Multiscale Modelling of Blast-Induced TBI Mechanobiology - From Body to Neuron to Molecule

Blast induced Traumatic Brain Injury (bTBI) has become a signature wound of the recent military operations and is becoming a significant factor of recent civilian blast explosion events. In spite of significant clinical and preclinical research on TBI, current understanding of injury mechanisms is limited and little is known about the short and long-term outcomes. Mathematical models of bTBI may provide capabilities to study brain injury mechanisms, perhaps accelerating the development of neuroprotective strategies and aiding in the development of improved personal protective equipment. The paper presents a novel multiscale simulation framework that couples the body/brain scale biomechanics with micro-scale mechanobiology to study the effects of “primary” micro-damage to neuro-axonal structures with the “secondary” injury and repair mechanisms. Our results show that oligodendrocyte myelinating processes distribute strains among neighbor axons and cause their off-axis deformations. Similar effects have been observed at the finer scale for the Tau-Microtubule interaction. The paper also discusses the need for coupled modeling of primary injury biomechanics, secondary injury mechanobiology and model based assessment of injury severity scores. A new integrated computational and experimental approach is described coupling micro-scale injury criteria for the primary micro-mechanical damage to brain tissue/cells as well as to investigate various secondary injury mechanisms.

Robotic fluidic coupling and interrogation of multiple vascularized organ chips

Organ chips can recapitulate organ-level (patho)physiology, yet pharmacokinetic and pharmacodynamic analyses require multi-organ systems linked by vascular perfusion. Here, we describe an ???interrogator??? that employs liquid-handling robotics, custom software and an integrated mobile microscope for the automated culture, perfusion, medium addition, fluidic linking, sample collection and in situ microscopy imaging of up to ten organ chips inside a standard tissue-culture incubator. The robotic interrogator maintained the viability and organ-specific functions of eight vascularized, two-channel organ chips (intestine, liver, kidney, heart, lung, skin, blood???brain barrier and brain) for 3 weeks in culture when intermittently fluidically coupled via a common blood substitute through their reservoirs of medium and endothelium-lined vascular channels. We used the robotic interrogator and a physiological multicompartmental reduced-order model of the experimental system to quantitatively predict the distribution of an inulin tracer perfused through the multi-organ human-body-on-chips. The automated culture system enables the imaging of cells in the organ chips and the repeated sampling of both the vascular and interstitial compartments without compromising fluidic coupling