A Comprehensive Review of Experimental Rodent Models of Repeated Blast TBI.

We reviewed the relevant literature delineating advances in the development of the experimental models of repeated blast TBI (rbTBI). It appears this subject is a relatively unexplored area considering the first work published in 2007 and the bulk of peer-reviewed papers was published post-2011. There are merely 34 papers published to date utilizing rodent rbTBI models. We performed an analysis and extracted basic parameters to capture the characteristics of the exposure conditions (the blast intensity, inter-exposure interval and the number of exposures), the age and weight of the animal models most commonly used in the studies, and their endpoints. Our analysis revealed three strains of rodents are predominantly used: Sprague Dawley and Long Evans rats and wild type (C57BL/6J) mice, and young adult animals 8 to 12-week-old are a preferred choice. Typical exposure conditions are the following: (1) peak overpressure in the 27-145 kPa (4-21 psi) range, (2) number of exposures: 2 (13.9%), 3 (63.9%), 5 (16.7%), or 12 (5.6%) with a single exposure used for a baseline comparison in 41.24% of the studies. Two inter-exposure interval durations were used: (1) short (1-30 min.) and (2) extended (24 h) between consecutive shock wave exposures. The experiments included characterization of repeated blast exposure effects on auditory, ocular and neurological function, with a focus on brain etiology in most of the published work. We present an overview of major histopathological findings, which are supplemented by studies implementing MRI (DTI) and behavioral changes after rbTBI in the acute (1-7 days post-injury), subacute (7-14 days), and chronic (>14 days) phases post-injury.

Effect of Tissue Material Properties in Blast Loading: Coupled Experimentation and Finite Element Simulation.

Computational models of blast-induced traumatic brain injury (bTBI) require a robust definition of the material models of the brain. The mechanical constitutive models of these tissues are difficult to characterize, leading to a wide range of values reported in literature. Therefore, the sensitivity of the intracranial pressure (ICP) and maximum principal strain to variations in the material model of the brain was investigated through a combined computational and experimental approach. A finite element model of a rat was created to simulate a shock wave exposure, guided by the experimental measurements of rats subjected to shock loading conditions corresponding to that of mild traumatic brain injury in a field-validated shock tube. In the numerical model, the properties of the brain were parametrically varied. A comparison of the ICP measured at two locations revealed that experimental and simulated ICP were higher in the cerebellum (p < 0.0001), highlighting the significance of pressure sensor locations within the cranium. The ICP and strain were correlated with the long-term bulk (p < 0.0001) and shear moduli (p < 0.0001), with an 80 MPa effective bulk modulus value matching best with experimental measurements. In bTBI, the solution is sensitive to the brain material model, necessitating robust validation methods.

Updated Lagrangian finite element formulations of various biological soft tissue non-linear material models: a comprehensive procedure and review.

Simplified material models are commonly used in computational simulation of biological soft tissue as an approximation of the complicated material response and to minimize computational resources. However, the simulation of complex loadings, such as long-duration tissue swelling, necessitates complex models that are not easy to formulate. This paper strives to offer the updated Lagrangian formulation comprehensive procedure of various non-linear material models for the application of finite element analysis of biological soft tissues including a definition of the Cauchy stress and the spatial tangential stiffness. The relationships between water content, osmotic pressure, ionic concentration and the pore pressure stress of the tissue are discussed with the merits of these models and their applications.

Microgravity control of autophagy modulates osteoclastogenesis.

Evidence indicates that astronauts experience significant bone loss during space mission. Recently, we used the NASA developed rotary cell culture system (RCCS) to simulate microgravity (µXg) conditions and demonstrated increased osteoclastogenesis in mouse bone marrow cultures. Autophagy is a cellular recycling process of nutrients. Therefore, we hypothesize that µXg control of autophagy modulates osteoclastogenesis. Real-time PCR analysis of total RNA isolated from mouse bone marrow derived non-adherent cells subjected to modeled µXg showed a significant increase in autophagic marker Atg5, LC3 and Atg16L mRNA expression compared to ground based control (Xg) cultures. Western blot analysis of total cell lysates identified an 8.0-fold and 7.0-fold increase in the Atg5 and LC3-II expression, respectively. Confocal microscopy demonstrated an increased autophagosome formation in µXg subjected RAW 264.7 preosteoclast cells. RT(2) profiler PCR array screening for autophagy related genes identified that µXg upregulates intracellular signaling molecules associated with autophagy, autophagosome components and inflammatory cytokines/growth factors which coregulate autophagy in RAW 264.7 preosteoclast cells. Autophagy inhibitor, 3-methyladenine (3-MA) treatment of mouse bone marrow derived non-adherent mononuclear cells showed a significant decrease in µXg induced Atg5 and LC3 mRNA expression in the presence or absence of RANK ligand (RANKL) stimulation. Furthermore, RANKL treatment significantly increased (8-fold) p-CREB transcription factor levels under µXg as compared to Xg cultures and 3-MA inhibited RANKL increased p-CREB expression in these cells. Also, 3-MA suppresses µXg elevated osteoclast differentiation in mouse bone marrow cultures. Thus, our results suggest that µXg induced autophagy plays an important role in enhanced osteoclast differentiation and could be a potential therapeutic target to prevent bone loss in astronauts during space flight missions.