Neural cell injury pathology due to high-rate mechanical loading

Abstract

Successful detection and prevention of brain injuries relies on the quantitative identification of cellular injury thresholds associated with the underlying pathology. Here, by combining a recently developed inertial microcavitation rheology technique with a 3D in vitro neural tissue model, we quantify and resolve the structural pathology and critical injury strain thresholds of neural cells occurring at high loading rates such as encountered in blast, cavitation or directed energy exposures. We find that neuronal dendritic spines characterized by MAP2 displayed the lowest physical failure strain at 7.3%, whereas microtubules and filamentous actin were able to tolerate appreciably higher strains (14%) prior to injury. Interestingly, while these critical injury thresholds were similar to previous literature values reported for moderate and lower strain rates ($<100$ 1/s), the pathology of primary injury reported here was distinctly different by being purely physical in nature as compared to biochemical activation during apoptosis or necrosis.

Statement of Significance

Mitigation and prevention of cellular injury is challenging in part due to the lack of quantitative correlation between mechanical insult and cellular pathology, especially at high deformation rates (>104 s⁻¹) that occur in blast and directed energy related brain injury, or laser and sonic-based medical procedures. By utilizing a recently developed inertial microcavitation rheology technique for generating high-rate deformations in a 3D in vitro neural tissue model, we quantitatively correlate critical stretch, strain and stress-based injury criteria to observed cell pathology. These quantitative experimental measurements provide unprecedented new detail into the cellular pathology of neural tissues affected by high-rate injury including the first quantitative high-rate injury threshold metrics.