Massive Solubility Changes in Neuronal Proteins upon Simulated Traumatic Brain Injury Reveal the Role of Shockwaves in Irreversible Damage.

We investigated the immediate molecular consequences of traumatic brain injuries (TBIs) using a novel proteomics approach. We simulated TBIs using an innovative laboratory apparatus that employed a 5.1 kg dummy head that held neuronal cells and generated a ≤4000 g-force acceleration upon impact. A Proteome Integral Solubility Alteration (PISA) assay was then employed to monitor protein solubility changes in a system-wide manner. Dynamic impacts led to both a reduction in neuron viability and massive solubility changes in the proteome. The affected proteins mapped not only to the expected pathways, such as those of cell adhesion, collagen, and laminin structures, as well as the response to stress, but also to other dense protein networks, such as immune response, complement, and coagulation cascades. The cellular effects were found to be mainly due to the shockwave rather than the g-force acceleration. Soft materials could reduce the impact's severity only until they were fully compressed. This study shows a way of developing a proteome-based meter for measuring irreversible shockwave-induced cell damage and provides a resource for identifying protein biomarkers of TBIs and potential drug targets for the development of products aimed at primary prevention and intervention.

Learning through a virtual patient vs. recorded lecture: a comparison of knowledge retention in a trauma case.

OBJECTIVES: To compare medical students' and residents' knowledge retention of assessment, diagnosis and treatment procedures, as well as a learning experience, of patients with spinal trauma after training with either a Virtual Patient case or a video-recorded traditional lecture. METHODS: A total of 170 volunteers (85 medical students and 85 residents in orthopedic surgery) were randomly allocated (stratified for student/resident and gender) to either a video-recorded standard lecture or a Virtual Patient-based training session where they interactively assessed a clinical case portraying a motorcycle accident. The knowledge retention was assessed by a test immediately following the educational intervention and repeated after a minimum of 2 months. Participants' learning experiences were evaluated with exit questionnaires. A repeated-measures analysis of variance was applied on knowledge scores. A total of 81% (n = 138) of the participants completed both tests. RESULTS: There was a small but significant decline in first and second test results for both groups (F(1, 135) = 18.154, p = 0.00). However, no significant differences in short-term and long-term knowledge retention were observed between the two teaching methods. The Virtual Patient group reported higher learning experience levels in engagement, stimulation, general perception, and expectations. CONCLUSIONS: Participants' levels engagement were reported in favor of the VP format. Similar knowledge retention was achieved through either a Virtual Patient or a recorded lecture.

A National Survey of Traumatic Brain Injuries Admitted to Hospitals in Sweden from 1987 to 2010.

BACKGROUND: With an increasing and aging population, there is a global demand for improving the primary prevention strategies aimed at reducing traumatic brain injuries (TBIs). The objective of the present epidemiological study was to evaluate the pattern of TBI in Sweden over a 24 years period (1987-2010). METHODS: The Swedish Hospital Discharge Register was used, where in-patient care with a main diagnosis of TBI according to ICD9/10 was included. External factors, age and gender distribution was evaluated. RESULTS: A decreasing number of annual incidence was observed, that is, from 230 to 156 per 100,000 inhabitants. A steady decrease of concussion was observed while other intracranial injuries increased especially traumatic subdural hemorrhage and subarachnoid hemorrhage. The study identified 3 groups of patients - young, adults and elderly. The highest incidence and the largest increase of incidence were seen in the oldest age group (85+ years) while the population under 65 years had a decreasing incidence of TBI. The most frequent etiology was fall accidents (57%) with a relative constant trend over the study period. CONCLUSIONS: More effort should be focused on different strategies for different age groups, especially the elderly group. A well-planned strategy for primary prevention guidelines for different age groups will have the chance to further reduce not only the health-care costs but also complications among elderly care.

Higher impact energy in traumatic brain injury interferes with noncovalent and covalent bonds resulting in cytotoxic brain tissue edema as measured with computational simulation.

BACKGROUND: Cytotoxic brain tissue edema is a complicated secondary consequence of ischemic injury following cerebral diseases such as traumatic brain injury and stroke. To some extent the pathophysiological mechanisms are known, but far from completely. In this study, a hypothesis is proposed in which protein unfolding and perturbation of nucleotide structures participate in the development of cytotoxic edema following traumatic brain injury (TBI). METHODS: An advanced computational simulation model of the human head was used to simulate TBI. The consequences of kinetic energy transfer following an external dynamic impact were analyzed including the intracranial pressure (ICP), strain level, and their potential influences on the noncovalent and covalent bonds in folded protein structures. RESULTS: The result shows that although most of the transferred kinetic energy is absorbed in the skin and three bone layers, there is a substantial amount of energy reaching the gray and white matter. The kinetic energy from an external dynamic impact has the theoretical potential to interfere not only with noncovalent but also covalent bonds when high enough. The induced mechanical strain and pressure may further interfere with the proteins, which accumulate water molecules into the interior of the hydrophobic structures of unfolded proteins. Simultaneously, the noncovalent energy-rich bonds in nucleotide adenosine-triphosphates may be perturbed as well. CONCLUSIONS: Based on the analysis of the numerical simulation data, the kinetic energy from an external dynamic impact has the theoretical potential to interfere not only with noncovalent, but also with covalent bonds when high enough. The subsequent attraction of increased water molecules into the unfolded protein structures and disruption of adenosine-triphosphate bonds could to some extent explain the etiology to cytotoxic edema.

Decompressive craniectomy (DC) at the non-injured side of the brain has the potential to improve patient outcome as measured with computational simulation.

OBJECTIVE: Decompressive craniectomy (DC) is efficient in reducing the intracranial pressure in several complicated disorders such as traumatic brain injury (TBI) and stroke. The neurosurgical procedure has indeed reduced the number of deaths. However, parallel with the reduced fatal cases, the number of vegetative patients has increased significantly. Mechanical stretching in axonal fibers has been suggested to contribute to the unfavorable outcome. Thus, there is a need for improving treatment procedures that allow both reduced fatal and vegetative outcomes. The hypothesis is that by performing the DC at the non-injured side of the head, stretching of axonal fibers at the injured brain tissue can be reduced, thereby having the potential to improve patient outcome. METHODS: Six patients, one with TBI and five with stroke, were treated with DC and where each patient's pre- and postoperative computerized tomography (CT) were analyzed and transferred to a finite element (FE) model of the human head and brain to simulate DC both at the injured and non-injured sides of the head. Poroelastic material was used to simulate brain tissue. RESULTS: The computational simulation showed slightly to substantially increased axonal strain levels over 40 % on the injured side where the actual DC had been performed in the six patients. However, when the simulation DC was performed on the opposite, non-injured side, there was a substantial reduction in axonal strain levels at the injured side of brain tissue. Also, at the opposite, non-injured side, the axonal strain level was substantially lower in the brain tissue. The reduced axonal strain level could be verified by analyzing a number of coronal sections in each patient. Further analysis of axial slices showed that falx may tentatively explain part of the different axonal strain levels between the DC performances at injured and opposite, non-injured sides of the head. CONCLUSIONS: By using a FE method it is possible to optimize the DC procedure to a non-injured area of the head thereby having the potential to reduce axonal stretching at the injured brain tissue. The postoperative DC stretching of axonal fibers may be influenced by different anatomical structures including falx. It is suggested that including computational FE simulation images may offer guidance to reduce axonal strain level tailoring the anatomical location of DC performance in each patient.

A pilot evaluation of an educational program that offers visualizations of cervical spine injuries: medical students' self-efficacy increases by training.

In this pilot study, a new method for visualization through imaging and simulation (VIS-Ed) for teaching diagnosis and treatment of cervical spine trauma was formatively evaluated. The aims were to examine if medical students' self-efficacy would change by training using VIS-Ed, and if so these changes were related to how they evaluated the session, and the user interface (UI) of this program. Using a one-group, pre-post course test design 43 Swedish medical students (4th year, 17 males, 26 females) practiced in groups of three participants. Overall the practice and the UI were considered as positive experiences. They judged VIS-Ed as a good interactive scenario-based educational tool. All students' self-efficacy increased significantly by training (p < 0.001). Spearman's rank correlation tests revealed that increased self-efficacy was only associated with: how the session was compared to as expected (p < 0.007). Students' self-efficacy increased significantly by training, but replication studies should determine if this training effect is gender-related.

Heating during infrared neural stimulation.

BACKGROUND AND OBJECTIVE: Infrared neural stimulation (INS) has recently evoked interest as an alternative to electrical stimulation. The mechanism of activation is the heating of water, which induces changes in cell membrane potential but may also trigger heat sensitive receptors. To further elucidate the mechanism, which may be dependent on cell type, a detailed description of the temperature distribution is necessary. A good control of the resulting temperature during INS is also necessary to avoid excessive heating that may damage the cells. Here we present a detailed model for the heating during INS and apply it for INS of in vitro neural networks of rat cerebral cortex neurons. STUDY DESIGN/MATERIALS AND METHODS: A model of the heating during INS of a cell culture in a non-turbid media was prepared using multiphysics software. Experimental parameters such as initial temperature, beam distribution, pulse length, pulse duration, frequency and laser-cell distance were used. To verify the model, local temperature measurements using open pipette resistance were conducted. Furthermore, cortical neurons in culture were stimulated by a 500 mW pulsed diode laser (wavelength 1,550 nm) launched into a 200 µm multimodal optical fiber positioned 300 µm from the glass surface. The radiant exposure was 5.2 J/cm(2) . RESULTS: The model gave detailed information about the spatial and temporal temperature distribution in the heated volume during INS. Temperature measurements using open pipette resistance verified the model. The peak temperature experienced by the cells was 48°C. Cortical neurons were successfully stimulated using the 1,550 nm laser and single cell activation as well as neural network inhibition were observed. CONCLUSION: The model shows the spatial and temporal temperature distribution in the heated volume and could serve as a useful tool for future studies of the heating during INS.

Consequences of the dynamic triple peak impact factor in Traumatic Brain Injury as Measured with Numerical Simulation.

There is a lack of knowledge about the direct neuromechanical consequences in traumatic brain injury (TBI) at the scene of accident. In this study we use a finite element model of the human head to study the dynamic response of the brain during the first milliseconds after the impact with velocities of 10, 6, and 2 meters/second (m/s), respectively. The numerical simulation was focused on the external kinetic energy transfer, intracranial pressure (ICP), strain energy density and first principal strain level, and their respective impacts to the brain tissue. We show that the oblique impacts of 10 and 6 m/s resulted in substantial high peaks for the ICP, strain energy density, and first principal strain levels, however, with different patterns and time frames. Also, the 2 m/s impact showed almost no increase in the above mentioned investigated parameters. More importantly, we show that there clearly exists a dynamic triple peak impact factor to the brain tissue immediately after the impact regardless of injury severity associated with different impact velocities. The dynamic triple peak impacts occurred in a sequential manner first showing strain energy density and ICP and then followed by first principal strain. This should open up a new dimension to better understand the complex mechanisms underlying TBI. Thus, it is suggested that the combination of the dynamic triple peak impacts to the brain tissue may interfere with the cerebral metabolism relative to the impact severity thereby having the potential to differentiate between severe and moderate TBI from mild TBI.

Decompressive craniectomy causes a significant strain increase in axonal fiber tracts.

Decompressive craniectomy (DC) allows for the expansion of a swollen brain outside the skull and has the potential to reduce intracranial pressure. However, the stretching of axons may contribute to an unfavorable outcome in patients treated with DC. In this study, we present a method for quantifying and visualizing axonal fiber deformation during both the pre-craniectomy and post-craniectomy periods to provide more insight into the mechanical effects of this treatment on axonal fibers. The deformation of the brain tissue in the form of a Lagrangian finite strain tensor for the entire brain was obtained by a non-linear image registration method based on the CT scanning data sets of the patient. Axonal fiber tracts were extracted from diffusion-weighted images. Based on the calculated brain tissue strain tensor and the observed axonal fiber tracts, the deformation of axonal fiber tracts in the form of a first principal strain, axonal strain and axonal shear strain were quantified. The greatest axonal fiber displacement was predominantly located in the treated region of the craniectomy, accompanied by a large axonal deformation close to the skull edge of the craniectomy. The distortion (stretching or shearing) of axonal fibers in the treated area of the craniectomy may influence the axonal fibers in such a way that neurochemical events are disrupted. A quantitative model may clarify some of the potential problems with this treatment.

Numerical impact simulation of gradually increased kinetic energy transfer has the potential to break up folded protein structures resulting in cytotoxic brain tissue edema.

Although the consequences of traumatic brain injury (TBI) and its treatment have been improved, there is still a substantial lack of understanding the mechanisms. Numerical simulation of the impact can throw further lights on site and mechanism of action. A finite element model of the human head and brain tissue was used to simulate TBI. The consequences of gradually increased kinetic energy transfer was analyzed by evaluating the impact intracranial pressure (ICP), strain level, and their potential influences on binding forces in folded protein structures. The gradually increased kinetic energy was found to have the potential to break apart bonds of Van der Waals in all impacts and hydrogen bonds at simulated impacts from 6 m/s and higher, thereby superseding the energy in folded protein structures. Further, impacts below 6 m/s showed none or very slight increase in impact ICP and strain levels, whereas impacts of 6 m/s or higher showed a gradual increase of the impact ICP and strain levels reaching over 1000 KPa and over 30%, respectively. The present simulation study shows that the free kinetic energy transfer, impact ICP, and strain levels all have the potential to initiate cytotoxic brain tissue edema by unfolding protein structures. The definition of mild, moderate, and severe TBI should thus be looked upon as the same condition and separated only by a gradual severity of impact.

Multipurpose heterofunctional dendritic scaffolds as crosslinkers towards functional soft hydrogels and implant adhesives in bone fracture applications.

Two sets of heterofunctional dendritic frameworks displaying an inversed and exact number of ene and azide groups have successfully been synthesized and post-functionalized with biorelevant molecules. Their facile scaffolding ability enabled the fabrication of soft and azide functional dendritic hydrogels with modulus close to muscle tissue. The dendritic scaffolds are furthermore shown to be promising primers for the development of novel bone fracture stabilization adhesives with shear strengths succeeding commercial Histroacryl®.

Influences of brain tissue poroelastic constants on intracranial pressure (ICP) during constant-rate infusion.

A 3D finite element (FE) model has been developed to study the mean intracranial pressure (ICP) response during constant-rate infusion using linear poroelasticity. Due to the uncertainties in the poroelastic constants for brain tissue, the influence of each of the main parameters on the transient ICP infusion curve was studied. As a prerequisite for transient analysis, steady-state simulations were performed first. The simulated steady-state pressure distribution in the brain tissue for a normal cerebrospinal fluid (CSF) circulation system showed good correlation with experiments from the literature. Furthermore, steady-state ICP closely followed the infusion experiments at different infusion rates. The verified steady-state models then served as a baseline for the subsequent transient models. For transient analysis, the simulated ICP shows a similar tendency to that found in the experiments, however, different values of the poroelastic constants have a significant effect on the infusion curve. The influence of the main poroelastic parameters including the Biot coefficient α, Skempton coefficient B, drained Young's modulus E, Poisson's ratio ν, permeability κ, CSF absorption conductance C(b) and external venous pressure p(b) was studied to investigate the influence on the pressure response. It was found that the value of the specific storage term S(ε) is the dominant factor that influences the infusion curve, and the drained Young's modulus E was identified as the dominant parameter second to S(ε). Based on the simulated infusion curves from the FE model, artificial neural network (ANN) was used to find an optimised parameter set that best fit the experimental curve. The infusion curves from both the FE simulation and using ANN confirmed the limitation of linear poroelasticity in modelling the transient constant-rate infusion.

Organic bioelectrodes in clinical neurosurgery.

BACKGROUND: Clinical neurosurgery deals with surgical procedures and intensive care of illnesses in the human central and peripheral nervous system. Neurosurgery should be looked upon as a high-tech specialty and very much dependent on new technological innovations aiming at improvements of patient's treatment and outcome. During the last decades neurosurgery has improved substantially thanks to the introduction of applied imaging technologies such as computerized tomography and magnetic resonance tomography, and new surgical modalities such as the microscope, brain navigation and neuroanesthesiology. Neurosurgical disorders, which should have the potential to benefit from conductive organic bioelectrodes, include traumatic brain and spinal cord injury and peripheral nerve injuries due to external violence in the restoration of healthy communication. This holds true also for cerebral nerves altered in their functions due to benign and malignant brain and spinal cord tumors. Further, new innovative devices in the field of functional nervous tissue disorders make the use of organic conductive electrodes attractive by considering the electrical neurochemical properties of neural interfaces. CONCLUSIONS: Although in its infancy, conducting organic polymers as bioelectrodes have several potential applications in clinical neurosurgery. The time it takes for new innovations and basic research to be transferred into clinical neurosurgery should not take too long. However, a prerequisite for successful implementation is the close interdisciplinary collaboration between engineers and clinicians. This article is part of a Special Issue entitled Organic Bioelectronics-Novel Applications in Biomedicine.

Increased strain levels and water content in brain tissue after decompressive craniotomy.

BACKGROUND: At present there is a debate on the effectiveness of the decompressive craniotomy (DC). Stretching of axons was speculated to contribute to the unfavourable outcome for the patients. The quantification of strain level could provide more insight into the potential damage to the axons. The aim of the present study was to evaluate the strain level and water content (WC) of the brain tissue for both the pre- and post-craniotomy period. METHODS: The stretching of brain tissue was quantified retrospectively based on the computerised tomography (CT) images of six patients before and after DC by a non-linear image registration method. WC was related to specific gravity (SG), which in turn was related to the Hounsfield unit (HU) value in the CT images by a photoelectric correction according to the chemical composition of brain tissue. RESULTS: For all the six patients, the strain level showed a substantial increase in the brain tissue close to the treated side of DC compared with that found at the pre-craniotomy period and ranged from 24 to 55 % at the post-craniotomy period. Increase of strain level was also observed at the brain tissue opposite to the treated side, however, to a much lesser extent. The mean area of craniotomy was found to be 91.1 ± 12.7 cm(2). The brain tissue volume increased from 27 to 127 ml, corresponding to 1.65 % and 8.13 % after DC in all six patients. Also, the increased volume seemed to correlate with increased strain level. Specifically, the overall WC of brain tissue for two patients evaluated presented a significant increase after the treatment compared with the condition seen before the treatment. Furthermore, the Glasgow Coma Scale (GCS) improved in four patients after the craniotomy, while two patients died. The GCS did not seem to correlate with the strain level. CONCLUSIONS: We present a new numerical method to quantify the stretching or strain level of brain tissue and WC following DC. The significant increase in strain level and WC in the post-craniotomy period may cause electrophysiological changes in the axons, resulting in loss of neuronal function. Hence, this new numerical method provides more insight of the consequences following DC and may be used to better define the most optimal size and area of the craniotomy in reducing the strain level development.

Training diagnosis and treatment of cervical spine trauma using a new educational program for visualization through imaging and simulation (VIS): a first evaluation by medical students.

In this pilot study we investigated how medical students evaluated a VIS practice session. Immediately after training 43 students answered a questionnaire on the training session. They evaluated VIS as a good interactive scenario based educational tool.

Influence of gravity for optimal head positions in the treatment of head injury patients.

BACKGROUND: Brain edema is a major neurological complication of traumatic brain injury (TBI), commonly including a pathologically increased intracranial pressure (ICP) associated with poor outcome. In this study, gravitational force is suggested to have a significant impact on the pressure of the edema zone in the brain tissue and the objective of the study was to investigate the significance of head position on edema at the posterior part of the brain using a finite element (FE) model. METHODS: A detailed FE model including the meninges, brain tissue and a fully connected cerebrospinal fluid (CSF) system was used in this study. Brain tissue was modelled as a poroelastic material consisting of an elastic solid skeleton composed of neurons and neuroglia, permeated by interstitial fluid. The effect of head positions (supine and prone position) due to gravity was investigated for a localized brain edema at the posterior part of the brain. RESULTS: The water content increment at the edema zone remained nearly identical for both positions. However, the interstitial fluid pressure (IFP) inside the edema zone decreased around 15% by having the head in a prone position compared with a supine position. CONCLUSIONS: The decrease of IFP inside the edema zone by changing patient position from supine to prone has the potential to alleviate the damage to central nervous system nerves. These observations indicate that considering the patient's head position during intensive care and at rehabilitation might be of importance to the treatment of edematous regions in TBI patients.

Stability of poly(3,4-ethylene dioxythiophene) materials intended for implants.

This study presents experiments designed to study the stability of the conducting polymer poly(3,4-ethylene dioxythiophene) (PEDOT), under simulated physiological conditions using phosphate-buffered saline (PBS) and hydrogen peroxide (H(2)O(2)) (0.01 M) at 37 degrees C over a 5- to 6-week period. Voltage pulsing in PBS was used as an additional test environment. The influence of switching the counter ion used in electropolymerization from polystyrene sulphonate (PSS) to heparin was investigated. Absorbance spectroscopy and cyclic voltammetry were used to evaluate the material properties. Most of the samples in H(2)O(2) lost both electroactivity and optical absorbance within the study period, but PEDOT:PSS was found slightly more stable than PEDOT:heparin. Polymers were relatively stable in PBS throughout the study period, with around 80% of electroactivity remaining after 5 weeks, disregarding delamination, which was a significant problem especially for polymer on indium tin oxide substrates. Voltage pulsing in PBS did not increase degradation. The counter ion influenced the time course of degradation in oxidizing agents.

Bifunctional dendrimers: from robust synthesis and accelerated one-pot postfunctionalization strategy to potential applications.

A fourth wheel: Two sets of bifunctional AB(2)C dendrimers having internal acetylene/azides and external hydroxy groups were constructed utilizing benign synthetic protocols. An in situ postfunctionalization strategy was successfully carried out to illustrate the chemoselective nature of these dendrimers. The dendrimers were also transformed into dendritic nanoparticles or utilized as dendritic crosslinkers for the fabrication hydrogels.