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Biofidelic dynamic compression of human cortical spheroids reproduces neurotrauma phenotypes.

ABSTRACT: Fundamental questions about patient heterogeneity and human-specific pathophysiology currently obstruct progress towards a therapy for traumatic brain injury (TBI). Human in vitro models have the potential to address these questions. Three-dimensional spheroidal cell culture protocols for human-origin neural cells have several important advantages over their two-dimensional monolayer counterparts. Three-dimensional spheroidal cultures may mature more quickly, develop more biofidelic electrophysiological activity and/or reproduce some aspects of brain architecture. Here, we present the first human in vitro model of non-penetrating TBI employing three-dimensional spheroidal cultures. We used a custom-built device to traumatize these spheroids in a quantifiable, repeatable and biofidelic manner, and correlated the heterogeneous mechanical strain field with the injury phenotype. Trauma reduced cell viability, mitochondrial membrane potential and spontaneous synchronous electrophysiological activity in the spheroids. Electrophysiological deficits emerged at lower injury severities than changes in cell viability. Also, traumatized spheroids secreted lactate dehydrogenase, a marker of cell damage, and neurofilament light chain, a promising clinical biomarker of neurotrauma. These results demonstrate that three-dimensional human in vitro models can reproduce important phenotypes of neurotrauma in vitro.

SUBMITTER: Shoemaker AR

PROVIDER: S-EPMC8713991 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Introduction: Mechanical properties of biological tissue are important for numerical simulations. Preservative treatments are necessary for disinfection and long-term storage when conducting biomechanical experimentation on materials. However, few studies have been focused on the effect of preservation on the mechanical properties of bone in a wide strain rate. The purpose of this study was to evaluate the influence of formalin and dehydration on the intrinsic mechanical properties of cortical bone from quasi-static to dynamic compression. Methods: Cube specimens were prepared from pig femur and divided into three groups (fresh, formalin, and dehydration). All samples underwent static and dynamic compression at a strain rate from 10−3 s−1 to 103 s−1. The ultimate stress, ultimate strain, elastic modulus, and strain-rate sensitivity exponent were calculated. A one-way ANOVA test was performed to determine if the preservation method showed significant differences in mechanical properties under at different strain rates. The morphology of the macroscopic and microscopic structure of bones was observed. Results: The results show that ultimate stress and ultimate strain increased as the strain rate increased, while the elastic modulus decreased. Formalin fixation and dehydration did not affect elastic modulus significantly whereas significantly increased the ultimate strain and ultimate stress. The strain-rate sensitivity exponent was the highest in the fresh group, followed by the formalin group and dehydration group. Different fracture mechanisms were observed on the fractured surface, with fresh and preserved bone tending to fracture along the oblique direction, and dried bone tending to fracture along the axial direction. Discussion: In conclusion, preservation with both formalin and dehydration showed an influence on mechanical properties. The influence of the preservation method on material properties should be fully considered in developing a numerical simulation model, especially for high strain rate simulation.

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Biofidelic dynamic compression of human cortical spheroids reproduces neurotrauma phenotypes.

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