Biomedical subjects

D F Meaney

Publications and source records attributed to D F Meaney.

31 records · Page 2Linked to original sources

PubMed1998

In vitro central nervous system models of mechanically induced trauma: a review.

Injury is one of the leading causes of death among all people below the age of 45 years. In the United States, traumatic brain injury (TBI) and spinal cord injury (SCI) together are responsible for an estimated 90,000 disabled persons annually. To improve treatment of the patient and thereby decrease the associated mortality, morbidity, and cost, several in vivo models of central nervous system (CNS) injury have been developed and characterized over the past two decades. To complement the ability of these in vivo models to reproduce the sequelae of human CNS injury, in vitro models of neuronal injury have also been developed. Despite the inherent simplifications of these in vitro systems, many aspects of the posttraumatic sequelae are faithfully reproduced in cultured cells, including ultrastructural changes, ionic derangements, alterations in electrophysiology, and free radical generation. This review presents a number of these in vitro systems, detailing the mechanical stimuli, the types of tissue injured, and the in vivo injury conditions most closely reproduced by the models. The data generated with these systems is then compared and contrasted with data from in vivo models of CNS injury. We believe that in vitro models of mechanical injury will continue to be a valuable tool to study the cellular consequences and evaluate the potential therapeutic strategies for the treatment of traumatic injury of the CNS.

Adult↗

PubMed1997

Characterization of diffuse axonal pathology and selective hippocampal damage following inertial brain trauma in the pig.

Dynamic deformation applied to white matter tracts is a common feature of human brain trauma, and may result in diffuse axonal injury (DAI). To produce DAI in an experimental model, we have utilized nonimpact inertial loading to induce brain trauma in miniature swine. This species was chosen due to its large gyrencephalic brain with substantial white matter domains. Twenty anesthetized (2% isoflurane) miniature swine were subjected to pure impulsive centroidal rotation 110 degrees in the coronal plane in 4 to 6 ms; peak accelerations ranged from 0.6 to 1.7 x 10(5) rad/s2. Seven days following injury, the brains were fixed (4% paraformaldehyde). Histopathologic examination was performed on 40 microns sections stained with cresyl violet (Nissl), antibodies targeting neurofilament (axonal damage), GFAP (astrocytes), and pig IgG (protein extravasation). Widespread multifocal axonal injury was observed in combination with gliosis throughout the brain, most commonly in the root of gyri and at the interface of the gray and white matter. Very little vascular disruption was noted in regions of axonal injury. Neuronal damage was primarily found in the CA1 and CA3 subfields of the hippocampus. These results suggest that this model is clinically relevant and useful for evaluating mechanisms of inertial brain trauma.

Animals↗

PubMed1996

Neuropathological sequelae of traumatic brain injury: relationship to neurochemical and biomechanical mechanisms.

Brain injury is the leading cause of death among individuals under the age of 45 years in the United States and Europe. Recently, the neuropathologic classification of posttraumatic brain damage has provided insight into the specific mechanisms underlying traumatically induced neuronal damage and death. Studies regarding the biomechanics of brain trauma have also provided great insight into the pathophysiologic mechanisms underlying specific patterns of posttraumatic cellular death. Based upon recent clinical evaluations and biomechanical studies, laboratory models of human brain injury have been developed that faithfully reproduce a number of important features of clinical brain trauma. Biomechanical models have been used to study both the acute sequelae of brain injury and the role of neurochemical alterations in contributing to the development of secondary or delayed cellular death and damage. This report reviews and integrates the laboratory investigations linking experimental models of brain injury to clinical diagnosis and treatment.

Animals↗

PubMed1995

A model of parasagittal controlled cortical impact in the mouse: cognitive and histopathologic effects.

Controlled cortical impact (CCI), using a pneumatically driven impactor to produce traumatic brain injury, has been characterized previously in both the ferret and in the rat. In the present study, we applied this technique to establish and characterize the CCI model of brain injury in another species, the mouse, evaluating cognitive and histopathologic outcome. In anesthetized (sodium pentobarbital, 65 mg/kg) male C57BL mice, we performed sham treatment (no injury, n = 12) or CCI injury (n = 12) at a velocity of 5.7-6.2 m/sec and depth of 1 mm, using a 3-mm diameter rounded-tip impounder, positioned over the left parietotemporal cortex (parasagittal). At this level of injury, we observed highly significant deficits in memory retention of a Morris water maze task 2 days following injury (p < 0.001). Postmortem histopathologic analysis performed at 48 h following injury revealed substantial cortical tissue loss in the region of impact and selective hippocampal neuronal cell loss in the CA2, CA3, and CA3c regions, using Nissl staining. Analysis of degenerating neurons using modified Gallyas silver staining techniques demonstrated consistent ipsilateral injury of neurons in the cortex adjacent to the impact site and in the dentate gyrus of the ipsilateral hippocampus. Bilateral degeneration was observed at the gray matter-white matter interface along the corpus callosum. Glial fibrillary acidic protein (GFAP) immunohistochemistry revealed extensive reactive gliosis appearing diffusely through the bilateral cortices, hippocampi, and thalami at 48 h postinjury. Breakdown of the blood-brain barrier was demonstrated with antimouse IgG immunohistochemistry, revealing extravasation of endogenous IgG throughout the ipsilateral cortex, hippocampus, and thalamus. These results suggest that this new model of parasagittal CCI in the mouse mimics a number of well-established sequelae observed in previously characterized brain injury models using other rodent species. This mouse model may be a particularly useful experimental tool for comparing behavioral and histopathologic characteristics of traumatic brain injury in wild-type and genetically altered mice.

Animals↗

PubMed1995

New magnetic resonance imaging techniques for the evaluation of traumatic brain injury.

Although current computerized tomography (CT) and magnetic resonance imaging (MRI) techniques have shown great utility in diagnosing various aspects traumatic brain injury, damage resulting from mild diffuse brain injury often goes undetected with these procedures. Newly developed MRI techniques, including magnetization transfer imaging (MTI) and diffusion-weighted imaging (DWI), have been proposed to have enhanced sensitivities for identifying damage induced by both diffuse and focal brain injury. Results from recent initial studies with experimental models of brain injury suggest that MTI may be useful for evaluating diffuse white matter damage, while DWI may demonstrate regions of focal contusion more acutely and with greater accuracy than conventional MRI procedures.

Brain Injuries↗

PubMed1995

Biomechanical analysis of experimental diffuse axonal injury.

The purpose of this paper is to present results from methodologies used in our laboratory that are targeted toward identifying specific brain injury thresholds. Results from studying one form of brain injury, diffuse axonal injury, are presented in this report. Physical models, or surrogates, of the skull-brain complex are used to estimate the relationship between inertial loading and brain deformation. A porcine model of diffuse axonal injury, developed with information from these physical models and earlier in vitro tissue modeling studies, is used to correlate histologic and radiologic evidence of axonal injury to predicted regions of injury from the experimental and theoretical analysis. These results form the basis for developing improved diffuse brain injury tolerance levels, as well as identifying new means of diagnostic and treatment techniques for diffuse axonal injury.

Animals↗

PubMed1995

1995 William J. Stickel Gold Award. High strain rate tissue deformation. A theory on the mechanical etiology of diabetic foot ulcerations.

Foot ulcerations are one of the most common and dangerous complications associated with chronic diabetes mellitus. Many studies have focused on neuropathy, in conjunction with elevated ground reactive forces, as the principal cause of these ulcerations. The authors discuss the mechanical cause of diabetic ulcerations at the cellular level. It is hypothesized that increased rate of tissue deformation associated with foot slap secondary to progressive motor neuropathy is the actual culprit, and not the magnitude of local pressure applied. The authors present a cellular model that shows that high rates of tissue deformation may result in elevated intracellular calcium concentrations, which may lead to cellular death, while comparable loads gradually applied do not. Furthermore, there is no significant difference in the response observed at 5 psi and 10 psi. Based on these findings, it is hypothesized that techniques such as ankle foot orthoses, which control the velocity of foot strike, may be useful in treating diabetic foot ulcerations.

Awards and Prizes↗

PubMed1995

Mechanical properties of implantable biomaterials.

This chapter was intended to review many of the terms used to describe the behavior of biomaterials including linear elastic, plastic, and viscoelastic behavior. Common testing methods for evaluating the behavior of biomaterials were also reviewed. Uniaxial loading, perhaps the most common testing procedure, can characterize both time-independent (i.e., linear elastic and plastic) and time-dependent (viscoelastic) materials with a controlled loading condition. Bending tests, because of their ease, are also popular and can describe linear elastic and plastic behavior fairly well. Vibratory methods to measure viscoelastic behavior, on the other hand, are less popular but are essential if the expected loading condition of the biomaterial will be fairly rapid. Taken together, these tests form the foundation for understanding the applicability of a specific material for use as an implant, and can be used to predict not only the failure thresholds for the implant but also the expected remodeling response of the bone once the implant has been placed in situ. For this reason, characterizing the mechanical properties of implant materials has been and will continue to be an important step in implant design.

Biocompatible Materials↗

PubMed1994

Distribution of forebrain diffuse axonal injury following inertial closed head injury in miniature swine.

Diffuse axonal injury (DAI) is one of the most frequently encountered types of brain damage resulting from closed head injury. This study was designed to verify whether DAI could be produced in miniature swine by rapid acceleration and deceleration of the head in the coronal plane. Hanford miniature swine (16-19 kg) were anesthetized with 3% isoflurane and their heads accelerated rapidly once through a 60-105 degrees arc in the coronal plane, producing only transient post-traumatic unconsciousness without prolonged coma. All animals made a good recovery and were sacrificed between 6 h and 10 days after injury. The response of forebrain projection systems to this injury was studied using neurofilament immunohistochemistry with antisera to nonphosphorylated (SMI-32) and phosphorylated (SMI-31) epitopes common to heavy (200 kDa) and medium (160 kDa) neurofilament proteins. In 9 of 12 animals, lesions characterized by foci of SMI-32 positive axonal retraction balls were present at the white matter/gray matter junction at the crests of gyri in the dorsolateral regions of the frontal, parietal, and temporal cortices and along margins of the lateral ventricles. A high density of pyramidal neuron perikarya in layers III and V within cortical gyri associated with subcortical DAI were intensely positive for SMI-31 immunohistochemistry. These results validate the use of miniature swine in studies of axonal injury and demonstrate that axonal injury analogous to that seen in the mildest form of DAI (grade I) can be produced in these animals without producing prolonged coma.

Animals↗

PubMed1994

Modification of the cortical impact model to produce axonal injury in the rat cerebral cortex.

Diffuse axonal injury (DAI) is a form of brain injury that is characterized by morphologic changes to axons throughout the brain and brainstem. Previous biomechanical studies have shown that primary axonal dysfunction, ranging from minor electrophysiologic disturbances to immediate axotomy, can be related to the rate and level of axonal deformation. Some existing rodent head injury models display varying degrees of axonal injury in the forebrain and brainstem, but the extent of axonal damage in the forebrain has been limited to the contused hemisphere. This study examined whether opening the dura mater over the contralateral hemisphere could direct mechanical deformation across the sagittal midline and produce levels of strain sufficient to cause a more widespread, bilateral forebrain axonal injury following cortical impact. Intracranial deformation patterns produced by this modified cortical impact technique were examined using surrogate skull-brain models. Modeling results revealed that the presence of a contralateral craniotomy significantly reduced surrogate tissue herniation through the foramen magnum, allowed surrogate tissue movement across the sagittal midline, and resulted in an appreciable increase in the shear strain in the contralateral cortex during the impact. To evaluate the injury pattern produced using this novel technique, rat brains were subjected to rigid indentor impact injury of their left somatosensory motor cortex (1.5 mm indentation, 4.5-4.9 m/sec velocity, and 22 msec dwell time) and examined after a 2-7 day survival period. Neurofilament immunohistochemistry revealed numerous axonal retraction balls in the subcortical white matter and overlying deep cortical layers in the right hemisphere beneath the contralateral craniotomy. Retraction balls were not seen at these positions in normals, sham controls, or animals that received cortical impact without contralateral craniotomy and dural opening. The results from these physical modeling and animal experiments indicate that opening of the contralateral dura mater permits translation of sufficient mechanical deformation across the midline to produce a more widespread pattern of axonal injury in the forebrain, a pattern that is distinct from those produced by existing fluid percussion and cortical impact techniques.

Animals↗

PubMed1992

Biomechanical aspects of a fluid percussion model of brain injury.

The fluid percussion model is in widespread use for the study of brain injury. However, the tissue deformation characteristics of the model have not been determined. Studies have suggested that at high levels of fluid percussion, the fluid percussion model is primarily a model of brainstem injury. It was proposed that this occurs as a direct result of the volume influx to the cranial vault at the moment of impact. This study examines the biomechanical deformation produced by the fluid percussion model. The purpose of this investigation was to describe the regional strain distribution in brain tissue at the moment of impact and to determine the effect of volume efflux produced by the percussion device. A cat skull was sectioned parasagittally and filled with an optically transparent gel. A grid pattern was painted in the midsagittal plane and was used to record the surrogate brain tissue deformation in response to fluid percussion loading. Motion of the grid pattern at low and high levels of fluid percussion loading was recorded using a high-speed camera, and a series of photographs developed from the high-speed film were analyzed to determine the intracranial strain distribution at these loading levels. The results of these studies indicated that the maximum site of strain was located in the region of the lower brainstem and that deformations were negligible in other regions of the brain. These studies provide an explanation for the pathophysiologic results obtained in a parallel series of experiments from which it was concluded that high-level fluid percussion is predominantly a model of lower brainstem injury.

Animals↗

PubMedDate not supplied

Magnetization transfer imaging of diffuse axonal injury following experimental brain injury in the pig: characterization by magnetization transfer ratio with histopathologic correlation.

PURPOSE: Our goal was to evaluate the use of the magnetization transfer ratio (MTR) in the detection of diffuse axonal injury (DAI) resulting from traumatic brain injury in a swine model. METHOD: DAI was created by applying a nonimpact, coronal plane, rotational acceleration to the heads of miniature swine (n = 4). GE imaging was performed with and without off-resonance MT saturation. Histologic correlation of axonal injury with MRI was performed 7 days postinjury. Thirty-one subcortical white matter regions and 10 deep white matter regions were selected for the direct comparison of histologic data and MTR measurements. RESULTS: Nineteen of 41 examined locations exhibited histologic evidence of axonal injury. The mean MTR in regions with axonal damage was significantly less than in regions without axonal damage. These changes were observed both in regions demonstrating high signal intensity on T2-weighted images (T2WI) (p <0.0001, n = 6) and in regions with no signal intensity change on T2WI (p < 0.05, n = 13). CONCLUSION: These results suggest that the measurement of MTR may have the potential for evaluation axonal damage in DAI following traumatic brain injury even when conventional T2WI does not demonstrate the lesion.

Animals↗

PubMedDate not supplied

Mechanical characterization of an in vitro device designed to quantitatively injure living brain tissue.

Due to the nonlinear, viscoelastic material properties of brain, its mechanical response is dependent upon its total strain history. Therefore, a low strain rate, large strain will likely produce a tissue injury unique from that due to a high strain rate, moderate strain. Due to a lack of current understanding of specific in vivo physiological injury mechanisms, a priori assumptions cannot be made that a low strain rate injury induced by currently employed in vitro injury devices is representative of clinical, nonimpact, inertial head injuries. In the present study, an in vitro system capable of mechanically injuring cultured tissue at high strain rates was designed and characterized. The design of the device was based upon existing systems in which a clamped membrane, on which cells have been cultured, is deformed. However, the present system incorporates three substantial improvements: (1) noncontact measurement of the membrane deflection during injury; (2) precise and independent control over several characteristics of the deflection; and (3) generation of mechanical insults over a wide range of strains (up to 0.65) and strain rates (up to 15 s[-1]). Such a system will be valuable in the elucidation of the mechanisms of mechanical trauma and determination of injury tolerance criteria on a cellular level utilizing appropriate mechanical injury parameters.

Brain Injuries↗