A subject-specific human head finite element model with embedded axonal fiber tractography obtained from diffusion tensor imaging was developed. The axonal fiber tractography finite element model was coupled with the volumetric elements in the head model using the embedded element method. This technique enables the calculation of axonal strains and real-time tracking of the mechanical response of the axonal fiber tracts. The coupled model was then verified using pressure and relative displacement-based (between skull and brain) experimental studies and was employed to analyze a head impact, demonstrating the applicability of this method in studying axonal injury. Following this, a comparison study of different injury criteria was performed. This model was used to determine the influence of impact direction on the extent of the axonal injury. The results suggested that the lateral impact loading is more dangerous compared to loading in the sagittal plane, a finding in agreement with previous studies. Through this analysis, we demonstrated the viability of the embedded element method as an alternative numerical approach for studying axonal injury in patient-specific human head models.

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Subject-specific computer models (male and female) of the human head were used to investigate the possible axonal deformation resulting from the primary phase blast-induced skull flexures. The corresponding axonal tractography was explicitly incorporated into these finite element models using a recently developed technique based on the embedded finite element method. These models were subjected to extensive verification against experimental studies which examined their pressure and displacement response under a wide range of loading conditions. Once verified, a parametric study was developed to investigate the axonal deformation for a wide range of loading overpressures and directions as well as varying cerebrospinal fluid (CSF) material models. This study focuses on early times during a blast event, just as the shock transverses the skull (< 5 milliseconds). Corresponding boundary conditions were applied to eliminate the rotation effects and the resulting axonal deformation. A total of 138 simulations were developed– 128 simulations for studying the different loading scenarios and 10 simulations for studying the effects of CSF material model variance–leading to a total of 10,702 simulation core hours. Extreme strains and strain rates along each of the fiber tracts in each of these scenarios were documented and presented here. The results suggest that the blast-induced skull flexures result in strain rates as high as 150–378 s-1. These high-strain rates of the axonal fiber tracts, caused by flexural displacement of the skull, could lead to a rate dependent micro-structural axonal damage, as pointed by other researchers.

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Purpose To investigate in vitro transdermal delivery of tofacitinib citrate across human skin using microporation by microneedles and iontophoresis alone and in combination. Methods In vitro permeation studies were conducted using vertical Franz diffusion cells. Microneedles composed of polyvinyl alcohol and carboxymethyl cellulose were fabricated and successfully characterized using scanning electron microscopy. The microchannels created were further characterized using histology, dye binding study, scanning electron microscopy, and confocal microscopy studies. The effect of microporation on delivery of tofacitinib citrate was evaluated alone and in combination with iontophoresis. In addition, the effect of current density on iontophoretic delivery was also investigated. Results Total delivery of tofacitinib citrate via passive permeation was found out to be 11.04 ± 1 μg/sq.cm. Microporation with microneedles resulted in significant enhancement where a 28-fold increase in delivery of tofacitinib citrate was observed with a total delivery of 314.7±33.32 μg/sq.cm. The characterization studies confirmed the formation of microchannels in the skin where successful disruption of stratum corneum was observed after applying microneedles. Anodal iontophoresis at 0.1 and 0.5 mA/sq.cm showed a total delivery of 18.56 μg/sq.cm and 62.07 μg/sq.cm, respectively. A combination of microneedle and iontophoresis at 0.5 mA/sq.cm showed the highest total delivery of 566.59 μg/sq.cm demonstrating a synergistic effect. A sharp increase in transdermal flux was observed for a combination of microneedles and iontophoresis. Conclusion This study demonstrates the use of microneedles and iontophoresis to deliver a therapeutic dose of tofacitinib citrate via transdermal route.

Introduction During training and combat operations, military personnel may be exposed to repetitive low-level blast while using explosives to gain entry or by firing heavy weapon systems such as recoilless weapons and high-caliber sniper rifles. This repeated exposure, even within allowable limits, has been associated with cognitive deficits similar to that of accidental and sports concussion such as delayed verbal memory, visual-spatial memory, and executive function. This article presents a novel framework for accurate calculation of the human body blast exposure in military heavy weapon training scenarios using data from the free-field and warfighter wearable pressure sensors. Materials and Methods The CoBi human body model generator tools were used to reconstruct multiple training scenes with different weapon systems. The CoBi Blast tools were used to develop the weapon signature and estimate blast overpressure exposure. The authors have used data from the free-field and wearable pressure sensors to evaluate the framework. Results Carl-Gustav and 0.50 caliber sniper training scenarios were used to demonstrate and validate the developed framework. These simulations can calculate spatially and temporally resolved blast loads on the whole human body and on specific organs vulnerable to blast loads, such as head, face, and lungs. Conclusions This framework has numerous advantages including easier model setup and shorter simulation times. The framework is an important step towards developing an advanced field-applicable technology to monitor low-level blast exposure during heavy weapon military training and combat scenarios.

Finite element models are frequently used to simulate traumatic brain injuries. However, current models are unable to capture the progressive damage caused by repeated head trauma. In this work, we propose a method for computing the history-dependent mechanical damage of axonal fiber bundle tracts in the brain. Through the introduction of multiple damage models, we provide the ability to link consecutive head impact simulations, so that potential injury to the brain can be tracked over time. In addition, internal damage variables are used to degrade the mechanical response of each axonal fiber bundle element. As a result, the stiffness of the aggregate tissue decreases as damage evolves. To counteract this degenerative process, we have also introduced a preliminary healing model that reverses the accumulated damage, based on a user-specified healing duration. Using two detailed examples, we demonstrate that damage produces a significant decrease in fiber stress, which ultimately propagates to the tissue level and produces a measurable decrease in overall stiffness. These results suggest that damage modeling has the potential to enhance current brain simulation techniques and lead to new insights, especially in the study of repetitive head injuries. KEYWORDSaxonal injury, diffusion tensor imaging, traumatic brain injury, damage mechanics, finite element analysis, composites, embedded element method, occupational brain injury, sub-concussive brain injury INTRODUCTIONTraumatic brain injury (TBI) is a significant cause of death and long-term disability [1]. In the United States, there were 2.8 million TBI-related emergency department visits, hospitalizations, and deaths in 2013 [2]. The structure of the brain can be divided into the gray and white matter regions. In general, gray matter tissue forms the outer layer of the brain and contains the neuron cell bodies, while white matter tissue forms the central region of the brain and contains neuron cell extensions, known as axons. These tightly bundled axons form a dense communication network that transmits signals between the neuron cell bodies. While axons account for the majority of white matter tissue, they are surrounded by a mixture of other components, such as glial cells and the extracellular matrix (ECM). However, this surrounding host material is much softer than the axons [3] [4]. As a result, white matter tissue is commonly treated as a fiber-reinforced composite in mechanical simulations [5] [6] [7] [8]. During severe head impacts, brain deformations can result in the widespread stretching and shearing of axons. This kind of TBI is classified as diffuse axonal injury (DAI) and is typically associated with motor vehicle crashes, sports injuries, and military blast trauma [9] [10]. DAI is the primary injury mechanism in more than 40% of all hospitalized TBIs [11] and can result in both physical and cognitive impairments, which may be temporary or permanent [12].In an effort to design safer products and study the underlying mechanisms of brain injury, there h...

Blast-induced traumatic brain injury (bTBI) has become a signature casualty of recent military operations. In spite of significant clinical and preclinical TBI research, current understanding of injury mechanisms and short- and long-term outcomes is limited. Mathematical models of bTBI biomechanics may help in better understanding of injury mechanisms and in the development of improved neuroprotective strategies. Until present, bTBI has been analyzed as a single event of a blast pressure wave propagating through the brain. In many bTBI events, the loads on the body and the head are spatially and temporarily distributed, involving the primary intracranial pressure wave, followed by the head rotation and then by head impact on the ground. In such cases, the brain microstructures may experience time/space distributed (consecutive) damage and recovery events. The paper presents a novel multiscale simulation framework that couples the body/brain scale biomechanics with micro-scale mechanobiology to study the effects of micro-damage to neuro-axonal structures. Our results show that the micro-mechanical responses of neuro-axonal structures occur sequentially in time with “damage” and “relaxation” periods in different parts of the brain. A new integrated computational framework is described coupling the brain-scale biomechanics with micro-mechanical damage to axonal and synaptic structures.