A fiber matrix model for fluid flow and streaming potentials in the canaliculi of an osteon

A theoretical model is developed to predict the fluid shear stress and streaming potential at the surface of osteocytic processes in the lacunar-canalicular porosity of an osteon when the osteon is subject to mechanical loads that are parallel or perpendicular to its axis. The theory developed in Weinbaumet al. (31) for the flow through a proteoglycan matrix in a canaliculus is employed in a poroelastic model for the osteon. Our formulation is a generalization of that of Petrovet al. (17). Our model predicts that, in order to satisfy the measured frequency dependence of the phase and magnitude of the SGP in macroscopic bone samples, the fiber spacing in the fluid annulus must lie in the narrow range 6–7 nm typical of the spacing of GAG sidechains along a protein monomer. The model predictions for the local SGP profiles in the osteon agree with the experimental observations of Starkebaumet al. (24). The theory predicts that the pore pressure relaxation time, τ_d, for a 150–300 μm diameter osteon with the foregoing matrix structure is approximately 0.03–0.13 sec, and that the amplitude of the mean fluid shear stress on the membrane of the osteocytic process at the mean areal radius of the osteon has a maximum at 28 Hz if τ_d = 0.06 sec. This maximum, which is independent of the magnitude of the loading, could be importantin vivo since the recent experiments of Turneret al. (28) and McLeodet al. (15) have a peak in the strain frequency spectrum between 20 and 30 Hz that also appears to be independent of the type (magnitude) of loading. Numerical predictions for the amplitude of the average fluid shear stress on the osteocytic membrane at the mean areal radius of the osteon show that the fluid shear stress associated with the low amplitude 20–30 Hz spectral strain component is at least as large as the average fluid shear stress associated with the high amplitude 1 Hz stride component, although the latter loading is an order of magnitude larger, and has a magnitude that lies within the middle of the range, 6–30 dynes/cm², where fluid shear stresses in tissue culture studies with osteoblast monolayers have elicited an intracellular Ca⁺⁺ response (31). The implications of these results for intracellular electrical communication are discussed.     

颅脑组织材料参数对儿童头部冲击响应的影响

目的针对目前对儿童颅脑组织材料参数的不确定性,研究直接冲击载荷条件下颅脑组织材料参数对儿童头部冲击响应的影响。方法应用已验证的3岁儿童头部有限元模型进行冲击仿真实验,采用正交实验设计和方差分析对儿童颅脑组织材料进行参数分析。结果颅骨弹性模量对儿童头部冲击响应具有显著性影响,随着颅骨弹性模量的增加,头部撞击侧颅内压力显著减小(P=0.000),对撞侧颅内压力显著增大(P=0.000),颅骨最大Von Mises应力显著增大(P=0.000)。脑组织的线性黏弹性材料参数对儿童头部冲击响应同样具有显著性影响,随着脑组织短效剪切模量的增加,脑组织最大主应变显著减小(P=0.000),脑组织最大剪应力则显著增加(P=0.000)。结论参数分析结果可为今后儿童头部有限元模型的材料选取提供参考依据,进而提升模型在预测临床上无法通过脑CT影像确诊的脑震荡等脑损伤时的准确性。     

Development of a Multimodal Blast Sensor for Measurement of Head Impact and Over-pressurization Exposure

It is estimated that 10–20% of United States soldiers returning from Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) have suffered at least one instance of blast-induced traumatic brain injury (bTBI) with many reporting persistent symptomology and long-term effects. This variation in blast response may be related to the complexity of blast waves and the many mechanisms of injury, including over-pressurization due to the shock wave and potential for blunt impacts to the head from shrapnel or from other indirect impacts (e.g., building, ground, and vehicle). To help differentiate the effects of primary, secondary, and tertiary effects of blast, a custom sensor was developed to simultaneously measure over-pressurization and blunt impact. Moreover, a custom, complementary filter was designed to differentiate the measurements of blunt (low-frequency bandwidth) from over-pressurization (high-frequency bandwidth). The custom sensor was evaluated in the laboratory using a shock tube to simulate shock waves and a drop fixture to simulate head impacts. Both bare sensors and sensor embedded within an ACH helmet coupon were compared to laboratory reference transducers under multiple loading conditions (n = 5) and trials at each condition (n = 3). For all comparative measures, peak magnitude, peak impulse, and cross-correlation measures, R ² values, were greater than 0.900 indicating excellent agreement of peak measurements and time-series comparisons with laboratory measures.     

Pathophysiology of battlefield associated traumatic brain injury

As more data is accumulated from Operation Iraqi Freedom and Operation Enduring Freedom (OEF in Afghanistan), it is becoming increasing evident that traumatic brain injury (TBI) is a serious and highly prevalent battle related injury. Although traditional TBIs such as closed head and penetrating occur in the modern battle space, the most common cause of modern battle related TBI is exposure to explosive blast. Many believe that explosive blast TBI is unique from the other forms of TBI. This is because the physical forces responsible for explosive blast TBI are different than those for closed head TBI and penetrating TBI. The unique force associated with explosive blast is the blast shock pressure wave. This shock wave occurs over a very short period, milliseconds, and has a specific profile known as the Freidlander curve. This pressure–time curve is characterized by an initial very rapid up-rise followed by a longer decay that reaches a negative inflection point before returning to baseline. This is important as the effect of this shock pressure on brain parenchyma is distinct. The diffuse interaction of the pressure wave with the brain leads to a complex cascade of events that affects neurons, axons, glia cells, and vasculature. It is only by properly studying this disease will meaningful therapies be realized.     

Development of an Endothelial–Smooth Muscle Cell Coculture Model Using Phenotype-Controlled Smooth Muscle Cells

A coculture of endothelial cells (ECs) and smooth muscle cells (SMCs), which mimics cellular interactions appearing in vivo, has been performed in studies on the relationship between atherogenesis and fluid shear stress conditions. Although healthy arteries in vivo consist of contractile phenotype SMCs, cultured cells used in many studies normally exhibit a synthetic phenotype. Here, we developed an EC–SMC coculture model to investigate the interactions between ECs and contractile SMCs, and examined the effect of shear stress applied to ECs on SMC phenotypes. Cultured human umbilical artery SMCs were differentiated into contractile states by arresting cell growth using a serum-free medium. Western blotting confirmed that SMC expression of contractile protein markers, α-smooth muscle actin (SMA) and calponin, increased to levels similar to those observed in arterial cells. After coculturing contractile SMCs with ECs separated by a collagen gel layer, the expression of α-SMA decreased under static conditions, indicating that the SMC phenotype tended to be synthetic by coculturing with ECs, but shear stress applied to cocultured ECs maintained the level of α-SMA expression in SMCs. The coculture model constructed in the present study will be a useful tool to investigate interactions between ECs and contractile SMCs under shear conditions.     

Development of a Finite Element Model for Blast Brain Injury and the Effects of CSF Cavitation

Blast-related traumatic brain injury is the most prevalent injury for combat personnel seen in the current conflicts in Iraq and Afghanistan, yet as a research community,we still do not fully understand the detailed etiology and pathology of this injury. Finite element (FE) modeling is well suited for studying the mechanical response of the head and brain to blast loading. This paper details the development of a FE head and brain model for blast simulation by examining both the dilatational and deviatoric response of the brain as potential injury mechanisms. The levels of blast exposure simulated ranged from 50 to 1000 kPa peak incident overpressure and 1–8 ms in positive-phase duration, and were comparable to real-world blast events. The frontal portion of the brain had the highest pressures corresponding to the location of initial impact, and peak pressure attenuated by 40–60% as the wave propagated from the frontal to the occipital lobe. Predicted brain pressures were primarily dependent on the peak overpressure of the impinging blast wave, and the highest predicted brain pressures were 30%less than the reflected pressure at the surface of blast impact. Predicted shear strain was highest at the interface between the brain and the CSF. Strain magnitude was largely dependent on the impulse of the blast, and primarily caused by the radial coupling between the brain and deforming skull.The largest predicted strains were generally less than 10%,and occurred after the shock wave passed through the head.For blasts with high impulses, CSF cavitation had a large role in increasing strain levels in the cerebral cortex and periventricular tissues by decoupling the brain from the skull. Relating the results of this study with recent experimental blast testing suggest that a rate-dependent strain-based tissue injury mechanism is the source primary blast TBI.     

Mouse Splenocyte Blast Transformation in the Presence of Plasma γ-Globulin Fraction Proteins and Their Complexes with Copper and Zinc

Plasma γ-globulin fraction proteins, copper and zinc cations, and metal complexes formed by these cations and human serum γ-globulin induce blast transformation of splenocytes from BALB/c mice at a level comparable to that induced by concanavalin A. Zinc bound to γ-globulin reduces by 25% and copper in complex with this protein stimulates by 1.6 times its capacity to induce blast transformation. Combinations with concanavalin A reproduce the effects of γ-globulin–metal complex under conditions of mitogen induction. Incorporation of ³H-thymidine in splenocytes incubated with combinations of γ-globulin–copper metalcomplex, copper cations, and control protein with concanavalin A was by 1.4, 1.3 (p<0.1), and 1.25 times higher (p<0.05), respectively, than after incubation with concanavalin A alone.     

Skull Flexure as a Contributing Factor in the Mechanism of Injury in the Rat when Exposed to a Shock Wave

The manner in which energy from an explosion is transmitted into the brain is currently a highly debated topic within the blast injury community. This study was conducted to investigate the injury biomechanics causing blast-related neurotrauma in the rat. Biomechanical responses of the rat head under shock wave loading were measured using strain gauges on the skull surface and a fiber optic pressure sensor placed within the cortex. MicroCT imaging techniques were applied to quantify skull bone thickness. The strain gauge results indicated that the response of the rat skull is dependent on the intensity of the incident shock wave; greater intensity shock waves cause greater deflections of the skull. The intracranial pressure (ICP) sensors indicated that the peak pressure developed within the brain was greater than the peak side-on external pressure and correlated with surface strain. The bone plates between the lambda, bregma, and midline sutures are probable regions for the greatest flexure to occur. The data provides evidence that skull flexure is a likely candidate for the development of ICP gradients within the rat brain. This dependency of transmitted stress on particular skull dynamics for a given species should be considered by those investigating blast-related neurotrauma using animal models.     

Collagen-Dependent Neurite Outgrowth and Response to Dynamic Deformation in Three-Dimensional Neuronal Cultures

In vitro models of brain injury that use thick 3-D cultures and control extracellular matrix constituents allow evaluation of cell–matrix interactions in a more physiologically relevant configuration than traditional 2-D cultures. We have developed a 3-D cell culture system consisting of primary rat cortical neurons distributed throughout thick (>500 μm) gels consisting of type IV collagen (Col) conjugated to agarose. Neuronal viability and neurite outgrowth were examined for a range of agarose (AG) percentages (1.0–3.0%) and initial collagen concentrations ([Col]_i; 0–600 μg/mL). In unmodified AG, 1.5% gels supported viable cultures with significant neurite outgrowth, which was not found at lower (≤1.0%) concentrations. Varying [Col]_i in 1.25% AG revealed the formation of dense, 3-D neurite networks at [Col]_i of 300 μg/mL, while neurons in unmodified AG and at higher [Col]_i (600 μg/mL) exhibited significantly less neurite outgrowth; although, neuronal survival did not vary with [Col]_i. The effect of [Col]_i on acute neuronal response following high magnitude, high rate shear deformation (0.50 strain, 30 s⁻¹ strain rate) was evaluated in 1.5% AG for [Col]_i of 30, 150, and 300 μg/mL, which supported cultures with similar baseline viability and neurite outgrowth. Conjugation of Col to AG also increased the complex modulus of the hydrogel. Following high rate deformation, neuronal viability significantly decreased with increasing [Col]_i, implicating cell–matrix adhesions in acute mechanotransduction events associated with traumatic loading. These results suggest interrelated roles for matrix mechanical properties and receptor-mediated cell–matrix interactions in neuronal viability, neurite outgrowth, and transduction of high rate deformation. This model system may be further exploited for the elucidation of mechanotransduction mechanisms and cellular pathology following mechanical insult. D. Kacy Cullen and M. Christian Lessing contributed equally to this work.     

Maximum Principal Strain and Strain Rate Associated with Concussion Diagnosis Correlates with Changes in Corpus Callosum White Matter Indices

On-field monitoring of head impacts, combined with finite element (FE) biomechanical simulation, allow for predictions of regional strain associated with a diagnosed concussion. However, attempts to correlate these predictions with in vivo measures of brain injury have not been published. This article reports an approach to and preliminary results from the correlation of subject-specific FE model-predicted regions of high strain associated with diagnosed concussion and diffusion tensor imaging to assess changes in white matter integrity in the corpus callosum (CC). Ten football and ice hockey players who wore instrumented helmets to record head impacts sustained during play completed high field magnetic resonance imaging preseason and within 10 days of a diagnosed concussion. The Dartmouth Subject-Specific FE Head model was used to generate regional predictions of strain and strain rate following each impact associated with concussion. Maps of change in fractional anisotropy (FA) and median diffusivity (MD) were generated for the CC of each athlete to correlate strain with change in FA and MD. Mean and maximum strain rate correlated with change in FA (Spearman ρ = 0.77, p = 0.01; 0.70, p = 0.031), and there was a similar trend for mean and maximum strain (0.56, p = 0.10; 0.6, p = 0.07), as well as for maximum strain with change in MD (−0.63, p = 0.07). Change in MD correlated with injury-to-imaging interval (ρ = −0.80, p = 0.006) but change in FA did not (ρ = 0.18, p = 0.62). These results provide preliminary confirmation that model-predicted strain and strain rate in the CC correlate with changes in indices of white matter integrity.     

Blast transformation of lymphocytes and the activity of natural killer cells in the presence of γ-globulinin vitro

The cytotoxic activity of natural killer cells against³H-uridine-labeled target cells (human erythromyeloleukosis cells K-562) and the intensity of spontaneous blast transformation are studiedin vitro in the presence of human serum γ-globulin. It is shown that spontaneous blast transformation is 49–51% due to the presence of aggregated γ-globulin, while the aggregate-free γ-globulin fraction does not induce this reaction. The cytotoxic activity of natural killer cellsin vitro declines in the presence of native γ-globulin, which is related to the influence of aggregated γ-globulin, the intensity of whose formation may increase upon a manyfold decrease in the γ-globulin content of the preparation. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 118, N ^o 12, pp. 625–630, December, 1994     

Mild Traumatic Brain Injury Predictors Based on Angular Accelerations During Impacts

Although Head Injury Criterion (HIC) is an effective criterion for head injuries caused by linear acceleration such as skull fractures, no criteria for head injuries caused by rotational kinematics has been accepted as effective so far. This study proposed two criteria based on angular accelerations for Traumatic Brain Injury (TBI), which we call Rotational Injury Criterion (RIC) and Power Rotational Head Injury Criterion (PRHIC). Concussive and non-concussive head acceleration data obtained from football head impacts were utilized to develop new injury criteria. A well-validated human brain Finite Element (FE) model was employed to find out effective injury criteria for TBI. Correlation analyses were performed between the proposed criteria and FE-based brain injury predictors such as Cumulative Strain Damage Measure (CSDM), which is defined as the percent volume of the brain that exceeds a specified first principal strain threshold, proposed to predict Diffuse Axonal Injury (DAI) which is one of TBI. The RIC was significantly correlated with the CSDMs with the strain thresholds of less than 15% (R > 0.89), which might predict mild TBI. In addition, PRHIC was also strongly correlated with the CSDMs with the strain thresholds equal to or greater than 20% (R > 0.90), which might predict more severe TBI.     

Revealing the Effect of Skull Deformation on Intracranial Pressure Variation During the Direct Interaction Between Blast Wave and Surrogate Head

Annals of Biomedical Engineering - Intracranial pressure (ICP) during the interaction between blast wave and the head is a crucial evaluation criterion for blast-induced traumatic brain injury...     

Concentration of monoaminergic neurotransmitters and their major metabolites in the hippocamp and brain stem in mice after administration of adrenocorticotropic hormone (ACTH4–10)

ACTH_4–10 increases the concentration of monoaminergic neurotransmitters and the number of their metabolites in the brain of CBA and 101/HY mice. Different reactions to the peptide were revealed in both strains: the alterations were found either in brain stem (CBA strain) or in the hippocamp (101/HY strain). Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 126, No. 9, pp. 350–352, September, 1998     

Regulation ofin vitro human lymphocyte blast transformation associated with γ-globulin fraction containing a carbohydrate component

Carbohydrate-enriched components were isolated from human serum γ-globulin by chelation of associated transition metals. Similar to the initial γ-globulin preparation, these components stimulatein vitro blast transformation of human lymphocytes from healthy donors and inhibit subsequent phytomitogen-induced lymphocyte blast transformation. Translated fromByulleten' Eksperimental'noi Biologii I Meditsiny, Vol. 127, No. 6, pp. 668–671, June, 1999     

第95百分位中国人头部颅脑相对位移的有限元评估

目的构建第95百分位中国人头部有限元模型,分别参照4种不同类型的颅脑相对位移试验对其进行有效性验证,并评估颅骨与脑组织之间的相对位移,同时探讨脑组织的剪应变分布。方法比较试验与仿真中的颅脑相对位移曲线,并结合动物试验和物理试验中所得出的结论,探讨较高剪应变出现的位置。结果仿真所得的颅脑相对位移曲线与试验结果基本吻合,由于脑组织总是恢复到初始状态,曲线总是出现波峰和波谷。较高剪应变出现在大脑颞叶、胼胝体和脑表面的位置,与动物试验和物理试验中所得出的结论较为相符。结论第95百分位中国人头部有限元模型具有良好的生物仿真度。由于头部的旋转运动,脑表面和脑组织深处都会出现较高的剪应变,从而导致损伤,故本文的研究结果为开展在交通事故中头部损伤机理的研究提供了科学的理论依据。     

Brain Injuries from Blast

Traumatic brain injury (TBI) from blast produces a number of conundrums. This review focuses on five fundamental questions including: (1) What are the physical correlates for blast TBI in humans? (2) Why is there limited evidence of traditional pulmonary injury from blast in current military field epidemiology? (3) What are the primary blast brain injury mechanisms in humans? (4) If TBI can present with clinical symptoms similar to those of Post-Traumatic Stress Disorder (PTSD), how do we clinically differentiate blast TBI from PTSD and other psychiatric conditions? (5) How do we scale experimental animal models to human response? The preponderance of the evidence from a combination of clinical practice and experimental models suggests that blast TBI from direct blast exposure occurs on the modern battlefield. Progress has been made in establishing injury risk functions in terms of blast overpressure time histories, and there is strong experimental evidence in animal models that mild brain injuries occur at blast intensities that are similar to the pulmonary injury threshold. Enhanced thoracic protection from ballistic protective body armor likely plays a role in the occurrence of blast TBI by preventing lung injuries at blast intensities that could cause TBI. Principal areas of uncertainty include the need for a more comprehensive injury assessment for mild blast injuries in humans, an improved understanding of blast TBI pathophysiology of blast TBI in animal models and humans, the relationship between clinical manifestations of PTSD and mild TBI from blunt or blast trauma including possible synergistic effects, and scaling between animals models and human exposure to blasts in wartime and terrorist attacks. Experimental methodologies, including location of the animal model relative to the shock or blast source, should be carefully designed to provide a realistic blast experiment with conditions comparable to blasts on humans. If traditional blast scaling is appropriate between species, many reported rodent blast TBI experiments using air shock tubes have blast overpressure conditions that are similar to human long-duration nuclear blasts, not high explosive blasts.     

Development,Validation, and Application of a Parametric Pediatric Head Finite Element Model for Impact Simulations

In this study, a statistical model of cranium geometry for 0- to 3-month-old children was developed by analyzing 11 CT scans using a combination of principal component analysis and multivariate regression analysis. Radial basis function was used to morph the geometry of a baseline child head finite element (FE) model into models with geometries representing a newborn, a 1.5-month-old, and a 3-month-old infant head. These three FE models were used in a parametric study of near-vertex impact conditions to quantify the sensitivity of different material parameters. Finally, model validation was conducted against peak head accelerations in cadaver tests under different impact conditions, and optimization techniques were used to determine the material properties. The results showed that the statistical model of cranium geometry produced realistic cranium size and shape, suture size, and skull/suture thickness, for 0- to 3-month-old children. The three pediatric head models generated by morphing had mesh quality comparable to the baseline model. The elastic modulus of skull had a greater effect on most head impact response measurements than other parameters. Head geometry was a significant factor affecting the maximal principal stress of the skull (p = 0.002) and maximal principal strain of the suture (p = 0.021) after controlling for the skull material. Compared with the newborn head, the 3-month-old head model produced 6.5% higher peak head acceleration, 64.8% higher maximal principal stress, and 66.3% higher strain in the suture. However, in the skull, the 3-month-old model produced 25.7% lower maximal principal stress and 11.5% lower strain than the newborn head. Material properties of the brain had little effects on head acceleration and strain/stress within the skull and suture. Elastic moduli of the skull, suture, dura, and scalp determined using optimization techniques were within reported literature ranges and produced impact response that closely matched those measured in previous cadaver tests. The method developed in this study made it possible to investigate the age effects from geometry changes on pediatric head impact responses. The parametric study demonstrated that it is important to consider the material properties and geometric variations together when estimating pediatric head responses and predicting head injury risks.     

Development of a Metric for Predicting Brain Strain Responses Using Head Kinematics

Diffuse brain injuries are caused by excessive brain deformation generated primarily by rapid rotational head motion. Metrics that describe the severity of brain injury based on head motion often do not represent the governing physics of brain deformation, rendering them ineffective over a broad range of head impact conditions. This study develops a brain injury metric based on the response of a second-order mechanical system, and relates rotational head kinematics to strain-based brain injury metrics: maximum principal strain (MPS) and cumulative strain damage measure (CSDM). This new metric, universal brain injury criterion (UBrIC), is applicable over a broad range of kinematics encountered in automotive crash and sports. Efficacy of UBrIC was demonstrated by comparing it to MPS and CSDM predicted in 1600 head impacts using two different finite element (FE) brain models. Relative to existing metrics, UBrIC had the highest correlation with the FE models, and performed better in most impact conditions. While UBrIC provides a reliable measurement for brain injury assessment in a broad range of head impact conditions, and can inform helmet and countermeasure design, an injury risk function was not incorporated into its current formulation until validated strain-based risk functions can be developed and verified against human injury data.     

Finite element analysis of brain contusion: An indirect impact study

The mechanism of brain contusion has been investigated using a series of three-dimensional (3D) finite element analyses. A head injury model was used to simulate forward and backward rotation around the upper cervical vertebra. Intracranial pressure and shear stress responses were calculated and compared. The results obtained with this model support the predictions of cavitation theory that a pressure gradient develops in the brain during indirect impact. Contrecoup pressure-time histories in the parasagittal plane demonstrated that an indirect impact induced a smaller intracranial pressure (−53.7 kPa for backward rotation, and −65.5 kPa for forward rotation) than that caused by a direct impact. In addition, negative pressures induced by indirect impact to the head were not high enough to form cavitation bubbles, which can damage the brain tissue. Simulations predicted that a decrease in skull deformation had a large effect in reducing the intracranial pressure. However, the areas of high shear stress concentration were consistent with those of clinical observations. The findings of this study suggest that shear strain theory appears to better account for the clinical findings in head injury when the head is subjected to an indirect impact.