Strain and rate-dependent neuronal injury in a 3D in vitro compression model of traumatic brain injury

Abstract

In the United States over 1.7 million cases of traumatic brain injury are reported yearly, but predictive correlation of cellular injury to impact tissue strain is still lacking, particularly for neuronal injury resulting from compression. Given the prevalence of compressive deformations in most blunt head trauma, this information is critically important for the development of future mitigation and diagnosis strategies. Using a 3D in vitro neuronal compression model, we investigated the role of impact strain and strain rate on neuronal lifetime, viability, and pathomorphology. We find that strain magnitude and rate have profound, yet distinctively different effects on the injury pathology. While strain magnitude affects the time of neuronal death, strain rate influences the pathomorphology and extent of population injury. Cellular injury is not initiated through localized deformation of the cytoskeleton but rather driven by excess strain on the entire cell. Furthermore we find that, mechanoporation, one of the key pathological trigger mechanisms in stretch and shear neuronal injuries, was not observed under compression.

Restoration of thalamo‐cortical connectivity after brain injury: recovery of consciousness, complex behavior, or passage of time?

“…Indeed, in the minutes, hours, and days post‐injury, the pathophysiology of brain injury is dominated by pathological levels of extracellular glutamate (Vespa et al, ), mitochondrial function (Verweij et al, ), cerebral blood flow (Martin et al, ), metabolic rates of glucose and oxygen (Hattori et al, ; Meyer, Kondo, Nomura, Sakamoto, & Teraura, ), and neurovascular coupling (del Zoppo & Mabuchi, ; Povlishock & Kontos, ) among others (Busl & Greer, ; Greve & Zink, ; Maas, Stocchetti, & Bullock, ; Werner & Engelhard, ). Furthermore, the timing of these dynamics may itself depend on a number of additional factors, including strain magnitude and strain rate, which have been shown in in‐vitro models of neuronal compression to affect the time of neuronal death and the pathomorphology and extent of neural population injury, respectively (Bar‐Kochba, Scimone, Estrada, & Franck, ). However, within a month post‐injury and independent of cognitive function, many of these processes are no longer as prominent (Bergsneider et al, ; Inoue et al, ; Vespa et al, ; Xiong, Gu, Peterson, Muizelaar, & Lee, ) and changes in neuronal connectivity as a consequence of these injuries are now the prevailing source (Adams et al, ; Graham, Adams, Murray, & Jennett, ; Graham, Maxwell, Adams, & Jennett, ; Lutkenhoff et al, , ).…”

The overlooked aspect of excitotoxicity: Glutamate‐independent excitotoxicity in traumatic brain injuries

“…However, a secondary porating event can occur hours after the initial injury, which has been proposed to be a result of the activation of degradative enzymes such as calpain (Cullen et al., ). Although these findings were recently challenged (Bar‐Kochba, Scimone, Estrada, & Franck, ), other groups reached similar conclusions on the plasma membrane permeability in in vitro injury models (Cullen & LaPlaca, ; Ellis, McKinney, Willoughby, Liang, & Povlishock, ; Geddes, Cargill, & LaPlaca, ; LaPlaca, Cullen, McLoughlin, & Cargill, ). With the results showing that TBI can induce pore formation in the membrane and cause fluorescent markers to pass through, it would be possible for?…”

Effects of nerve bundle geometry on neurotrauma evaluation

“…The loss of nerve membrane integrity due to an applied deformation leads to changes in electrical signal propagation . Furthermore, injury pathologies in nerve fibers are also initiated and influenced by strain and strain rate, which have a significant impact on the time of neural death and pathomorphology, respectively . For instance, experimental studies on human axons show that morphological changes may tolerate dynamic stretch at strains up to 65 %, manifesting both an elastic recovery and a delayed elastic response along the fiber length …”