energy in driving changes in cartilage glycosaminoglycan (GAG) content. It delineates the distinct regenerative contributions of fluid velocity and dissipated energy, alongside the degenerative contribution of maximum shear strain, to GAG adaptation in both intact and damaged cartilage under physiological mechanical loading. Remarkably, the model predicts increased GAG production even in damaged cartilage, consistent with our in vitro experimental findings. Beyond advancing our understanding of mechanical loadings role in cartilage homeostasis, our model aligns with contemporary ambitions by exploring the potential of in silico trials to optimize mechanical loading in degenerative joint disease, fostering personalized rehabilitation.

bioengineering↗

bioRxiv2023

Force-mediated recruitment and reprogramming of healthy endothelial cells drive vascular lesion growth

Force-driven cellular interactions are known to play a critical role in cancer cell invasion, but have remained largely unexplored in the context of vascular abnormalities, partly due to a lack of suitable genetic and cellular models. One such vascular abnormality, cerebral cavernous malformation (CCM) is characterized by leaky, tumor-like vessels in the brain, where CCM mutant cells recruit wild-type cells from the surrounding endothelium to form mosaic lesions and promote lesion growth; however the mechanisms underlying this recruitment remain poorly understood. Here, we use 3D traction force microscopy in a in-vitro model of early angiogenic invasion to reveal that hyper-angiogenic CCM2-silenced endothelial cells enhance angiogenic invasion of neighboring wild-type cells through force and extracellular matrix-guided mechanisms. We show that mechanically hyperactive CCM2-silenced tips guide wild-type cells by exerting and transmitting pulling forces and by leaving degraded paths in the matrix as cues promoting invasion in a ROCKs-dependent manner. This transmission of forces is associated with a reinforcement of {beta}1 integrin-dependent adhesive sites and actin cytoskeleton in the wild-type followers. We also show that during this process wild-type cells are reprogrammed into stalk cells through activation of matrisome and DNA replication programs, eventually leading to cell proliferation. These observations unveil a novel vascular lesion growth mechanism where CCM2 mutants hijack the function of wild-type cells to fuel CCM lesion growth. By integrating biophysical computational methodologies to quantify cellular forces with advanced molecular techniques, we provide new insights in the etiology of vascular malformations, and open up avenues to study the role of cell mechanics in tissue heterogeneity and disease progression.

bioengineering↗