Computation of axonal elongation in head trauma finite element simulation

In the case of head trauma, elongation of axons is thought to result in brain damage and to lead to Diffuse Axonal Injuries (DAI). Mechanical parameters have been previously proposed as DAI metric. Typically, brain injury parameters are expressed in terms of pressure, shearing stresses or invariants of the strain tensor. Addressing axonal deformation within the brain during head impact can improve our understanding of DAI mechanisms. A new technique based on directional measurements of water diffusion in soft tissue using Magnetic Resonance Imaging (MRI), called Diffusion Tensor Imaging (DTI), provides information on axonal orientation within the brain. The present study aims at coupling axonal orientation from a 12-patient-based DTI 3D picture, called "DTI atlas", with the Strasbourg University Finite Element Head Model (SUFEHM). This information is then integrated in head trauma simulation by computing axonal elongation for each finite element of the brain model in a post-processing of classical simulation results. Axonal elongation was selected as computation endpoint for its strong potential as a parameter for DAI prediction and location. After detailing the coupling technique between DTI atlas and the head FE model, two head trauma cases presenting different DAI injury levels are reconstructed and analyzed with the developed methodology as an illustration of axonal elongation computation. Results show that anisotropic brain structures can be realistically implemented into an existing finite element model of the brain. The feasibility of integrating axon fiber direction information within a dedicated post-processor is also established in the context of the computation of axonal elongation. The accuracy obtained when estimating level and location of the computed axonal elongation indicates that coupling classical isotropic finite element simulation with axonal structural anisotropy is an efficient strategy. Using this method, tensile elongation of the axons can be directly invoked as a mechanism for Diffuse Axonal Injury.     

Intracranial diffuse axonal injury at autopsy

An illustrative case of diffuse axonal injury (DAI) emphasizes features that help to separate focal outer head trauma owing to blows and/or falls from angular acceleration head injuries associated with diffuse inner brain lesions. In the past, explaining significant neurological deficits and death as the result of diffuse closed head trauma received from high-speed automobile accidents has been difficult as well as confusing. The long-term consequences from such diffuse inner cerebral trauma are still poorly defined. Head injuries sustained in automobile accidents have been associated with diffuse brain damage characterized by axonal injury at the moment of impact. The reported victim of a motor vehicle accident showed post-mortem findings for both inner cerebral trauma and focal outer cerebral damage. The diffuse degeneration of cerebral white matter is associated with sagittal and lateral acceleration with centroaxial trauma and has a different pathogenesis from outer focal head trauma, typified by subdural hematomas and coup injuries. Unlike outer cerebral injury, over 50 percent of victims with diffuse axonal injury die within two weeks. These individuals characteristically have no lucid interval and remain unconscious, vegetative, or severely disabled until death. Compared to head trauma victims without diffuse axonal injury, there is a lower incidence of skull fractures, subdural hemorrhages, or other intracranial mass effect as well as outer brain contusions. Primary brainstem injuries often demonstrated at autopsy are seen in the reported victim. Diffuse axonal injury is produced by various angles of acceleration with prolonged acceleration/deceleration usually accompanying traffic accidents. Less severe diffuse axonal injury causes concussion.     

A micromechanical hyperelastic modeling of brain white matter under large deformation

A finite element based micromechanical model has been developed for analyzing and characterizing the microstructural as well as homogenized mechanical response of brain tissue under large deformation. The model takes well-organized soft tissue as a fiber-reinforced composite with nonlinear and anisotropic behavior assumption for the fiber as well as the matrix of composite matter. The procedure provides a link between the macroscopic scale and microscopic scale as brain tissue undergoes deformation. It can be used to better understand how macroscopic stresses are transferred to the microstructure or cellular structure of the brain. A repeating unit cell (RUC) is created to stand as a representative volume element (RVE) of the hyperelastic material with known properties of the constituents. The model imposes periodicity constraints on the RUC. The RUC is loaded kinematically by imposing displacements on it to create the appropriate normal and shear stresses. The homogenized response of the composite, the average stresses carried within each of the constituents, and the maximum local stresses are all obtained. For each of the normal and shear loading scenarios, the impact of geometrical variables such as the axonal fiber volume fraction and undulation of the axons are evaluated. It was found that axon undulation has significant impact on the stiffness and on how stresses were distributed between the axon and the matrix. As axon undulation increased, the maximum stress and stress in the matrix increased while the stress in the axons decreased. The axon volume fraction was found to have an impact on the tissue stiffness as higher axon volume fractions lead to higher stresses both in the composite and in the constituents. The direction of loading clearly has a large impact on how stresses are distributed amongst the constituents. This micromechanics tool provides the detailed micromechanics stresses and deformations, as well as the average homogenized behavior of the RUC, which can be efficiently used in mechanical characterization of brain tissue.     

Diffuse axonal injury in infants with nonaccidental craniocerebral trauma: enhanced detection by beta-amyloid precursor protein immunohistochemical staining

OBJECTIVE: Accurate identification of diffuse axonal injury is important in the forensic investigation of infants who have died from traumatic brain injury. beta-Amyloid precursor protein (beta-APP) immunohistochemical staining is highly sensitive in identifying diffuse axonal injury. However, the effectiveness of this method in brain-injured infants has not been well established. The present study was undertaken to assess the utility of beta-APP immunohistochemistry in detecting diffuse axonal injury in infants with either shaken baby syndrome or blunt head trauma. MATERIALS AND METHODS: Archival formalin-fixed, paraffin-embedded blocks from infants (<1 year old) with shaken baby syndrome (7 cases) and blunt head trauma (3) and blocks from 7 control cases that included nontraumatic cerebral edema (1), acute hypoxic-ischemic encephalopathy (1), and normal brain (5) were immunostained for beta-APP. A semiquantitative assessment of the severity of axonal staining was made. Corresponding hematoxylin-eosin-stained sections were examined for the presence of axonal swellings. RESULTS: Immunostaining for beta-APP identified diffuse axonal injury in 5 of 7 infants with shaken baby syndrome and 2 of 3 infants with blunt head trauma. Immunoreactive axons were easily identified and were present in the majority of the sections examined. By contrast, hematoxylineosin staining revealed axonal swellings in only 3 of 7 infants with shaken baby syndrome and 1 of 3 infants with blunt head trauma. Most of these sections had few if any visible axonal swellings, which were often overlooked on initial review of the slides. No beta-APP immunoreactivity was observed in any of the 7 control cases. CONCLUSIONS: Immunostaining for beta-APP can easily and reliably identify diffuse axonal injury in infants younger than 1 year and is considerably more sensitive than routine hematoxylin-eosin staining. We recommend its use in the forensic evaluation of infants with fatal craniocerebral trauma.     

Diffuse axonal injury caused by assault.

The case reports of 50 fatal head injuries caused by assault and managed at the Institute of Neurological Sciences, Glasgow, were reviewed. Fifteen cases had diffuse axonal injury. Diffuse axonal injury is a well recognised type of brain damage brought about by a head injury, usually as a result of a road traffic accident or fall from a height. It does not seem to be widely appreciated that it may also occur as a result of an assault. This has important medicolegal implications.     

Fatal head injury in children.

A comprehensive neuropathological study was undertaken on 87 children aged between 2 and 15 years with fatal head injuries to identify those features which occurred at the time of head injury (fractured skull, contusions, intracranial haematoma and diffuse axonal injury) and those which were subsequently produced by complicating processes (hypoxic brain damage, raised intracranial pressure, infection and brain swelling). The types of brain brain damage identified were remarkably similar to those seen in adults. The only difference was the prevalence of diffuse brain swelling in children.     

Cerebral endothelial damage after severe head injury.

We demonstrate that in head injuries the degree of cerebral endothelial activation or injury depends on the type of brain injury and the patients age, and that in severe head injuries measuring the serum levels of thrombomodulin (TM) and von Willebrand factor (vWF) is useful in evaluating cerebral endothelial injury and activation. The values of vWF in the cases of focal brain injury were significantly higher than in the cases of diffuse axonal injury. The serum levels of TM in focal brain injuries were higher than in diffuse axonal injuries, but the differences were not statistically significant. In patients with delayed traumatic intracerebral hematoma (DTICH), vWF levels were much higher than in patients without DTICH. The values of TM and vWF in elderly patients were significantly higher than in younger patients. These findings indicate that: 1) the degree of endothelial activation in focal brain injury is significantly higher than in diffuse brain injury; 2) the degree of cerebral endothelial injury in patients with DTICH is much higher than in those without DTICH; and 3) the degree of cerebral endothelial activation and injury in elderly head injury patients is significantly higher than in younger patients.     

Diffuse axonal injury in head injury: definition, diagnosis and grading

Diffuse axonal injury is one of the most important types of brain damage that can occur as a result of non-missile head injury, and it may be very difficult to diagnose post mortem unless the pathologist knows precisely what he is looking for. Increasing experience with fatal non-missile head injury in man has allowed the identification of three grades of diffuse axonal injury. In grade 1 there is histological evidence of axonal injury in the white matter of the cerebral hemispheres, the corpus callosum, the brain stem and, less commonly, the cerebellum; in grade 2 there is also a focal lesion in the corpus callosum; and in grade 3 there is in addition a focal lesion in the dorsolateral quadrant or quadrants of the rostral brain stem. The focal lesions can often only be identified microscopically. Diffuse axonal injury was identified in 122 of a series of 434 fatal non-missile head injuries--10 grade 1, 29 grade 2 and 83 grade 3. In 24 of these cases the diagnosis could not have been made without microscopical examination, while in a further 31 microscopical examination was required to establish its severity.     

8-羟基-2-(二丙基氨基)四氢萘干预弥漫性轴索损伤模型大鼠低氧诱导因子1α的表达

文题释义： 8-羟基-2-(二丙基氨基)四氢萘(8-hydroxy-2-(di-n-propylamino)tetralin,8-OH-DPAT)：是五羟色胺1A (5-HTlA)受体激动剂的一种,长久以来一直做为抗精神类药物被广泛研究,其在减轻焦虑和抑郁症的治疗作用的机制已经有据可查,除此以外,5-HTlA受体激动剂仍具有降低体温及神经保护作用。 脑弥漫性轴索损伤(diffuse axonal injury,DAI)：是头部遭受加速性旋转外力作用时,因剪应力造成的以脑内神经轴索肿胀断裂为主要特征的损伤。一般认为,当头部加速运动时,脑组织因受瞬时产生的剪力和张力作用而发生应变,使神经轴索、毛细血管和小血管损伤。弥漫性轴索损伤好发于神经轴索聚集区,如胼胝体、脑干头端背外侧、大脑半球的灰质和白质交界处、小脑、内囊、基底节核团附近及透明隔等处。 背景：8-羟基-2-(二丙基氨基)四氢萘(8-hydroxy-2-(di-n-propylamino)tetralin,8-OH-DPAT)具有降低脑温的作用,且此作用可能是其发挥神经保护作用的潜在机制之一。 目的：观察8-OH-DPAT对弥漫性轴索损伤大鼠脑组织低氧诱导因子1α表达的影响,探讨8-OH-DPAT对弥漫性轴索损伤大鼠神经保护作用的途径。 方法：实验方案经北部战区动物实验伦理委员会批准。将Wistar大鼠随机分为4组：模型组(n=35)、恒温组(n=35)、8-OH-DPAT组(n=35)和正常组(n=7)。除正常组外,其他各组均参照Marmarou法制作弥漫性轴索损伤模型,恒温组和8-OH-DPAT组建模成功后腹腔注射8-OH-DPAT,模型组和正常组腹腔注射生理盐水;恒温组用恒温毯维持体温(37.0±0.5) ℃。每隔1 h测量大鼠脑温。分别于弥漫性轴索损伤后6,12,24,72, 168 h观察大鼠脑组织的损伤程度以及血清和损伤脑组织中低氧诱导因子1α的表达。 结果与结论：①造模后1 h,与恒温组和模型组比较,8-OH-DPAT组大鼠脑温明显下降(P < 0.05),至造模后2 h降至最低(P < 0.05),之后缓慢上升;②苏木精-伊红染色显示,模型组大鼠脑组织损伤最为严重,恒温组次之,8-OH-DPAT组损伤最轻;③免疫组织化学和ELISA结果显示,正常组血清及脑组织低氧诱导因子1α表达很低;弥漫性轴索损伤后6 h,模型组血清及脑组织低氧诱导因子1α表达增多,24 h达高峰,之后逐渐减少;与模型组比较,恒温组和8-OH-DPAT组对应时间点血清及脑组织低氧诱导因子1α表达明显减少(P < 0.05或P < 0.01),8-OH-DPAT组减少更明显(P < 0.01);④结果说明,8-OH-DPAT对弥漫性轴索损伤大鼠脑组织的神经保护作用与其降低大鼠脑温,减少损伤脑组织低氧诱导因子1α的表达有关。 ORCID: 0000-0002-4637-3553(毛振立) 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程     

Traumatically induced axonal injury: pathogenesis and pathobiological implications.

This work reviews the pathobiology of traumatically induced axonal injury. Drawing upon literature gleaned from the experimental and clinical setting, this review attempts to emphasize that, other than the most destructive insults, traumatic brain injury does not typically cause direct mechanical disruption of the axon. Rather, this review documents that with traumatic injury focal, subtle axonal change occurs, and that over time, such change leads to impaired axoplasmic transport, continued axonal swelling, and ultimate disconnection. The initial intra-axonal events that trigger the above described sequence of reactive axonal change are considered with focus on the possibility of either traumatically altered axolemmal permeability, direct cytoskeletal damage/perturbation, or more overt metabolic/functional disturbances. Not only does this review focus on the sequence of traumatically induced axonal change, but also, it considers its attendant consequences in terms of Wallerian degeneration and subsequent deafferentation. The concept that traumatically induced diffuse axonal injury leads to diffuse deafferentation is emphasized together with its pathobiological implications for morbidity and recovery. The potential for either adaptive or maladaptive neuroplasticity subsequent to such diffuse deafferentation is considered in the context of mild, moderate and severe traumatic brain injury.     

Evaluation of Three Animal Models for Concussion and Serious Brain Injury

Three animal models were evaluated in this study involving head impacts of the rat, including the Marmarou drop-weight and two momentum-exchange techniques. In series 1, 36 Wistar rats were hit on the side of the free-moving head using Marmarou’s 450 g impact mass at 4.4, 5.4, and 6.3 m/s. Head acceleration was measured and injuries were observed. The 6.3-m/s side impact resulted in no deaths, no skull fractures, infrequent contusions, and some injuries consistent with diffuse axonal injury. In series 2, 57 Marmarou drop-weight tests were conducted to study head biomechanical responses. Marmarou’s technique involves a head impact followed by prolonged loading into a foam pad under the animal. Based on the literature, the 2 m (6.3 m/s) Marmarou drop causes death, skull fracture, brain and spinal cord contusions, and diffuse axonal injury. These injuries are more severe than that occurring with impact of similar mass and velocity to the free-moving head. Impacts to the free-moving head provide more realistic animal models to study concussion and severe brain injury.     

Gliding contusions in nonmissile head injury in humans

"Gliding" contusions, ie, hemorrhagic lesions in the parasagittal white matter, were analyzed in 434 fatal nonmissile head injuries in humans. It is concluded that gliding contusions are a type of diffuse brain damage occurring at the moment of injury. Gliding contusions are significantly associated with road-traffic accidents, with the absence of a skull fracture or a "lucid interval," and with the presence of diffuse axonal injury and deep hemispheric traumatic hematomas.     

Diverse changes in microglia morphology and axonal pathology during the course of 1 year after mild traumatic brain injury in pigs

Over 2.8 million people experience mild traumatic brain injury (TBI) in the United States each year, which may lead to long‐term neurological dysfunction. The mechanical forces that are caused by TBI propagate through the brain to produce diffuse axonal injury (DAI) and trigger secondary neuroinflammatory cascades. The cascades may persist from acute to chronic time points after injury, altering the homeostasis of the brain. However, the relationship between the hallmark axonal pathology of diffuse TBI and potential changes in glial cell activation or morphology have not been established in a clinically relevant large animal model at chronic time points. In this study, we assessed the tissue from pigs subjected to rapid head rotation in the coronal plane to generate mild TBI. Neuropathological assessments for axonal pathology, microglial morphological changes, and astrocyte reactivity were conducted in specimens out to 1‐year post‐injury. We detected an increase in overall amyloid precursor protein pathology, as well as periventricular white matter and fimbria/fornix pathology after a single mild TBI. We did not detect the changes in corpus callosum integrity or astrocyte reactivity. However, detailed microglial skeletal analysis revealed changes in morphology, most notably increases in the number of microglial branches, junctions, and endpoints. These subtle changes were most evident in periventricular white matter and certain hippocampal subfields, and were observed out to 1‐year post‐injury in some cases. These ongoing morphological alterations suggest persistent change in neuroimmune homeostasis. Additional studies are needed to characterize the underlying molecular and neurophysiological alterations, as well as potential contributions to neurological deficits.     

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.     

猫头半约束非撞击致伤DAI动物模型的有限元分析

对猫头半约束非撞击致伤弥漫性轴索损伤（Diffuse axonal injury,DAI)动物模型进行生物力学分析，探讨DAI发生机理。这一锚头颅CT断层确定各层节面点并数字化，在有限元专用vizi CAD系统建立猫头颅三维有限元网格体模型，用SuperSAP有限元软件（93版）分析15只猫头半约束非撞击致伤时颅脑最大主应力、最小主应力、von Mises应力值及其在各层面的分布。结果表明；颅骨纵轴各层面应力在施载点同侧前后最高，并向颅底延伸，在颅脑内，脑表浅应力分布最高，但由于小脑幕、大脑镰及隆起的岩滩，鞍床突等结构，应力并非均匀向脑深部递减，而在邻近这些结构的脑组织，大小脑脚、脑干、胼胝体、基底节区有很高的应力分布， 这种应力分布特征与前期动物实验的病理损害分布一致。据此得出结论，脑内质点应力差值致脑组织剪应变 损伤，猫颅骨不规则的几何形状、小脑幕、大脑镰结构是导致旋转暴力向脑内传递广泛而不均一的主要原因。     

The wear of oriented UHMWPE under isotropically rough and scratched counterface test conditions

Unidirectional wear tests of UHMWPE against smooth counterfaces show that molecular chains at the surface of virgin material become oriented parallel to the sliding direction giving low wear rate. It is postulated that under more abrasive conditions and predominantly unidirectional motion as in knee prostheses, it may proof beneficial to provide molecular orientation of the bulk material. Therefore strips of UHMWPE were oriented by die drawing at elevated temperature and the resulting anisotropic material subjected to tensile tests, small punch tests and also unidirectional wear tests both parallel and perpendicular to the draw direction. The tensile tests showed that, in the parallel direction, the oriented UHMWPE became stiffer and less ductile compared to the virgin UHMWPE. In the perpendicular direction, there were reductions in yield stress, 5% proof stress and energy to failure compared to the virgin material. The small punch test showed that the oriented UHMWPE exhibited apparent hardening when tested in both parallel and perpendicular directions but the mechanical behaviour in the perpendicular direction was comparable to the virgin UHMWPE. The wear tests demonstrated that the oriented UHMWPE did not show any significant improvement of wear resistance for sliding against either isotropically rough or scratched counterfaces. There was no clear dependency between the mechanical properties and wear factors of the oriented UHMWPE.     

Fiber Stretch and Reorientation Modulates Mesenchymal Stem Cell Morphology and Fibrous Gene Expression on Oriented Nanofibrous Microenvironments

Because differentiation of mesenchymal stem cells (MSCs) is enacted through the integration of soluble signaling factors and physical cues, including substrate architecture and exogenous mechanical stimulation, it is important to understand how micropatterned biomaterials may be optimized to enhance differentiation for the formation of functional soft tissues. In this work, macroscopic strain applied to MSCs in an aligned nanofibrous microenvironment elicited cellular and nuclear deformations that varied depending on scaffold orientation. Reorientation of aligned, oriented MSCs corresponded at the microscopic scale with the affine approximation of their deformation based on macroscopic strains. Moreover, deformations at the subcellular scale corresponded with scaffold orientation, with changes in nuclear shape depending on the direction of substrate alignment. Notably, these deformations induced changes in gene expression that were also dependent on scaffold and cell orientations. These findings demonstrate that directional biases in substrate microstructure convey direction-dependent mechanosensitivity to MSCs and provide an experimental framework in which to explore the mechanistic underpinnings of this response.     

Effects of head size and morphology on dynamic responses to impact loading

Head responses subjected to impact loading are studied using the finite element method. The dynamic responses of the stress, strain, strain energy density and the intracranial pressure govern the intracranial tissues and skull material failures, and therefore, the traumatic injuries. The objectivity and consistency of the prevailing head traumatic injury criteria, i.e., the energy absorption, the gravity centre acceleration and the head injury criterion (HIC), are examined with regard to the head dynamic responses. In particular, the structural intensity (STI) (the vector representation of energy flow rate) is calculated and discussed. From the simulations, the STI, instead of the gravity centre acceleration, the HIC and the energy absorption criteria, is found to be consistent with the dynamic response quantities. The different local skull curvatures at impact have a marginal effect whereas the locations of the impact loadings have significant effects on the dynamics responses or the head injury. The STI also shows the failure patterns.     

Continuous cyclic stretch induces osteoblast alignment and formation of anisotropic collagen fiber matrix

Bone tissue geometry shows a highly anisotropic architecture, which is derived from its genetic regulation and mechanical environment. Osteoblasts are responsible not only for bone formation, through the secretion of collagen type I, but also for sensing the mechanical stimuli due to bone surface strain. Mechanotransduction by osteoblasts is therefore considered one of the regulators of anisotropic bone tissue morphogenesis. The orientation of osteoblasts and the secreted collagen matrix was successfully regulated by applying a continuous mechanical stress on osteoblasts for a long period. Under a continuous cyclic stretch of 4% magnitude at a rate of 2 cycles min^?1, osteoblasts reoriented their actin stress fibers in the direction that minimizes the strain applied to them. Extended culture of up to 2 weeks resulted in the formation of collagen fibers in the extracellular spaces, and the preferred orientation of these fibers was parallel to the direction of cell elongation. To the best of our knowledge, this is the first report to establish anisotropic bone matrix architecture following the alignment of osteoblasts under mechanical stimuli for long-term cultivation.