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Biomedical subjects

S S Margulies

Publications and source records attributed to S S Margulies.

At least 19 recordsLinked to original sources
PubMed2001

Keratinocyte growth factor reduces alveolar epithelial susceptibility to in vitro mechanical deformation.

Keratinocyte growth factor (KGF) is a potent mitogen that prevents lung epithelial injury in vivo. We hypothesized that KGF treatment reduces ventilator-induced lung injury by increasing the alveolar epithelial tolerance to mechanical strain. We evaluated the effects of in vivo KGF treatment to rats on the response of alveolar type II (ATII) cells to in vitro controlled, uniform deformation. KGF (5 mg/kg) or saline (no-treatment control) was instilled intratracheally in rats, and ATII cells were isolated 48 h later. After 24 h in culture, both cell groups were exposed to 1 h of continuous cyclic strain (25% change in surface area); undeformed wells were included as controls. Cytotoxicity was evaluated quantitatively with fluorescent immunocytochemistry. There was >1% cell death in undeformed KGF-treated and control groups. KGF pretreatment significantly reduced deformation-related cell mortality to only 2.2 +/- 1.3% (SD) from 49 +/- 5.5% in control wells (P < 0.001). Effects of extracellular matrix, actin cytoskeleton, and phenotype of KGF-treated and control cells were examined. The large reduction in deformation-induced cell death demonstrates that KGF protects ATII cells by increasing their strain tolerance and supports KGF treatment as a potential preventative measure for ventilator-induced lung injury.

Actins↗
PubMed2001

Role of stretch on tight junction structure in alveolar epithelial cells.

Previous studies have demonstrated that high tidal volumes can cause interstitial and alveolar edema, with degradation of pulmonary epithelial barrier integrity. Separate studies have shown that F-actin disruption and decreased intracellular ATP (ATP(i)) levels in the nonpulmonary epithelium can increase tight junction (TJ) permeability. We hypothesized that large epithelial stretch perturbs ATP(i) and actin architecture, each of which adversely affects TJ structure, and thus increases TJ permeability. Primary alveolar epithelial cells were subjected to a uniform 25% or 37% change in surface area (DeltaSA), cyclic biaxial stretch (15 cycles/min) for 1 h, or treated with either glycolytic metabolic inhibitors or cytoskeletal disrupting agents. Unstretched, untreated cells served as controls. Changes in the TJ proteins occludin and ZO-1 were determined by immunocytochemical evaluation. A stretch amplitude of 25% DeltaSA did not produce any significant cytologic changes compared with controls, but an amplitude of 37% DeltaSA stretch resulted in significant decreases in the intensity of the peripheral occludin band, the degree of cell-cell attachment (CCA), and total cellular occludin content. ATP depletion significantly diminished the occludin band intensity and decreased CCA. Actin disruption did not affect TJ protein band intensities (although the occludin distribution became punctate) but altered CCA. Untreated cells stretched cyclically at 25% or 50% DeltaSA for 1 h had significantly decreased ATP(i) compared with unstretched controls. These results suggest that stretch-induced ATP(i) reduction and actin perturbation disrupt TJ structure and CCA, which may lead to the alveolar flooding associated with high tidal volumes.

Actins↗
PubMed2000

Infant skull and suture properties: measurements and implications for mechanisms of pediatric brain injury.

The mechanical properties of the adult human skull are well documented, but little information is available for the infant skull. To determine the age-dependent changes in skull properties, we tested human and porcine infant cranial bone in three-point bending. The measurement of elastic modulus in the human and porcine infant cranial bone agrees with and extends previous published data [McPherson, G. K., and Kriewall, T. J. (1980), J. Biomech., 13, pp. 9-16] for human infant cranial bone. After confirming that the porcine and human cranial bone properties were comparable, additional tensile and three-point bending studies were conducted on porcine cranial bone and suture. Comparisons of the porcine infant data with previously published adult human data demonstrate that the elastic modulus, ultimate stress, and energy absorbed to failure increase, and the ultimate strain decreases with age for cranial bone. Likewise, we conclude that the elastic modulus, ultimate stress, and energy absorbed to failure increase with age for sutures. We constructed two finite element models of an idealized one-month old infant head, one with pediatric and the other adult skull properties, and subjected them to impact loading to investigate the contribution of the cranial bone properties on the intracranial tissue deformation pattern. The computational simulations demonstrate that the comparatively compliant skull and membranous suture properties of the infant brain case are associated with large cranial shape changes, and a more diffuse pattern of brain distortion than when the skull takes on adult properties. These studies are a fundamental initial step in predicting the unique mechanical response of the pediatric skull to traumatic loads associated with head injury and, thus, for defining head injury thresholds for children.

Adult↗
PubMed2000

Dynamic mechanical stretch of organotypic brain slice cultures induces differential genomic expression: relationship to mechanical parameters.

Although the material properties of biological tissues are reasonably well established, recent studies have suggested that the biological response of brain tissue and its constituent cells may also be viscoelastic and sensitive to both the magnitude and rate of a mechanical stimulus. Given the potential involvement of changes in gene expression in the pathogenic sequelae after head trauma, we analyzed the expression of 22 genes related to cell death and survival and found that a number of these genes were differentially regulated after mechanical stretch of an organotypic brain slice culture. Twenty-four hours after stretch, the expression of BDNF, NGF, and TrkA was significantly increased, whereas that of bcl-2, CREB, and GAD65 was significantly decreased (MANOVA followed by ANOVA, p < 0.05). Expression of CREB and GAD65 was negatively correlated with strain, whereas expression of APP695 was negatively correlated with strain rate (all p < 0.05). This study demonstrates that a subset of genes involved in cell death and survival are differentially regulated after dynamic stretch in vitro and that the expression of specific genes is correlated with mechanical parameters of that stretch.

Analysis of Variance↗
PubMed2000

Maturation-dependent response of the piglet brain to scaled cortical impact.

OBJECT: The goal of this study was to investigate the relationship between maturational stage and the brain's response to mechanical trauma in a gyrencephalic model of focal brain injury. Age-dependent differences in injury response might explain certain unique clinical syndromes seen in infants and young children and would determine whether specific therapies might be particularly effective or even counterproductive at different ages. METHODS: To deliver proportionally identical injury inputs to animals of different ages, the authors have developed a piglet model of focal contusion injury by using specific volumes of rapid cortical displacement that are precisely scaled to changes in size and dimensions of the growing brain. Using this model, the histological response to a scaled focal cortical impact was compared at 7 days after injury in piglets that were 5 days, 1 month, and 4 months of age at the time of trauma. Despite comparable injury inputs and stable physiological parameters, the percentage of hemisphere injured differed significantly among ages, with the youngest animals sustaining the smallest lesions (0.8%, 8.4%, and 21.5%, for 5-day-, 1-month-, and 4-month-old animals, respectively, p = 0.0018). CONCLUSIONS: These results demonstrate that, for this particular focal injury type and severity, vulnerability to mechanical trauma increases progressively during maturation. Because of its developmental and morphological similarity to the human brain, the piglet brain provides distinct advantages in modeling age-specific responses to mechanical trauma. Differences in pathways leading to cell death or repair may be relevant to designing therapies appropriate for patients of different ages.

Age Factors↗
PubMed1999

A fiber-reinforced composite model of the viscoelastic behavior of the brainstem in shear.

Brainstem trauma occurs frequently in severe head injury, often resulting in fatal lesions due to importance of brainstem in crucial neural functions. Structurally, the brainstem is composed of bundles of axonal fibers distinctly oriented in a longitudinal direction surrounded by an extracellular matrix. We hypothesize that the oriented structure and architecture of the brainstem dictates this mechanical response and results in its selective vulnerability in rotational loading. In order to understand the relationship between the biologic architecture and the mechanical response and provide further insight into the high vulnerability of this region, a structural and mathematical model was created. A fiber-reinforced composite model composed of viscoelastic fibers surrounded by a viscoelastic matrix was used to relate the biological architecture of the brainstem to its anisotropic mechanical response. Relevant model parameters measured include the brainstem's composite complex moduli and relative fraction of matrix and fiber. The model predicted that the fiber component is three times stiffer and more viscous than the matrix. The fiber modulus predictions were compared with experimental tissue measurements. The optic nerve, a bundle of tightly packed longitudinally arranged myelinated fibers with little matrix, served as a surrogate for the brainstem fiber component. Model predictions agreed with experimental measures, offering a validation of the model. This approach provided an understanding of the relationship between the specific biologic architecture of the brainstem and the anisotropic mechanical response and allowed insight into reasons for the selective vulnerability of this region in rotational head injury.

Animals↗
PubMed1999

Alveolar epithelial surface area-volume relationship in isolated rat lungs.

In vitro studies of the alveolar epithelial response to deformation require knowledge of the in situ mechanical environment of these cells. Because of the presence of tissue folding and crumpling, previous measurements of the alveolar surface area available for gas exchange are not equivalent to the epithelial surface area. To identify epithelial deformations in uniformly inflated lungs representative of the in vivo condition, we studied isolated Sprague-Dawley rat lungs (n = 31) fixed by perfusion with glutaraldehyde on deflation after cycling three times at high lung volume (10-25 cmH2O). The epithelial basement membrane in 45 electron micrographs (x12,000)/rat was traced, digitally scanned, and analyzed. Epithelial basement membrane surface area (EBMSA) was computed from a morphometric relationship. EBMSA was found to increase 5, 16, 12, and 40% relative to EBMSA at 24% total lung capacity at lung volumes of 42, 60, 82, and 100% total lung capacity, respectively. The increases in EBMSA suggest that epithelial cells undergo significant deformations with large inflations and that alveolar basement membrane deformation may contribute to lung recoil at high lung pressures.

Air Pressure↗
PubMed1998

In vivo human cervical spinal cord deformation and displacement in flexion.

STUDY DESIGN: In vivo, quasi-static distortion of the human cervical spinal cord was measured in five volunteers during flexion of the neck using a motion-tracking magnetic resonance imaging technique. OBJECTIVES: To measure cord distortion and movement in living subjects. SUMMARY OF BACKGROUND DATA: In situ spinal cord measurements in human and rhesus monkey cadavers taken at full flexion demonstrate that the entire cervical cord elongates approximately 10% of its length at a neutral position, but no data are available at other angles of flexion, or in living subjects. METHODS: The spatial modulation of magnetization pulse sequence created a series of parallel lines in the image that deform with the tissue. A custom-designed device was built to guide the flexion of the neck and enhance motion reproducibility. Midsagittal plane images were acquired before and after flexion. The tagged line pattern in each pair of magnetic resonance images was compared to compute distortion and movement of the cervical spinal cord at varying degrees of flexion. RESULTS: Between a neutral posture and full flexion, the entire cord (C2-C7) elongated linearly with head flexion, increasing 10% and 6% of its initial length along the posterior and anterior surfaces, respectively. Average displacement was on the order of 1-3 mm, and varied with region. Specifically, the upper cord showed caudad movement in the spinal canal, and the lower cord moved cephalad, again with larger movements on the posterior surface. CONCLUSIONS: The cervical cord elongates and displaces significantly during head flexion in human volunteers, offering valuable information regarding the normal milieu of the cord.

Adult↗
PubMed1998

Material characterization of the brainstem from oscillatory shear tests.

Traumatic damage to the brainstem occurs frequently when the brain skull complex experiences injurious loading especially during those traumatic situations that produce diffuse axonal injury (DAI). DAI has been shown to be dependent on load direction and correlated with regional tissue deformation in response to rotational inertial loads. Possible mechanisms for the selective vulnerability of the brainstem are (1) the geometry of the central nervous system is responsible for producing high tissue strains in these regions, (2) regional differences in overall material stiffness result in larger deformations at these sites, and (3) the anisotropic mechanical properties of these regions lead to a sensitivity to the rotational load direction and magnitude. This paper investigates the latter two hypotheses by performing oscillatory shear tests on adult porcine brainstem in three mutually perpendicular directions. The complex shear moduli were calculated over a range of frequencies (20-200 Hz), for three levels of peak engineering strain (2.5%, 5.0%, and 7.5%). The directional data demonstrated that the brainstem exhibits significant transversely isotropic behavior. Both components of the complex modulus in which the axonal fibers are oriented parallel to the plane of shear but transverse to the shear direction were significantly higher than those of the other two, mutually indistinguishable test cases across the range of strains tested. By comparison with similar tests on cerebral tissue, these data demonstrated that the brainstem displays a stiffer biomechanical response. These differences were present for both components of the complex shear modulus and were greater as the magnitude of the applied strain increased. The regional stiffness and anisotropic response of the brainstem coupled with its location as a narrow bridge between CNS regions interact to result in the selective vulnerability of this region in rotational loading.

Animals↗
PubMed1998

Age-dependent material properties of the porcine cerebrum: effect on pediatric inertial head injury criteria.

During growth and development, the immature central nervous system undergoes rapid alterations in constituents and structure. We hypothesize that these alterations are accompanied by changes in the mechanical properties of brain tissue which, in turn, influence the response of the brain to traumatic inertial loads. Samples of frontal cerebrum from neonatal (2-3 days) and adult pigs were harvested and tested within 3 h post-mortem. The complex shear modulus of the samples was measured in a custom-designed oscillatory shear testing device at engineering shear strain amplitudes of 2.5% or 5% from 20-200 Hz, at 25 degrees C and 100% humidity. In this range, the elastic and viscous components of the complex shear modulus increased significantly with the development of the cerebral region of the brain. Using an idealized model of the developing head, the age-dependent material properties of brain tissue were shown to affect the mechanical response of the brain to inertial loading. This study is a first step toward developing head injury tolerance criteria specifically for the pediatric population.

Aging↗
PubMed1998

Equibiaxial deformation-induced injury of alveolar epithelial cells in vitro.

Deformation of the alveolar epithelial basement membrane with lung inflation has been implicated in blood-gas barrier breakdown during the development of ventilator-induced lung injury. To determine the vulnerability of alveolar epithelial cells to deformation-induced injury, we developed a cell-stretching device that subjects cells to cyclic, equibiaxial strains. Alveolar epithelial type II cells from primary culture were tested 1 and 5 days after seeding, during which time the cells underwent major morphological and phenotypic changes. Cells were subjected to changes in surface area of 12, 24, 37, and 50%, which corresponded to lung inflation of approximately 60, 80, 100, and >100% of total lung capacity. Deformation-induced injury of alveolar epithelial cells, assessed with a fluorescent cell viability assay, increased with deformation magnitude and decreased with time elapsed after seeding. In cells stretched after 1 day in culture, the percentage of dead cells after a single deformation ranged from 0.5 to 72% over the range of deformations used. In cells stretched at 5 days, the percentage of dead cells ranged from 0 to 9% when exposed to identical deformation protocols. These results suggest that morphological and phenotypic changes with time in culture fundamentally change the vulnerability of alveolar epithelial cells to deformation.

Animals↗
PubMed1998

MRI study of regional variations of pharyngeal wall compliance in cats.

Upper airway compliance indicates the potential of the airway to collapse and is relevant to the pathogenesis of obstructive sleep apnea. We hypothesized that compliance would vary over the rostral-to-caudal extent of the pharyngeal airway. In a paralyzed isolated upper airway preparation in cats, we controlled static upper airway pressure during magnetic resonance imaging (MRI, 0.391-mm resolution). We measured cross-sectional area and anteroposterior and lateral dimensions from three-dimensional reconstructed MRIs in axial slices orthogonal to the airway centerline. High-retropalatal (HRP), midretropalatal (MRP), and hypopharyngeal (HYP) regions were defined. Regional compliance was significantly increased from rostral to caudal regions as follows: HRP < MRP < HYP (P < 0.0001), and compliance differences among regions were directly related to collapsibility. Thus our findings in the isolated upper airway of the cat support the hypothesis that regional differences in pharyngeal compliance exist and suggest that baseline regional variations in compliance and collapsibility may be an important factor in the pathogenesis and treatment of obstructive sleep apnea.

Air Pressure↗
PubMed1998

Kinematic response of the neck to voluntary and involuntary flexion.

METHODS: The dynamic head-neck responses of human subjects and cadavers undergoing involuntary impact loading conditions have been studied extensively in order to define the kinematics of the neck undergoing rapid movements, but little detailed information is available regarding slower, voluntary motions. In this study, the dynamic kinematics of head/neck complex during subject-controlled, or voluntary head motion have been investigated to compare with the kinematics to involuntary response. Five male human subjects experienced two-types of posterior/anterior neck flexion: flexion initiated under their own volition, and flexion in response to -15Gx acceleration of the torso. Tri-axial photo target mounts were placed on a custom-fit plate at the mouth, on the first thoracic vertebra, and on the sled. High speed movie cameras captured the photo target motion. Linear and angular displacement and velocity of the head and T1 and sled were computed using customized data-processing software. The neck kinematics were represented by a 2-pin linkage which connected the anatomical origins of the head and T1. RESULTS: The results show that maximum neck flexion relative to the torso was not significantly different between the voluntary and involuntary head motions, but that the head motion was significantly greater during the involuntary sled maneuvers. Maximum flexion velocities of 450 and 1236 degrees x s(-1) were sustained during the voluntary and involuntary maneuvers, respectively. CONCLUSION: These findings are important in understanding the kinematics of the human head/neck complex undergoing rapid and slow movements, and will be valuable in future studies determining a realistic physiological performance corridor for the human neck.

Acceleration↗
PubMed1997

A high-frequency shear device for testing soft biological tissues.

Accurate mechanical property data obtained at large shear deformations and high frequencies are a fundamental component of realistic numerical simulations of soft tissue injury. Although many commercial systems exist for testing shear properties of viscoelastic materials with properties similar to soft biological tissue, none are capable of determining properties at high loading rates necessary for modeling soft tissue injury. Previous custom shear testing systems, though capable of high-frequency loading, indirectly measure tissue properties by using analytical corrections for inertial effects. To address these limitations, a new custom designed oscillatory shear testing apparatus (STA) capable of testing soft biological tissues in simple shear has been constructed and validated. Through a proper selection of sample thickness, direct measurement of material properties at high frequencies is achieved mechanically without analytical inertial adjustments. The complex shear modulus of three mixtures of silicone gel with viscoelastic properties in a range similar to soft biological tissue was characterized in the STA over a dynamic frequency range of 20-200 Hz and validated with a commercially available solids rheometer. The frequency-dependent complex shear modulus measurements of the STA were within 10% of the rheometer measurements for all mixtures over the entire frequency range tested. The STA represents substantive improvement over current shear testing methods by providing direct measurement of the shear behavior of soft viscoelastic material at high frequencies. Mechanical property data gained from this device will provide a more realistic basis for numerical simulations of biological structures.

Brain↗
PubMed1996

Regional ventilation in statically and dynamically hyperinflated dogs.

Using the parenchymal marker technique in normal anesthetized dogs, we compared the dynamics of regional lung expansion between two ventilation strategies designed to increase mean thoracic volume. Dynamic hyperinflation (DH was produced by ventilating the lungs at a rate of 50 breaths/min and with a duty cycle of 0.5. Static hyperinflation (SH) was produced through the application of extrinsic positive end-expiratory pressure while the lungs were ventilated at a rate of 15 breaths/min and with a duty cycle of 0.15. Regional tidal volume (VT,r), regional functional residual volume, and the time delay between regional expansion and the flow signal at the common airway were computed for up to 100 regions/lobe in 5 animals. Ventilation strategy had no effect on the overall variance of VT,r within lobes. Although the VT,r measured during SH correlated with VT,r measured during DH, the average correlation coefficient was only 0.69. Ventilation rate-related differences in VT,r and regional functional residual capacity varied with the regional time delay in ways qualitatively consistent with parallel inhomogeneity of unit time constants. However, a large component of frequency-dependent behavior remains unexplained by established mechanisms. We conclude that DH and SH should not be considered equivalent lung unit recruitment strategies.

Animals↗
PubMed1996

Zone of apposition in the passive diaphragm of the dog.

We determined the regional area of the diaphragmatic zone of apposition (ZAP) as well as the regional craniocaudal extent of the ZAP (ZAPht) of the passive diaphragm in six paralyzed anesthetized beagle dogs (8-12 kg) at residual lung volume (RV), functional residual capacity (FRC), FRC + 0.25 and FRC + 0.5 inspiratory capacity, and total lung capacity (TLC) in prone and supine postures. To identify the caudal boundary of the ZAP, 17 lead markers (1 mm) were sutured to the abdominal side of the costal and crural diaphragms around the diaphragm insertion on the chest wall. Two weeks later, the dogs' caudal thoraces were scanned by the use of the dynamic spatial reconstructor (DSR), a prototype fast volumetric X-ray computer tomographic scanner, developed at the Mayo Clinic. The three-dimensional spatial coordinates of the markers were identified (+/- 1.4 mm), and the cranial boundary of the ZAP was determined from 30-40 1.4-mm-thick sagittal and coronal slices in each DSR image. We interpolated the DSR data to find the position of the cranial and caudal boundaries of the ZAP every 5 degrees around the thorax and computed the distribution of regional variation of area of the ZAP and ZAPht as well as the total area of ZAP. The ZAPht and area of ZAP increased as lung volume decreased and were largest near the lateral extremes of the rib cage. We measured the surface area of the rib cage cephaled to the ZAP (AL) in both postures in another six beagle dogs (12-16 kg) of similar stature, scanned previously in the DSR. We estimated the entire rib cage surface area (Arc = AZAP + AL). The AZAP as a percentage of Arc increased more than threefold as lung volume decreased from TLC to RV, from approximately 9 to 29% of Arc.

Anesthesia, General↗
PubMed1994

Finite-element analysis of stress in the canine diaphragm.

Stress in the diaphragm, transdiaphragmatic pressure, and diaphragm shape are interrelated by a balance of forces. Using precise in vivo measurements of diaphragm shape and transdiaphragmatic pressure distribution in combination with finite-element analysis (ANSYS), we determined the direction and magnitude of stress in the passive diaphragm at relaxation volume. Lead spheres sutured along muscle bundles identified muscle bundle location and orientation in vivo. The x, y, and z coordinates of the lead spheres and entire surface of the diaphragm, excluding the zone of apposition, were determined to within 1.4 mm. Thin shell elements were used to construct a finite-element model of the diaphragm with a 2.1- to 4.2-mm internodal spacing. The diaphragm was assumed to have a uniform thickness of 2.5 mm, and magnitude and direction of the principal stresses were computed. The results show that 1) diaphragm stress is nonuniform and anisotropic (i.e., varies both with location on diaphragm surface and direction examined), 2) largest stress (sigma 1) is aligned with muscle bundles and is two to four times larger than sigma 2 (perpendicular to sigma 1 in diaphragm plane), and 3) stress along the muscle bundles is larger in vivo under conditions of biaxial stress than at same length in vitro under uniaxial stress. Although diaphragm stress and tension have often been assumed to be uniform, our finding that stress is oriented primarily along the muscle fibers should be considered in future models of the diaphragm.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗