Liver injuries in frontal crash situations a coupled numerical—experimental approach

From clinical knowledge, it has been established that hepatic traumas frequently lead to lethal injuries. In frontal or lateral crash situations, these injuries can be induced by pure deceleration effects or blunt trauma due to belt or steering wheel impact. Concerning the liver under frontal decelerations, how could one investigate organ behaviour leading to the injury mechanisms? This work couples experimental organ decelerations measurements (with 19 tests on cadaver trunks) and finite element simulation, provides a first analysis of the liver behaviour within the abdomen. It shows the influence of the liver attachment system that leads to liver trauma and also torsion effects between the two lobes of the liver. Injury mechanisms were evaluated through the four phases of the liver kinematics under frontal impact: (1) postero-anterior translation, (2) compression and sagittal rotation, (3) rotation in the transverse plane and (4) relaxation.     

Experimental and finite element analysis for prediction of kidney injury under blunt impact

Kidneys are third most injured organs in abdominal trauma after liver and spleen; this study therefore is an attempt to understand the behaviour of kidneys under blunt trauma. Dynamic impact tests were performed on 20 fresh porcine kidneys to study the injury propagation in the organ, and the acceleration of the impactor was measured. A kidney model was developed with structural details like capsule and cortex. The kidney cortex was modelled with solid hexahedral elements and the capsule was modelled with quadratic shell elements. The material models for the capsule and cortex were used from the experimental data reported in our previous study. The developed model was calibrated using previous and current experimental results to reproduce the injuries of the organ in terms of acceleration of the impactor, and the injuries sustained by the organ during the experiments. The developed kidney model is observed to be robust and can be integrated with the available human body finite element models to simulate accidents and to predict or simulate injuries.     

Blunt Liver Injury with Intact Ribs under Impacts on the Abdomen: A Biomechanical Investigation

Abdominal trauma accounts for nearly 20% of all severe traffic injuries and can often result from intentional physical violence, from which blunt liver injury is regarded as the most common result and is associated with a high mortality rate. Liver injury may be caused by a direct impact with a certain velocity and energy on the abdomen, which may result in a lacerated liver by penetration of fractured ribs. However, liver ruptures without rib cage fractures were found in autopsies in a series of cases. All the victims sustained punches on the abdomen by fist. Many studies have been dedicated to determining the mechanism underlying hepatic injury following abdominal trauma, but most have been empirical. The actual process and biomechanism of liver injury induced by blunt impact on the abdomen, especially with intact ribs remained, are still inexhaustive. In order to investigate this, finite element methods and numerical simulation technology were used. A finite element human torso model was developed from high resolution CT data. The model consists of geometrically-detailed liver and rib cage models and simplified models of soft tissues, thoracic and abdominal organs. Then, the torso model was used in simulations in which the right hypochondrium was punched by a fist from the frontal, lateral, and rear directions, and in each direction with several impact velocities. Overall, the results showed that liver rupture was primarily caused by a direct strike of the ribs induced by blunt impact to the abdomen. Among three impact directions, a lateral impact was most likely to cause liver injury with a minimum punch speed of 5 m/s (the momentum was about 2.447 kg.m/s). Liver injuries could occur in isolation and were not accompanied by rib fractures due to different material characteristics and injury tolerance.     

Nonlinear viscoelastic constitutive model for bovine liver tissue

Soft tissue mechanical characterisation is important in many areas of medical research. Examples span from surgery training, device design and testing, sudden injury and disease diagnosis. The liver is of particular interest, as it is the most commonly injured organ in frontal and side motor vehicle crashes, and also assessed for inflammation and fibrosis in chronic liver diseases. Hence, an extensive rheological characterisation of liver tissue would contribute to advancements in these areas, which are dependent upon underlying biomechanical models. The aim of this paper is to define a liver constitutive equation that is able to characterise the nonlinear viscoelastic behaviour of liver tissue under a range of deformations and frequencies. The tissue response to large amplitude oscillatory shear (1–50%) under varying preloads (1–20%) and frequencies (0.5–2 Hz) is modelled using viscoelastic-adapted forms of the Mooney–Rivlin, Ogden and exponential models. These models are fit to the data using classical or modified objective norms. The results show that all three models are suitable for capturing the initial nonlinear regime, with the latter two being capable of capturing, simultaneously, the whole deformation range tested. The work presented here provides a comprehensive analysis across several material models and norms, leading to an identifiable constitutive equation that describes the nonlinear viscoelastic behaviour of the liver.

     

High leptospiremia is associated with low gamma–delta T cell counts

The role of innate immune cells either to mount appropriate defense mechanisms or to drive uncontrolled tissue injuries during acute leptospirosis is poorly understood. This study aimed at characterizing the selective mobilization of innate immune cells and the level of target organ injuries in response to leptospiremia. We focused on gamma-delta (γ–δ) T cells. Patients were prospectively assessed for cell count by cytometry, for bacterial load by PCR in plasma samples and for levels of soluble acute phase tissue enzymes. We found that the level of γ–δ T cells was low and inversely correlated to liver injuries and leptospiremia.     

Development of a Murine Model of Blunt Hepatic Trauma

Despite the prevalence of blunt hepatic trauma in humans, there are few rodent models of blunt trauma that can be used to study the associated inflammatory responses. We present a mouse model of blunt hepatic trauma that was created by using a cortical contusion device. Male mice were anesthetized with ketamine–xylazine–buprenorphine and placed in left lateral recumbency. A position of 2 mm ventral to the posterior axillary line and 5 mm caudal to the costal margin on the right side was targeted for impact. An impact velocity of 6 m/s and a piston depth of 12 mm produced a consistent pattern of hepatic injury with low mortality. All mice that recovered from anesthesia survived without complication for the length of the study. Mice were euthanized at various time points (n = 5 per group) until 7 d after injury for gross examination and collection of blood and peritoneal lavage fluids. Some mice were reanesthetized for serial monitoring of hepatic lesions via MRI. At 2 h after trauma, mice consistently displayed laceration, hematoma, and discoloration of the right lateral and caudate liver lobes, with intraabdominal hemorrhage but no other gross injuries. Blood and peritoneal lavage fluid were collected from all mice for cytokine analysis. At 2 h after trauma, there were significant increases in plasma IL10 as well as peritoneal lavage fluid IL6 and CXCL1/KC; however, these levels decreased within 24 h. At 7 d after trauma, the mice had regained body weight, and the hepatic lesions, which initially had increased in size during the first 48 h, had returned to their original size. In summary, this technique produced a reliable, low mortality, murine model that recreates features of blunt abdominal liver injury in human subjects with similar acute inflammatory response.Abbreviation: CXCL1/KC, keratinocyte-derived chemokineTrauma is the most frequent cause of mortality worldwide,¹¹ and in cases of blunt abdominal trauma, the liver is the most frequently injured organ.⁴ In humans, traumatic injuries to the liver are graded (I through VI) according to the American Association for the Surgery of Trauma Liver Injury Scale, which is based on the severity of lesions, including hematomas, lacerations and vascular disruption.¹⁰ Parenchymal injuries (grades I through III) are more common than are major vascular injuries (grades V and VI), correlating with the greater hemodynamic stability and lower early mortality rates of parenchymal damage.⁴ Although early mortality rates may be low in low-grade injuries, the overall mortality rates for abdominal traumas involving liver are greater than that of abdominal trauma without liver damage. Late mortality after liver injury is associated with immunologic dysfunction, leading to systemic inflammatory response syndrome, sepsis, and multiple-organ failure.⁶To study the complex immune responses surrounding blunt hepatic trauma, an appropriate animal model is imperative, but few animal models of liver trauma have been described. Swine traditionally have been the preferred model because of similarity of the liver anatomy and lesions to those of human cases.² Nonpenetrating models have been developed in swine and involve impact by crossbow or other blunted projectiles.²⁰ The first rodent model of trauma was developed by positioning anesthetized rats under a column containing a flat weight.³ In that model, the severity of injury could be adjusted by the height of the column. This model was distinctive in its use of the least sentient species to date. The large animal models and even the rat model would readily support studies of treatment modalities and the measurement of hemodynamic parameters. For extensively characterizing the immunopathology associated with liver trauma, a murine model could offer distinct advantages, including the ready availability of transgenic mice and the extensive array of reagents for immunologic studies.The purpose of the current study was to develop a reliable and reproducible, closed abdominal, murine model of blunt hepatic trauma that is suitable for studies of posttraumatic immune dysfunction and related complications. Our first aim was to develop a low-mortality model that demonstrated gross and microscopic hepatic lesions similar to those seen in humans. The second study aim was to define selected systemic and local immune responses, including immune cell counts and cytokine levels. In addition, we examined the potential use of a noninvasive imaging technique (MRI) for the sequential evaluation of hepatic lesions.     

Finite element investigation of the loading rate effect on the spinal load-sharing changes under impact conditions

Sudden deceleration and frontal/rear impact configurations involve rapid movements that can cause spinal injuries. This study aimed to investigate the rotation rate effect on the L2–L3 motion segment load-sharing and to identify which spinal structure is at risk of failure and at what rotation velocity the failure may initiate?Five degrees of sagittal rotations at different rates were applied in a detailed finite-element model to analyze the responses of the soft tissues and the bony structures until possible fractures. The structural response was markedly different under the highest velocity that caused high peaks of stresses in the segment compared to the intermediate and low velocities. Under flexion, the stress was concentrated at the upper pedicle region of L2 and fractures were firstly initiated in this region and then in the lower endplate of L2. Under extension, maximum stress was located in the lower pedicle region of L2 and fractures started in the left facet joint, then they expanded in the lower endplate and in the pedicle region of L2. No rupture has resulted at the lower or intermediate velocities. The intradiscal pressure was higher under flexion and decreased when the endplate was fractured, while the contact forces were greater under extension and decreased when the facet surface was cracked. The highest ligaments stresses were obtained under flexion and did not reach the rupture values. The endplate, pedicle and facet surface represented the potential sites of bone fracture. Results showed that spinal injuries can result at sagittal rotation velocity exceeding 0.5°/ms.     

Organ and gestational age effects of maternal nutrient restriction on global methylation in fetal baboons

Background  A sub-optimal intrauterine environment alters the trajectory of fetal development with profound effects on life-time health. Altered methylation, a proposed epigenetic mechanism responsible for these changes, has been studied in non-primate species but not nonhuman primates. We tested the hypotheses that global methylation in fetal baboon demonstrates organ specificity, gestational age specificity, and changes with maternal nutritional status.
Methods  We measured global DNA methylation in fetuses of control fed (CTR) and nutrient restricted mothers fed 70% of controls (MNR) for brain, kidney, liver and heart at 0.5 and 0.9 gestation (G).
Results  We observed organ and gestation specific changes that were modified by maternal diet. Methylation in CTR fetuses was highest in frontal cortex and lowest in liver. MNR decreased methylation in 0.5G kidney and increased methylation in 0.9G kidney and frontal cortex.
Conclusion  These results demonstrate a potential epigenetic mechanism whereby reduced maternal nutrition has long-term programming effects on fetal organ development.     

Numerical investigations of rib fracture failure models in different dynamic loading conditions

Rib fracture is one of the most common thoracic injuries in vehicle traffic accidents that can result in fatalities associated with seriously injured internal organs. A failure model is critical when modelling rib fracture to predict such injuries. Different rib failure models have been proposed in prediction of thorax injuries. However, the biofidelity of the fracture failure models when varying the loading conditions and the effects of a rib fracture failure model on prediction of thoracic injuries have been studied only to a limited extent. Therefore, this study aimed to investigate the effects of three rib failure models on prediction of thoracic injuries using a previously validated finite element model of the human thorax. The performance and biofidelity of each rib failure model were first evaluated by modelling rib responses to different loading conditions in two experimental configurations: (1) the three-point bending on the specimen taken from rib and (2) the anterior–posterior dynamic loading to an entire bony part of the rib. Furthermore, the simulation of the rib failure behaviour in the frontal impact to an entire thorax was conducted at varying velocities and the effects of the failure models were analysed with respect to the severity of rib cage damages. Simulation results demonstrated that the responses of the thorax model are similar to the general trends of the rib fracture responses reported in the experimental literature. However, they also indicated that the accuracy of the rib fracture prediction using a given failure model varies for different loading conditions.     

Use of quadruped models in thoraco-abdominal biomechanics research

Pigs and dogs have become common models of human thoraco-abdominal impact response. This paper summarizes a comparative analysis of the dog and pig to the live human accomplished through a series of necropsies performed on pigs and dogs. The results are summarized below. Emphasis is placed on specific aspects which are felt to be important for impact biomechanics. In particular, emphasis is placed upon the effect of tethering structures because of their potential in explaining mechanisms of injury for specific types of trauma such as aortic and certain liver injuries. Some aspects of tethering in the pig and dog are significantly different from that of the live human so care should be taken when using these animals in thoraco-abdominal biomechanics experiments.     

Investigation of pediatric neck response and muscle activation in low-speed frontal impacts

Pediatric necks present different responses and injury patterns compared with those of adults in motor vehicle crashes (MVCs). To evaluate the effect of different muscle modeling methodologies, three muscle models were developed and simulated under low-speed frontal impact conditions with an average peak acceleration of 3g's. The muscle activation curve for the curve-guided model, the muscle segment was curved using guiding nodes, was further optimized based on experimental data. The pediatric neck model was also simulated under more severe frontal impact conditions with an average peak acceleration of 8g's. Simulation results revealed that the curve-guided model needed more muscle force than the straight-guided model, in which the muscle segment was straight with guiding nodes, and the curve-constrained model, in which the muscle segment was curved without guiding nodes and which imposes more constraints on the head and neck than the curve-guided model. The predicted head responses for the child finite element neck model were within or close to the experimental corridors of 3- and 8-g's frontal impacts. The neck injuries for a 10-year-old child commonly occurred at the interspinous ligament in the C7–T1 segment. The model could be used to analyze the responses and injuries of pediatric neck and head in low-speed frontal impacts.     

Characterization of Chemically Induced Liver Injuries Using Gene Co-Expression Modules

Liver injuries due to ingestion or exposure to chemicals and industrial toxicants pose a serious health risk that may be hard to assess due to a lack of non-invasive diagnostic tests. Mapping chemical injuries to organ-specific damage and clinical outcomes via biomarkers or biomarker panels will provide the foundation for highly specific and robust diagnostic tests. Here, we have used DrugMatrix, a toxicogenomics database containing organ-specific gene expression data matched to dose-dependent chemical exposures and adverse clinical pathology assessments in Sprague Dawley rats, to identify groups of co-expressed genes (modules) specific to injury endpoints in the liver. We identified 78 such gene co-expression modules associated with 25 diverse injury endpoints categorized from clinical pathology, organ weight changes, and histopathology. Using gene expression data associated with an injury condition, we showed that these modules exhibited different patterns of activation characteristic of each injury. We further showed that specific module genes mapped to 1) known biochemical pathways associated with liver injuries and 2) clinically used diagnostic tests for liver fibrosis. As such, the gene modules have characteristics of both generalized and specific toxic response pathways. Using these results, we proposed three gene signature sets characteristic of liver fibrosis, steatosis, and general liver injury based on genes from the co-expression modules. Out of all 92 identified genes, 18 (20%) genes have well-documented relationships with liver disease, whereas the rest are novel and have not previously been associated with liver disease. In conclusion, identifying gene co-expression modules associated with chemically induced liver injuries aids in generating testable hypotheses and has the potential to identify putative biomarkers of adverse health effects.     

Wound healing in development

Wound healing is the inherent ability of an organism to protect itself against injuries. Cumulative evidence indicates that the healing process patterns in part embryonic morphogenesis and may result in either organ regeneration or scarring, phenomena that are developmental stage‐ or age‐dependent. Skin is the largest organ. Its morphogenesis and repair mechanisms have been studied extensively due not only to its anatomical location, which allows easy access and observation, but also to its captivating structure and vital function. Thus, this review will focus on using skin as a model organ to illustrate new insights into the mechanisms of wound healing that are developmentally regulated in mammals, with special emphasis on the role of the Wnt signaling pathway and its crosstalk with TGF‐β signaling. Relevant information from studies of other organs is discussed where it applies, and the clinical impact from such knowledge and emerging concepts on regenerative medicine are discussed in perspective. Birth Defects Research (Part C) 96:213–222, 2012. © 2012 Wiley Periodicals, Inc.     

Melatonin and its protective role in attenuating warm or cold hepatic ischaemia/reperfusion injury

Although the liver is the only organ with regenerative capacity, various injury factors induce irreversible liver dysfunction and end‐stage liver disease. Liver resection and liver transplantation (LT) are effective treatments for individuals with liver failure, liver cirrhosis and liver cancers. The remnant or transplanted liver tissues will undergo hepatic ischaemia/reperfusion (IR), which leads to oxidative stress, inflammation, immune injury and liver damage. Moreover, systemic ischaemia induced by trauma, stroke, myocardial ischaemia, haemorrhagic shock and other injury factors also induces liver ischaemia/reperfusion injury (IRI) in individuals. Hepatic IRI can be divided into warm IRI, which is induced by liver surgery and systemic ischaemia, and cold IRI, which is induced by LT. Multiple studies have shown that melatonin (MT) acts as an endogenous free radical scavenger with antioxidant capacity and is also able to attenuate hepatic IRI via its anti‐inflammatory and antiapoptotic capacities. In this review, we discuss the potential mechanisms and current strategies of MT administration in liver surgery for protecting against warm or cold hepatic IRI. We highlight strategies to improve the efficacy and safety of MT for attenuating hepatic IRI in different conditions. After the potential mechanisms underlying the interactions between MT and other important cellular processes during hepatic IR are clarified, more opportunities will be available to use MT to treat liver diseases in the future.     

Effects of obesity on occupant responses in frontal crashes: a simulation analysis using human body models

The objective of this study is to investigate the effects of obesity on occupant responses in frontal crashes using whole-body human finite element (FE) models representing occupants with different obesity levels. In this study, the geometry of THUMS 4 midsize male model was varied using mesh morphing techniques with target geometries defined by statistical models of external body contour and exterior ribcage geometry. Models with different body mass indices (BMIs) were calibrated against cadaver test data under high-speed abdomen loading and frontal crash conditions. A parametric analysis was performed to investigate the effects of BMI on occupant injuries in frontal crashes based on the Taguchi method while controlling for several vehicle design parameters. Simulations of obese occupants predicted significantly higher risks of injuries to the thorax and lower extremities in frontal crashes compared with non-obese occupants, which is consistent with previous field data analyses. These higher injury risks are mainly due to the increased body mass and relatively poor belt fit caused by soft tissues for obese occupants. This study demonstrated the feasibility of using a parametric human FE model to investigate the obesity effects on occupant responses in frontal crashes.     

Dynamic organ culture of precision liver slices for in vitro toxicology

The lack of a reproducible method for the production of thin tissue slices has hindered the use of liver slices as an in vitro tool for hepatotoxicity studies. Fresh human, rat, and rabbit liver was processed using a mechanical slicer. With this instrument, precision (5% of thickness) liver slices in the submillimeter range could be produced at a rapid rate. Slices were prepared from fresh livers in chilled, oxygenated buffer to minimize trauma. Following incubation for up to 20 h in a dynamic organ culture system, histology of incubated slices suggested that 250 m precision-cut slices were optimum in regard to morphology relative to liver slices incubated under conventional organ culture conditions. Addition of bromobenzene to the culture showed time-dependent hepatotoxicity based on two classic parameters of cell degeneration. Histological evidence is presented which suggests the usefulness of this system for hepatotoxicity studies and the production of focal necrosis in vitro.     

Activated Kupffer cells cause a hypermetabolic state after gentle in situ manipulation of liver in rats

Harvesting trauma to the graft dramatically decreases survival after liver transplantation. Since activated Kupffer cells play a role in primary nonfunction, the purpose of this study was to test the hypothesis that organ manipulation activates Kupffer cells. To mimic what occurs with donor hepatectomy, livers from Sprague-Dawley rats underwent dissection with or without gentle organ manipulation in a standardized manner in situ. Perfused livers exhibited normal values for O(2) uptake (105 +/- 5 micromol. g(-1). h(-1)) measured polarigraphically; however, 2 h after organ manipulation, values increased significantly to 160 +/- 8 micromol. g(-1). h(-1) and binding of pimonidazole, a hypoxia marker, increased about threefold (P < 0.05). Moreover, Kupffer cells from manipulated livers produced three- to fourfold more tumor necrosis factor-alpha and PGE(2), whereas intracellular calcium concentration increased twofold after lipopolysaccharide compared with unmanipulated controls (P < 0.05). Gadolinium chloride and glycine prevented both activation of Kupffer cells and effects of organ manipulation. Furthermore, indomethacin given 1 h before manipulation prevented the hypermetabolic state, hypoxia, depletion of glycogen, and release of PGE(2) from Kupffer cells. These data indicate that gentle organ manipulation during surgery activates Kupffer cells, leading to metabolic changes dependent on PGE(2) from Kupffer cells, which most likely impairs liver function. Thus modulation of Kupffer cell function before organ harvest could be beneficial in human liver transplantation and surgery.     

Extent and distribution of tibial osteochondral disruption during simulated landing impact with axial tibial rotation restraint

Post-traumatic knee osteochondral injuries are often coupled with anterior cruciate ligament (ACL) injury mechanisms during landing. However, it is not well understood whether restraining axial tibial rotation during landing would influence the extent and distribution of osteochondral disruption. Using ski landing as an example, this study subjected knee specimens to simulated landing impact without and with axial tibial rotation restraint, and investigated the extent and distribution of osteochondral disruption at the tibial plateau. Twenty-one porcine knee specimens were randomly divided into three test conditions, namely: (1) control, (2) impact only (I), and 3) impact with restraint (IR). Simulated landing impact was applied to the specimens based on a single 10 Hz haversine. Osteochondral explants were obtained from anterior, middle and posterior regions of medial and lateral tibial compartments. The extent of cartilage and trabecular disruption in these explants was examined based on histology, SEM and microCT. Only specimens in unrestrained condition incurred ACL failure upon impact. Restraining axial tibial rotation during simulated impact generally inflicted cartilage damage and deformation, and further caused trabecular disruption. Axial tibial rotation restraint did not necessarily restrict anterior tibial translation, as indicated by the presence of relative posterior femoral translation and osteochondral disruption at anterior–posterior tibial regions. While the results obtained in the current study may not be completely translatable to human models, there is likelihood that restraining axial tibial rotation during landing may help to prevent ACL failure, but will also induce osteochondral disruption in most tibial regions.     

Trauma among the Shanidar Neandertals

Four of the adult Neandertals from Shanidar Cave, Iraq, Shanidar 1, 3, 4, and 5, show evidence of antemortem trauma. Shanidar 1 sustained injuries to the right frontal squama, the left lateral orbit, the right humerus and right fifth metatarsal. Associated with this trauma are hypoplasia or atrophy of the right clavicle, scapula, and humerus, osteomyelitis of the right clavicle, degenerative joint disease at the right knee, ankle, and first tarsometatarsal joint, and remodeling of the left tibia. Shanidar 3 experienced trauma-related degenerative joint disease at the right talocrural and talocalcaneal joints and sustained a penetrating wound across the left ninth rib. Shanidar 4 suffered a fracture of the right seventh or eighth rib, and Shanidar 5 had a scalp wound over the left frontal. A high frequency of antemortem trauma associated with the survival of the injured individuals appears to have been characteristic of the Neandertals.