A Mechanistic End-to-End Concussion Model That Translates Head Kinematics to Neurologic Injury.

Past concussion studies have focused on understanding the injury processes occurring on discrete length scales (e.g., tissue-level stresses and strains, cell-level stresses and strains, or injury-induced cellular pathology). A comprehensive approach that connects all length scales and relates measurable macroscopic parameters to neurological outcomes is the first step toward rationally unraveling the complexity of this multi-scale system, for better guidance of future research. This paper describes the development of the first quantitative end-to-end (E2E) multi-scale model that links gross head motion to neurological injury by integrating fundamental elements of tissue and cellular mechanical response with axonal dysfunction. The model quantifies axonal stretch (i.e., tension) injury in the corpus callosum, with axonal functionality parameterized in terms of axonal signaling. An internal injury correlate is obtained by calculating a neurological injury measure (the average reduction in the axonal signal amplitude) over the corpus callosum. By using a neurologically based quantity rather than externally measured head kinematics, the E2E model is able to unify concussion data across a range of exposure conditions and species with greater sensitivity and specificity than correlates based on external measures. In addition, this model quantitatively links injury of the corpus callosum to observed specific neurobehavioral outcomes that reflect clinical measures of mild traumatic brain injury. This comprehensive modeling framework provides a basis for the systematic improvement and expansion of this mechanistic-based understanding, including widening the range of neurological injury estimation, improving concussion risk correlates, guiding the design of protective equipment, and setting safety standards.

A model for predicting primary blast lung injury.

BACKGROUND: This article presents a model-based method for predicting primary blast injury. On the basis of the normalized work injury mechanism from previous work, this method presents a new model that accounts for the effects of blast orientation and species difference. METHODS: The analysis used test data from a series of extensive experimental studies sponsored by the US Army Medical Research and Materiel Command. In these studies, more than 1200 sheep were exposed to air blast in free-field and confined enclosures, and lung injuries were quantified as the percentage of surface area contused. Blast overpressure data were collected using blast test devices placed at matching locations to represent loadings to the thorax. Adopting the modified Lobdell model with further modifications specifically for blast and scaling, the thorax deformation histories for the left, chest, and right sides of the thorax were calculated for all sheep subjects. Using the calculated thorax velocities, effective normalized work was computed for each test subject representing the irreversible work performed on the lung tissues normalized by lung volume and ambient pressure. RESULTS: Dose-response curves for four categories of injuries (trace, slight, moderate, and severe) were developed by performing log-logistic correlations of the computed normalized work with the injury outcomes, including the effect of multiple shots. A blast lethality correlation was also established. CONCLUSION: Validated by sheep data, the present work revalidates the previous understanding and findings of the blast lung injury mechanism and provides an anthropomorphic model for primary blast injury prediction that can be used for occupational and survivability analysis. LEVEL OF EVIDENCE: Economic and decision analysis, level III.

An integrated exercise response and muscle fatigue model for performance decrement estimates of workloads in oxygen-limiting environments.

The performance dynamic physiology model (DPM-PE) integrates a modified muscle fatigue model with an exercise physiology model that calculates the transport and delivery of oxygen to working muscles during exposures of oxygen-limiting environments. This mathematical model implements a number of physiologic processes (respiration, circulation, tissue metabolism, diffusion-limited gas transfer at the blood/gas lung interface, and ventilatory control with afferent feedback, central command and humoral chemoreceptor feedback) to replicate the three phases of ventilatory response to a variety of exertion patterns, predict the delivery and transport of oxygen and carbon dioxide from the lungs to tissues, and calculate the amount of aerobic and anaerobic work performed. The ventilatory patterns from passive leg movement, unloaded work, and stepped and ramping loaded work compare well against data. The model also compares well against steady-state ventilation, cardiac output, blood oxygen levels, oxygen consumption, and carbon dioxide generation against a range of exertion levels at sea level and at altitude, thus demonstrating the range of applicability of the exercise model. With the ability to understand and predict gas transport and delivery of oxygen to working muscle tissue for different workloads and environments, the correlation between blood oxygen measures and the recovery factor of the muscle fatigue model was explored. Endurance data sets in normoxia and hypoxia were best replicated using arterial oxygen saturation as the correlate with the recovery factor. This model provides a physiologically based method for predicting physical performance decrement due to oxygen-limiting environments.

Assessing the application of acute toxic gas standards.

OBJECTIVE: In this paper, we compare acute toxic gas standards developed for occupational, military, and civilian use that predict or establish guidelines for limiting exposure to inhaled toxic gases. CONTEXT: Large disparities between guidelines exist for similar exposure scenarios, raising questions about why differences exist, as well as the applicability of each standard. The motivation and rationale behind the development of the standards is explored with emphasis on the experimental data used to set the standards. METHODS: The Toxic Gas Assessment Software (TGAS) is used to quantitatively compare current acute exposure standards, such as: Acute Exposure Guidelines (AEGL), Immediate Danger to Life or Health (IDLH), Purser, International Organization for Standardization (ISO 13571), and Federal Aviation Administration (FAA). The TGAS software does this by calculating the body-mass-normalized internal doses of each gas exposure in each standard, which is then plotted on a cumulative distribution function for a normal or susceptible population to visualize the relationship of the standards to each other. To focus the comparison, acute toxic gas standards for five common fire gases, carbon monoxide (CO), hydrogen cyanide (HCN), hydrogen chloride (HCl), nitrogen dioxide (NO2), and acrolein (C3H4O), are explored. RESULTS: It was found that differences between standards can be reconciled when the target population, effect endpoint, and incidence level are taken into account. CONCLUSION: By analyzing the standards with respect to these factors, we can acquire a better understanding of the applicability of each.

Development and validation of subject-specific finite element models for blunt trauma study.

This study developed and validated finite element (FE) models of swine and human thoraxes and abdomens that had subject-specific anatomies and could accurately and efficiently predict body responses to blunt impacts. Anatomies of the rib cage, torso walls, thoracic, and abdominal organs were reconstructed from X-ray computed tomography (CT) images and extracted into geometries to build FE meshes. The rib cage was modeled as an inhomogeneous beam structure with geometry and bone material parameters determined directly from CT images. Meshes of soft components were generated by mapping structured mesh templates representative of organ topologies onto the geometries. The swine models were developed from and validated by 30 animal tests in which blunt insults were applied to swine subjects and CT images, chest wall motions, lung pressures, and pathological data were acquired. A comparison of the FE calculations of animal responses and experimental measurements showed a good agreement. The errors in calculated response time traces were within 10% for most tests. Calculated peak responses showed strong correlations with the experimental values. The stress concentration inside the ribs, lungs, and livers produced by FE simulations also compared favorably to the injury locations. A human FE model was developed from CT images from the Visible Human project and was scaled to simulate historical frontal and side post mortem human subject (PMHS) impact tests. The calculated chest deformation also showed a good agreement with the measurements. The models developed in this study can be of great value for studying blunt thoracic and abdominal trauma and for designing injury prevention techniques, equipments, and devices.

Incorporation of acute dynamic ventilation changes into a standardized physiologically based pharmacokinetic model.

A seven-compartment physiologically based pharmacokinetic (PBPK) model incorporating a dynamic ventilation response has been developed to predict normalized internal dose from inhalation exposure to a large range of volatile gases. The model uses a common set of physiologic parameters, including standardized ventilation rates and cardiac outputs for rat and human. This standardized model is validated against experimentally measured blood and tissue concentrations for 21 gases. For each of these gases, body-mass-normalized critical internal dose (blood concentration) is established, as calculated using exposure concentration and time duration specified by the lowest observed adverse effect level (LOAEL) or the acute exposure guideline level (AEGL). The dynamic ventilation changes are obtained by combining the standardized PBPK model with the Toxic Gas Assessment Software 2.0 (TGAS-2), a validated acute ventilation response model. The combined TGAS-2P model provides a coupled, transient ventilation and pharmacokinetic response that predicts body mass normalized internal dose that is correlated with deleterious outcomes. The importance of ventilation in pharmacokinetics is illustrated in a simulation of the introduction of Halon 1301 into an environment of fire gases.

Finite element models of rib as an inhomogeneous beam structure under high-speed impacts.

Fracture of ribs commonly occurs during blunt impacts and can lead to serious injuries or even fatality. The finite element (FE) modeling of ribs under impacts, however, is difficult due to the complex geometry, the difficulty in determining material parameters, and the amount of the computational time required. This study develops a method of modeling ribs as inhomogeneous beam structures. The geometries are reconstructed from images acquired with X-ray computed tomography. Bone material properties, orthotropic or isotropic, are determined from the CT pixel values. From the material distribution inside the cross-section, generalized classical beam formulations use to determine the local homogenized stiffness of the nodes along the rib. To compare the accuracy and efficiency of the method, detailed three-dimensional (3D) FE models of ribs are also developed. Simulations of three benchmark problems that represent different loading or impact conditions demonstrate that the beam FE model is very efficient and is at least as accurate as a very finely meshed 3D FE model. Finally, the rib FE model is used to study blunt trauma injury of animal tests under high-speed impacts. The consistency between predictions and experimental results shows that the developed rib model is a great value to study of blunt trauma caused by high-speed impacts.

An internal dose model of incapacitation and lethality risk from inhalation of fire gases.

A mathematical model for estimating the likelihood of incapacitation and lethality from the inhalation of toxic gases is presented. The model computes an internal dose, equal to retained toxic gas per body mass, which is used to extrapolate outcomes across species. Account is taken for ventilation changes due to species, activity, and chemical response. The internal dose is correlated with each outcome using a cumulative, log-normal, probability distribution, which allows the estimation of tolerances for any population incidence. No internal interactions of gases are modeled and probabilities are combined independently. The model compares favorably with combined gas and large animal data.

Biomechanically based criteria for rib fractures induced by high-speed impact.

Biomechanically based correlations for rib fractures induced by high-speed impact were developed from animal studies, finite-element simulations, and statistical analysis. Using subject-specific finite-element models of swine thorax developed from medical images and customized for each animal subject, simulations were conducted for animal tests. The peak motions, internal forces, stresses, and strains were calculated for individual ribs. Statistical analysis then was used to determine represented variables that were statistically significant and that better fit the test data. The findings showed that the main loading modes during impacts are local bending and shearing. Stress-based variables fit the injury data very well. Strains also were relevant, but did not correlate with the data as well as stresses. The results also indicate that motion responses, such as displacement and velocity, and internal forces are not good correlates in high-speed impacts. The regression risk curves were developed using the stresses as correlates, and the threshold values are given consistent with bone strength data.

A mathematical model of ventilation response to inhaled carbon monoxide.

A comprehensive mathematical model, describing the respiration, circulation, oxygen metabolism, and ventilatory control, is assembled for the purpose of predicting acute ventilation changes from exposure to carbon monoxide in both humans and animals. This Dynamic Physiological Model is based on previously published work, reformulated, extended, and combined into a single model. Model parameters are determined from literature values, fitted to experimental data, or allometrically scaled between species. The model predictions are compared with ventilation-time history data collected in goats exposed to carbon monoxide, with quantitatively good agreement. The model reaffirms the role of brain hypoxia on hyperventilation during carbon monoxide exposures. Improvement in the estimation of total ventilation, through a more complete knowledge of ventilation control mechanisms and validated by animal data, will increase the accuracy of inhalation toxicology estimates.

The metabolic cost of force generation.

INTRODUCTION: The purpose of this study was to provide support, based on a review of existing data, for a general relationship between metabolic cost and force generated. There are confounding factors that can affect metabolic cost, including muscle contraction type (isometric, eccentric, or concentric), length, and speed as well as fiber type (e.g., fast or slow) and moment arm distances. Despite these factors, empirical relationships for metabolic cost have been found that transcend species and movements. METHODS: We revisited the various equations that have been proposed to relate metabolic rate with mass, velocity, and step contact time during running and found that metabolic rate was proportional to the external force generated and the number of steps per unit time. This relationship was in agreement with a previously proposed hypothesis that the metabolic cost to generate a single application of a unit external force is a constant. RESULTS: Data from the literature were collected for a number of different activities and species to support the hypothesis. Running quadrupedal and bipedal species, as well as human cycling, cross-country skiing, running (forward, backward, on an incline, and against a horizontal force), and arm activities (running, cycling, and ski poling), all had a constant metabolic cost per unit external force per application. CONCLUSION: The proportionality constant varied with activity, possibly reflecting differences in the aspects of muscular contraction, fiber types, or mechanical advantage in each activity. It is speculated that a more general relation could be obtained if biomechanical analyses to account for other factors, such as contraction length, were included.

An internal dose model for interspecies extrapolation of immediate incapacitation risk from inhalation of fire gases.

A quantitative mathematical model assesses incapacitation risk in humans from toxic gas inhalation. A body-mass-normalized internal dose for each gas is calculated from an inhalation equation in which ventilation is a function of species, activity, and the gases inhaled. Uptake in the dead space considers U.S. Environmental Protection Agency (EPA) gas categories. The probability of incapacitation is a function of normalized internal dose and follows a cumulative distribution curve whose parameters are found from small-animal incapacitation data. No internal interaction of gases is modeled, and probabilities are combined independently. The model compares favorably with combined gas and large-animal incapacitation data.