Computational modeling investigation of pulsed high peak power microwaves and the potential for traumatic brain injury.

When considering safety standards for human exposure to radiofrequency (RF) and microwave energy, the dominant concerns pertain to a thermal effect. However, in the case of high-power pulsed RF/microwave energy, a rapid thermal expansion can lead to stress waves within the body. In this study, a computational model is used to estimate the temperature profile in the human brain resulting from exposure to various RF/microwave incident field parameters. The temperatures are subsequently used to simulate the resulting mechanical response of the brain. Our simulations show that, for certain extremely high-power microwave exposures (permissible by current safety standards), very high stresses may occur within the brain that may have implications for neuropathological effects. Although the required power densities are orders of magnitude larger than most real-world exposure conditions, they can be achieved with devices meant to emit high-power electromagnetic pulses in military and research applications.

Evaluation of adenosine A1 receptor agonists as neuroprotective countermeasures against Soman intoxication in rats.

Soman, an organophosphorus (OP) compound, disrupts nervous system function through inactivation of acetylcholinesterase (AChE), the enzyme that breaks down acetylcholine at synapses. Left untreated, a state of prolonged seizure activity (status epilepticus, SE) is induced, causing widespread neuronal damage and associated cognitive and behavioral impairments. Previous research demonstrated that therapeutic stimulation of A1 adenosine receptors (A1ARs) can prevent or terminate soman-induced seizure. This study examined the ability of three potent A1AR agonists to provide neuroprotection and, ultimately, prevent observable cognitive and behavioral deficits following exposure to soman. Sprague Dawley rats were challenged with a seizure-inducing dose of soman (1.2 x LD50) and treated 1 min later with one of the following A1AR agonists: (6)-Cyclopentyladenosine (CPA), 2-Chloro-N6-cyclopentyladenosine (CCPA) or N-bicyclo(2.2.1)hept-2-yl-5'-chloro-5'-deoxyadenosine (cdENBA). An active avoidance shuttle box task was used to evaluate locomotor responses to aversive stimuli at 3, 7 and 14 days post-exposure. Animals treated with CPA, CCPA or cdENBA demonstrated a higher number of avoidance responses and a faster reaction to the aversive stimulus than the soman/saline control group across all three sessions. Findings suggest that A1AR agonism is a promising neuroprotective countermeasure, capable of preventing the long-term deficits in learning and memory that are characteristic of soman intoxication.

In Vivo Evaluation of A1 Adenosine Agonists as Novel Anticonvulsant Medical Countermeasures to Nerve Agent Intoxication in a Rat Soman Seizure Model.

Organophosphorus nerve agents (NAs) irreversibly inhibit acetylcholinesterase, which results in the accumulation of acetylcholine and widespread excitotoxic seizure activity. Because current medical countermeasures (anticholinergics, AChE reactivators, and benzodiazepines) lack sufficient anti-seizure efficacy when treatment is delayed, those intoxicated are at risk for severe brain damage or death if treatment is not immediately available. Toward developing a more effective anti-seizure treatment for NA intoxication, this study evaluated the efficacy of A1 adenosine (ADO) receptor (A1AR) agonists in a rat soman seizure model. One minute after exposure to soman (1.6 × LD50, subcutaneous), rats were treated intraperitoneally with one of the following agonists at increasing dose levels until anti-seizure efficacy was achieved: N6-cyclopentaladenosine (CPA), 2-chloro-N6-cyclopentyladenosine (CCPA), and (±)-5'-chloro-5'-deoxy-ENBA (ENBA). All A1AR agonists were efficacious in preventing seizure and promoting survival. The effective doses for the A1AR agonists were 60 mg/kg CPA, 36 mg/kg CCPA, and 62 mg/kg ENBA. Whereas vehicle-treated rats experienced 100% seizure and 21% survival (N = 28), ADO treatments reduced seizure occurrence and improved survival rates: 8% seizure and 83% survival with CPA (60 mg/kg, N = 12), 17% seizure and 75% survival with CCPA (36 mg/kg, N = 12), and 8% seizure, 83% survival with ENBA (62 mg/kg, N = 12). The brains of ADO-treated rats were also protected from damage as indicated by neurohistopathological analysis. While all ADO agonists provided neuroprotection, rats receiving CCPA and ENBA experienced less severe ADO-induced side effects (e.g., sedation, hypothermia, bradycardia) than with CPA. The data from this study suggest that the ADO signaling pathway is a promising mechanism for countering seizure activity induced by NAs.

Mechanisms of acetylcholinesterase protection against sarin and soman by adenosine A1 receptor agonist N6-cyclopentyladenosine.

Organophosphorus nerve agents (NAs) irreversibly inhibit acetylcholinesterase (AChE), the enzyme responsible for breaking down the neurotransmitter acetylcholine (ACh). The over accumulation of ACh after NA exposure leads to cholinergic toxicity, seizure, and death. Current medical countermeasures effectively mitigate peripheral symptoms, however; the brain is often unprotected. Alternative acute treatment with the adenosine A1 receptor agonist N6-cyclopentyladensosine (CPA) has previously been demonstrated to prevent AChE inhibition as well as to suppress neuronal activity. The mechanism of AChE protection is unknown. To elucidate the feasibility of potential CPA-AChE interaction mechanisms, we applied a truncated molecular model approach and density functional theory. The candidate mechanisms studied are reversible enzyme inhibition, enzyme reactivation, and NA blocking prior to enzyme conjugation. Our thermodynamic data suggest that CPA can compete with the NAs sarin and soman for the active site of AChE, but may, in contrast to NAs, undergo back-reaction. We found a strong interaction between CPA and NA conjugated AChE, making enzyme reactivation unlikely but possibly allowing for CPA protection through the prevention of NA aging. The data also indicates that there is an affinity between CPA and unbound NAs. The results from this study support the hypothesis that CPA counters NA toxicity via multiple mechanisms and is a promising therapeutic strategy that warrants further development.

Expedited CT-Based Methods for Evaluating Fracture Severity to Assess Risk of Post-Traumatic Osteoarthritis After Articular Fractures.

BACKGROUND: Post-traumatic osteoarthritis (PTOA) is common after intra-articular fractures of the tibial plafond. An objective CT-based measure of fracture severity was previously found to reliably predict whether PTOA developed following surgical treatment of such fractures. However, the extended time required obtaining the fracture energy metric and its reliance upon an intact contralateral limb CT limited its clinical applicability. The objective of this study was to establish an expedited fracture severity metric that provided comparable PTOA predictive ability without the prior limitations. METHODS: An expedited fracture severity metric was computed from the CT scans of 30 tibial plafond fractures using textural analysis to quantify disorder in CT images. The expedited method utilized an intact surrogate model to enable severity assessment without requiring a contralateral limb CT. Agreement between the expedited fracture severity metric and the Kellgren-Lawrence (KL) radiographic OA score at two-year follow-up was assessed using concordance. The ability of the metric to differentiate between patients that did or did not develop PTOA was assessed using the Wilcoxon Ranked Sum test. RESULTS: The expedited severity metric agreed well (75.2% concordance) with the KL scores. The initial fracture severity of cases that developed PTOA differed significantly (p = 0.004) from those that did not. Receiver operating characteristic analysis showed that the expedited severity metric could accurately predict PTOA outcome in 80% of the cases. The time required to obtain the expedited severity metric averaged 14.9 minutes/ case, and the metric was obtained without using an intact contralateral CT. CONCLUSION: The expedited CT-based methods for fracture severity assessment present a solution to issues limiting the utility of prior methods. In a relatively short amount of time, the expedited methodology provided a severity score capable of predicting PTOA risk, without needing to have the intact contralateral limb included in the CT scan. The described methods provide surgeons an objective, quantitative representation of the severity of a fracture. Obtained prior to the surgery, it provides a reasonable alternative to current subjective classification systems. The expedited severity metric offers surgeons an objective means for factoring severity of joint insult into treatment decision-making.

Evaluation of acetylcholine, seizure activity and neuropathology following high-dose nerve agent exposure and delayed neuroprotective treatment drugs in freely moving rats.

Organophosphorus nerve agents such as soman (GD) inhibit acetylcholinesterase, producing an excess of acetylcholine (ACh), which results in respiratory distress, convulsions and status epilepticus that leads to neuropathology. Several drugs (topiramate, clobazam, pregnanolone, allopregnanolone, UBP 302, cyclopentyladenosine [CPA], ketamine, midazolam and scopolamine) have been identified as potential neuroprotectants that may terminate seizures and reduce brain damage. To systematically evaluate their efficacy, this study employed in vivo striatal microdialysis and liquid chromatography to respectively collect and analyze extracellular ACh in freely moving rats treated with these drugs 20 min after seizure onset induced by a high dose of GD. Along with microdialysis, EEG activity was recorded and neuropathology assessed at 24 h. GD induced a marked increase of ACh, which peaked at 30 min post-exposure to 800% of control levels and then steadily decreased toward baseline levels. Approximately 40 min after treatment, only midazolam (10 mg/kg) and CPA (60 mg/kg) caused a significant reduction of ACh levels, with CPA reducing ACh levels more rapidly than midazolam. Both drugs facilitated a return to baseline levels at least 55 min after treatment. At 24 h, only animals treated with CPA (67%), midazolam (18%) and scopolamine (27%) exhibited seizure termination. While all treatments except for topiramate reduced neuropathology, CPA, midazolam and scopolamine showed the greatest reduction in pathology. Our results suggest that delayed treatment with CPA, midazolam, or scopolamine is effective at reducing GD-induced seizure activity and neuropathology, with CPA and midazolam capable of facilitating a reduction in GD-induced ACh elevation.

Computational techniques for the assessment of fracture repair.

The combination of high-resolution three-dimensional medical imaging, increased computing power, and modern computational methods provide unprecedented capabilities for assessing the repair and healing of fractured bone. Fracture healing is a natural process that restores the mechanical integrity of bone and is greatly influenced by the prevailing mechanical environment. Mechanobiological theories have been proposed to provide greater insight into the relationships between mechanics (stress and strain) and biology. Computational approaches for modelling these relationships have evolved from simple tools to analyze fracture healing at a single point in time to current models that capture complex biological events such as angiogenesis, stochasticity in cellular activities, and cell-phenotype specific activities. The predictive capacity of these models has been established using corroborating physical experiments. For clinical application, mechanobiological models accounting for patient-to-patient variability hold the potential to predict fracture healing and thereby help clinicians to customize treatment. Advanced imaging tools permit patient-specific geometries to be used in such models. Refining the models to study the strain fields within a fracture gap and adapting the models for case-specific simulation may provide more accurate examination of the relationship between strain and fracture healing in actual patients. Medical imaging systems have significantly advanced the capability for less invasive visualization of injured musculoskeletal tissues, but all too often the consideration of these rich datasets has stopped at the level of subjective observation. Computational image analysis methods have not yet been applied to study fracture healing, but two comparable challenges which have been addressed in this general area are the evaluation of fracture severity and of fracture-associated soft tissue injury. CT-based methodologies developed to assess and quantify these factors are described and results presented to show the potential of these analysis methods.

Stimulation of central A1 adenosine receptors suppresses seizure and neuropathology in a soman nerve agent seizure rat model.

The current regimen for treating nerve agent poisoning does not sufficiently suppress the excitotoxic activity that causes severe brain damage, especially in cases where treatment is delayed and nerve agent-induced status epilepticus develops. New therapeutic targets are required to improve survivability and minimize neuropathology after irreversible acetylcholinesterase inactivation. Earlier studies have shown that systemic delivery of adenosine agonists decreases nerve agent lethality; however, the mechanism of protection remains to be understood. The primary aim of this study was to investigate the role of central adenosine receptor (AR) stimulation in neuroprotection by directly injecting (6)-cyclopentyladenosine (CPA), an adenosine agonist specific to the A1 receptor subtype (A1R), into the brain intracerebroventricularly (ICV) in a soman seizure rat model. In addition to general A1R stimulation, we hypothesized that bilateral micro-injection of CPA into the cholinergic basal forebrain (BF) could also suppress excitotoxic activity. The results from these studies demonstrated that centrally administered adenosine agonists are anti-seizure and neuroprotective. CPA-delivered ICV prevented seizure and convulsion in 100% of the animals. Moreover, neuropathological evaluation indicated that adenosine treatments reduced brain damage from severe to minimal. Inhibition of the BF via CPA had varied results. Some animals were protected by treatment; however, others displayed similar pathology to the control. Overall, these data suggest that stimulating central ARs could be an effective target for the next generation countermeasures for nerve agent intoxication.

A simulation trainer for complex articular fracture surgery.

BACKGROUND: The purposes of this study were (1) to develop a physical model to improve articular fracture reduction skills, (2) to develop objective assessment methods to evaluate these skills, and (3) to assess the construct validity of the simulation. METHODS: A surgical simulation was staged utilizing surrogate tibial plafond fractures. Multiple three-segment radio-opacified polyurethane foam fracture models were produced from the same mold, ensuring uniform surgical complexity between trials. Using fluoroscopic guidance, five senior and seven junior orthopaedic residents reduced the fracture through a limited anterior window. The residents were assessed on the basis of time to completion, hand movements (tracked with use of a motion capture system), and quality of the obtained reduction. RESULTS: All but three of the residents successfully reduced and fixed the fracture fragments (one senior resident and two junior residents completed the reduction but were unsuccessful in fixating all fragments). Senior residents had an average time to completion of 13.43 minutes, an average gross articular step-off of 3.00 mm, discrete hand motions of 540 actions, and a cumulative hand motion distance of 79 m. Junior residents had an average time to completion of 14.75 minutes, an average gross articular step-off of 3.09 mm, discrete hand motions of 511 actions, and a cumulative hand motion distance of 390 m. CONCLUSIONS: The large difference in cumulative hand motion distance, despite comparable numbers of discrete hand motion events, indicates that senior residents were more precise in their hand motions. The present experiment establishes the basic construct validity of the simulation trainer. Further studies are required to demonstrate that this laboratory-based model for articular fracture reduction training, along with an objective assessment of performance, can be used to improve resident surgical skills.

ASB Clinical Biomechanics Award Paper 2010 Virtual pre-operative reconstruction planning for comminuted articular fractures.

BACKGROUND: Highly comminuted intra-articular fractures are complex and difficult injuries to treat. Once emergent care is rendered, the definitive treatment objective is to restore the original anatomy while minimizing surgically induced trauma. Operations that use limited or percutaneous approaches help preserve tissue vitality, but reduced visibility makes reconstruction more difficult. A pre-operative plan of how comminuted fragments would best be re-positioned to restore anatomy helps in executing a successful reduction. METHODS: In this study, the methods for virtually reconstructing a tibial plafond fracture were developed and applied to clinical cases. Building upon previous benchtop work, novel image analysis techniques and puzzle solving algorithms were developed for clinical application. Specialty image analysis tools were used to segment the fracture fragment geometries from CT data. The original anatomy was then restored by matching fragment native (periosteal and subchondral) bone surfaces to an intact template, generated from the uninjured contralateral limb. FINDINGS: Virtual reconstructions obtained for ten tibial plafond fracture cases had average alignment errors of 0.39 (0.5 standard deviation) mm. In addition to precise reduction planning, 3D puzzle solutions can help identify articular deformities and bone loss. INTERPRETATION: The results from this study indicate that 3D puzzle solving provides a powerful new tool for planning the surgical reconstruction of comminuted articular fractures.

A computational/experimental platform for investigating three-dimensional puzzle solving of comminuted articular fractures.

Reconstructing highly comminuted articular fractures poses a difficult surgical challenge, akin to solving a complicated three-dimensional (3D) puzzle. Preoperative planning using computed tomography (CT) is critically important, given the desirability of less invasive surgical approaches. The goal of this work is to advance 3D puzzle-solving methods towards use as a preoperative tool for reconstructing these complex fractures. A methodology for generating typical fragmentation/dispersal patterns was developed. Five identical replicas of human distal tibia anatomy were machined from blocks of high-density polyetherurethane foam (bone fragmentation surrogate), and were fractured using an instrumented drop tower. Pre- and post-fracture geometries were obtained using laser scans and CT. A semi-automatic virtual reconstruction computer program aligned fragment native (non-fracture) surfaces to a pre-fracture template. The tibiae were precisely reconstructed with alignment accuracies ranging from 0.03 to 0.4 mm. This novel technology has the potential to significantly enhance surgical techniques for reconstructing comminuted intra-articular fractures, as illustrated for a representative clinical case.

Objective CT-based metrics of articular fracture severity to assess risk for posttraumatic osteoarthritis.

OBJECTIVES: Intra-articular fractures predispose patients to posttraumatic osteoarthritis (PTOA) with associated chronic joint pain and decreased function. The success of articular fracture management is dependent on how the fracture is treated and on fracture type and severity. The purpose of the present study was to correlate objective computed tomography (CT)-based indices of intra-articular fracture severity with subsequent joint degeneration. It was hypothesized that an injury severity metric that included objective measures of articular disruption, of fracture energy, and of fragment displacement/dispersal would be a useful predictor of PTOA. METHODS: Novel CT-based image analysis techniques were used to quantify acute injury characteristics in a prospective series of 20 tibial plafond fractures managed by articulated external fixation with later definitive surgical fracture reduction performed after soft tissue swelling had sufficiently resolved. PTOA severity was assessed 2 years postinjury using the Kellgren-Lawrence radiographic grading scale. A predictive model was developed by linearly regressing these 2-year Kellgren-Lawrence outcomes on the CT-based severity metrics. RESULTS: A combined acute severity score involving articular disruption and fracture energy successfully predicted PTOA severity (R2 = 0.70), whereas fragment displacement/dispersal and surgeon opinion correlated much less well with degeneration (R = 0.42 and 0.47). The concordance between the combined metric and PTOA severity was 88%. CONCLUSIONS: The findings of this study indicate that objective CT-based metrics of acute injury severity can reliably predict intermediate-term PTOA outcomes in this challenging class of articular fractures. Quantitative biomechanical assessment of injury characteristics provides new possibilities to improve fracture management and to guide PTOA research.

Utility of double-contrast multi-detector CT scans to assess cartilage thickness after tibial plafond fracture.

The pathophysiology of post-traumatic osteoarthritis (PTOA) after intra-articular fractures is poorly understood. Pursuit of a better understanding of this disease is complicated by inability to accurately monitor its onset, progression and severity. Common radiographic methods used to assess PTOA do not provide sufficient image quality for precise cartilage measurements. Double-contrast MDCT is an alternative method that may be useful, since it produces high-quality images in normal ankles. The purpose of this study was to assess this technique's performance in assessing cartilage maintenance in ankles with an intra-articular fracture. Thirty-six tibial plafond fractures were followed over two years, with thirty-one MDCTs being obtained four months after injury, and twenty-two MDCTs after two years. Unfortunately, clinical results with this technique were unreliable due to pathology (presumed arthrofibrosis) and technical problems (pooling of contrast). The arthrofibrosis that developed in many patients inhibited proper joint access and contrast infiltration, although high-quality images were obtained in eleven patients. In this patient subset, in which focal regions of cartilage degeneration could be visualized, thickness could be measured with a high degree of fidelity. While thus useful in selected instances, double-contrast MDCT was too unreliable to be recommended to assess these particular types of injuries.

A method for the estimation of normative bone surface area to aid in objective CT-based fracture severity assessment.

The reliable assessment of fracture severity plays a critical part in treatment, providing essential information to guide clinical decision-making. However, current classification schemes such as the AO/OTA are constrained by limitations intrinsic to subjective categorical systems. A recently developed objective CT-based assessment methodology quantifies fracture severity by calculating the mechanical energy expended during bony fragmentation. Specifically, fracture energy is determined by comparing the bone free surface area in the fractured limb to that in the intact contralateral limb. Unfortunately, the contralateral limb is not routinely scanned in the course of fracture assessment. Consequently, fracture energy can not be obtained, since there is no datum against which to compare the fractured limb. To facilitate the application of this novel technique to large multi-center and retrospective studies where the intact contralateral CT scan is unavailable, this study aimed to establish a normative, anthropometrically scaled intact bone model to be used as a substitute datum. A mathematical model that estimated free bone surface area along the intact contralateral limb was regressed from a study group of 22 tibial plafond fracture patients. The regressed tibia model provided suitably accurate estimates of the directly measured intact surfaces areas (average error of 15%). The differences between regressed and actual bone surface areas did not ultimately affect the stratification of fracture severity, as fracture energy measures using the regressed model maintained a 0.90 concordance with the original analysis. The results from this study suggest that normative bone surface area can be incorporated into the novel CT-based objective fracture severity assessment technique.

Intra-articular contact stress distributions at the ankle throughout stance phase-patient-specific finite element analysis as a metric of degeneration propensity.

A contact finite element (FE) formulation is introduced, amenable to patient-specific analysis of cumulative cartilage mechano-stimulus attributable to habitual functional activity. CT scans of individual human ankles are segmented to delineate bony margins. Each bone surface is projected outward to create a second surface, and the intervening volume is then meshed with continuum hexahedral elements. The tibia is positioned relative to the talus into a weight-bearing apposition. The articular members are first engaged under light preload, then plantar-/dorsi-flexion kinematics and resultant loadings are input for serial FE solutions at 13 instants of the stance phase of level walking gait. Cartilage stress histories are post-processed to recover distributions of cumulative stress-time mechano-stimulus, a metric of degeneration propensity. Consistency in computed contact stress exposures presented for seven intact ankles stood in contrast to the higher magnitude and more focal exposures in an incongruously reduced tibial plafond fracture. This analytical procedure provides patient-specific estimates of degeneration propensity due to various mechanical abnormalities, and it provides a platform from which the mechanical efficacy of alternative surgical interventions can be estimated.