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1.
Artigo em Inglês | MEDLINE | ID: mdl-34413579

RESUMO

Sophisticated three-dimensional microstructures fabricated using the negative tone SU-8 photoresist are used in many biomedical and microfluidic applications. Scanning electron microscopy (SEM) and profilometry are commonly used metrological techniques for the dimensional characterization of fabricated SU-8 microstructures but are not viable for non-destructive measurements and characterization of subsurface features like hidden microchannels. In this study, we report a unique methodology for the non-destructive dimensional characterization of SU-8 microstructures using the emitted autofluorescence radiation from fabricated SU-8 microstructures to generate depth profiles. The relationship between autofluorescence emission intensities and the thicknesses of the microstructures measured using SEM was determined and used to characterize the dimensions of unknown SU-8 microstructures based on their autofluorescence intensities. Lateral dimensions were also measured. This relationship was used to create highly accurate depth profiles for different types of microstructures including hidden subsurface features. These results were validated by comparison with SEM. The results suggest a feasible and accurate non-destructive, low cost, metrological technique to characterize SU-8 surface and subsurface microstructures using autofluorescence emission intensities.

2.
J Neural Eng ; 18(4)2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-33984848

RESUMO

Objective.Our laboratory has proposed chemical stimulation of retinal neurons using exogenous glutamate as a biomimetic strategy for treating vision loss caused by photoreceptor (PR) degenerative diseases. Although our previousin-vitrostudies using pneumatic actuation indicate that chemical retinal stimulation is achievable, an actuation technology that is amenable to microfabrication, as needed for anin-vivoimplantable device, has yet to be realized. In this study, we sought to evaluate electroosmotic flow (EOF) as a mechanism for delivering small quantities of glutamate to the retina. EOF has great potential for miniaturization.Approach.An EOF device to dispense small quantities of glutamate was constructed and its ability to drive retinal output tested in anin-vitropreparation of PR degenerate rat retina.Main results.We built and tested an EOF microfluidic system, with 3D printed and off-the-shelf components, capable of injecting small volumes of glutamate in a pulsatile fashion when a low voltage control signal was applied. With this device, we produced excitatory and inhibitory spike rate responses in PR degenerate rat retinae. Glutamate evoked spike rate responses were also observed to be voltage-dependent and localized to the site of injection.Significance.The EOF device performed similarly to a previously tested conventional pneumatic microinjector as a means of chemically stimulating the retina while eliminating the moving plunger of the pneumatic microinjector that would be difficult to miniaturize and parallelize. Although not implantable, the prototype device presented here as a proof of concept indicates that a retinal prosthetic based on EOF-driven chemical stimulation is a viable and worthwhile goal. EOF should have similar advantages for controlled dispensing of charged neurochemicals at any neural interface.


Assuntos
Eletro-Osmose , Retina , Animais , Biomimética , Ácido Glutâmico , Células Fotorreceptoras , Ratos
3.
Adv Mater ; 33(25): e2100026, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33984170

RESUMO

Recently developed methods for transforming 2D patterns of thin-film materials into 3D mesostructures create many interesting opportunities in microsystems design. A growing area of interest is in multifunctional thermal, electrical, chemical, and optical interfaces to biological tissues, particularly 3D multicellular, millimeter-scale constructs, such as spheroids, assembloids, and organoids. Herein, examples of 3D mechanical interfaces are presented, in which thin ribbons of parylene-C form the basis of transparent, highly compliant frameworks that can be reversibly opened and closed to capture, envelop, and mechanically restrain fragile 3D tissues in a gentle, nondestructive manner, for precise measurements of viscoelastic properties using techniques in nanoindentation. Finite element analysis serves as a design tool to guide selection of geometries and material parameters for shape-matching 3D architectures tailored to organoids of interest. These computational approaches also quantitate all aspects of deformations during the processes of opening and closing the structures and of forces imparted by them onto the surfaces of enclosed soft tissues. Studies of cerebral organoids by nanoindentation show effective Young's moduli in the range from 1.5 to 2.5 kPa depending on the age of the organoid. This collection of results suggests broad utility of compliant 3D mesostructures in noninvasive mechanical measurements of millimeter-scale, soft biological tissues.

4.
Sci Adv ; 7(12)2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33731359

RESUMO

Three-dimensional (3D), submillimeter-scale constructs of neural cells, known as cortical spheroids, are of rapidly growing importance in biological research because these systems reproduce complex features of the brain in vitro. Despite their great potential for studies of neurodevelopment and neurological disease modeling, 3D living objects cannot be studied easily using conventional approaches to neuromodulation, sensing, and manipulation. Here, we introduce classes of microfabricated 3D frameworks as compliant, multifunctional neural interfaces to spheroids and to assembloids. Electrical, optical, chemical, and thermal interfaces to cortical spheroids demonstrate some of the capabilities. Complex architectures and high-resolution features highlight the design versatility. Detailed studies of the spreading of coordinated bursting events across the surface of an isolated cortical spheroid and of the cascade of processes associated with formation and regrowth of bridging tissues across a pair of such spheroids represent two of the many opportunities in basic neuroscience research enabled by these platforms.

5.
Transl Neurosci ; 12(1): 76-82, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33623714

RESUMO

This study investigated dietary supplementation as a prophylactic for neuroinflammation following traumatic brain injury (TBI) in a preclinical model. Adult male Sprague-Dawley rats received 30 days of supplementation with either water or two dietary supplements. The first consisted of high-dose omega-3 fatty acid (O3FA) (supplement A) along with vitamin D3 and vitamin E. The second had the same ingredients at different doses with an addition of cannabidiol (supplement B). Rats were subjected to an impact TBI and then euthanized 7 days post-injury and neuroinflammation quantified by histological detection of glial fibrillary acidic protein (GFAP), a marker of astrocyte activation, and CD68, a marker of microglial activity. There was a trend toward increased GFAP staining in injured, unsupplemented animals as compared to sham, unsupplemented animals, consistent with increased activation of astrocytes in response to trauma which was reversed by supplement A but not by supplement B. The pattern of CD68 staining across groups was similar to that of GFAP staining. There was a trend toward an increase in the injured unsupplemented group, relative to sham which was reversed by supplement A but not by supplement B. CD68 staining in injured animals was concentrated in the perivascular domain. The consistency between trends across different measures of neuroinflammation showing benefits of high-dose O3FA supplementation following TBI suggests that the observed effects are real. These findings are preliminary, but they justify further study to determine the functional benefits associated with improvements in histological outcomes and understand associated dose-response curves.

6.
ASN Neuro ; 12: 1759091420922929, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32403948

RESUMO

There is a critical need for understanding the progression of neuropathology in blast-induced traumatic brain injury using valid animal models to develop diagnostic approaches. In the present study, we used diffusion imaging and magnetic resonance (MR) morphometry to characterize axonal injury in white matter structures of the rat brain following a blast applied via blast tube to one side of the brain. Diffusion tensor imaging was performed on acute and subacute phases of pathology from which fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity were calculated for corpus callosum (CC), cingulum bundle, and fimbria. Ventricular volume and CC thickness were measured. Blast-injured rats showed temporally varying bilateral changes in diffusion metrics indicating persistent axonal pathology. Diffusion changes in the CC suggested vasogenic edema secondary to axonal injury in the acute phase. Axonal pathology persisted in the subacute phase marked by cytotoxic edema and demyelination which was confirmed by ultrastructural analysis. The evolution of pathology followed a different pattern in the cingulum bundle: axonal injury and demyelination in the acute phase followed by cytotoxic edema in the subacute phase. Spatially, structures close to midline were most affected. Changes in the genu were greater than in the body and splenium; the caudal cingulum bundle was more affected than the rostral cingulum. Thinning of CC and ventriculomegaly were greater only in the acute phase. Our results reveal the persistent nature of blast-induced axonal pathology and suggest that diffusion imaging may have potential for detecting the temporal evolution of blast injury.


Assuntos
Traumatismos por Explosões/diagnóstico por imagem , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Corpo Caloso/diagnóstico por imagem , Imagem de Tensor de Difusão/métodos , Substância Branca/diagnóstico por imagem , Animais , Traumatismos por Explosões/complicações , Lesões Encefálicas Traumáticas/etiologia , Masculino , Ratos , Ratos Sprague-Dawley
7.
J Neurophysiol ; 122(3): 1174-1185, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31116639

RESUMO

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of upper and lower motor neurons, which manifests clinically as progressive weakness. Although several epidemiological studies have found an association between traumatic brain injury (TBI) and ALS, there is not a consensus on whether TBI is an ALS risk factor. It may be that it can cause ALS in a subset of susceptible patients, based on a history of repetitive mild TBI and genetic predisposition. This cannot be determined based on clinical observational studies alone. Better preclinical models are necessary to evaluate the effects of TBI on ALS onset and progression. To date, only a small number of preclinical studies have been performed, mainly in the superoxide dismutase 1 transgenic rodents, which, taken together, have mixed results and notable methodological limitations. The more recent incorporation of additional animal models such as Drosophila flies, as well as patient-induced pluripotent stem cell-derived neurons, should facilitate a better understanding of a potential functional interaction between TBI and ALS.


Assuntos
Esclerose Amiotrófica Lateral , Concussão Encefálica , Proteínas de Ligação a DNA , Células-Tronco Pluripotentes Induzidas , Superóxido Dismutase-1 , Esclerose Amiotrófica Lateral/etiologia , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/fisiopatologia , Animais , Concussão Encefálica/complicações , Concussão Encefálica/metabolismo , Concussão Encefálica/fisiopatologia , Humanos
8.
Clin Biomech (Bristol, Avon) ; 64: 114-121, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-29449041

RESUMO

BACKGROUND: Traumatic brain injury poses an enormous clinical challenge. Rats are the animals most widely used in pre-clinical experiments. Biomechanical simulations of these experiments predict the distribution of mechanical stress and strain across key tissues. It is in theory possible to dramatically increase our understanding of traumatic brain injury pathophysiology by correlating stress and strain with histological and functional injury outcomes. This review summarizes the state of the art in biomechanical simulation of traumatic brain injury in the rat. It also places this body of knowledge in the context of the wider effort to understand traumatic brain injury in rats and in humans. METHODS: Peer-reviewed research articles on biomechanical simulation of traumatic brain injury in the rat were reviewed and summarized. FINDINGS: When mathematical models of traumatic brain injury in the rat first emerged, they relied on scant data regarding biomechanical properties. The data on relevant biomechanical properties has increased recently. However, experimental models of traumatic brain injury in the rat have also become less homogeneous. New and modified models have emerged that are biomechanically distinct from traditional models. INTERPRETATION: Important progress in mathematical modeling and measurement of biomechanical properties has led to credible, predictive simulations of traditional, experimental models of traumatic brain injury in the rat, such as controlled cortical impact. However, recent trends such as the increasing popularity of closed head models and blast models create new biomechanical challenges. Investigators studying rat brain biomechanics must continue to innovate to keep pace with these developments.


Assuntos
Fenômenos Biomecânicos , Lesões Encefálicas Traumáticas/fisiopatologia , Animais , Simulação por Computador , Modelos Animais de Doenças , Análise de Elementos Finitos , Cabeça , Humanos , Modelos Teóricos , Ratos , Estresse Mecânico
9.
J Neurosci Methods ; 312: 154-161, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30529411

RESUMO

BACKGROUND: Unbiased screening studies have repeatedly identified actin-related proteins as one of the families of proteins most influenced by neurotrauma. Nevertheless, the status quo model of cytoskeletal reorganization after neurotrauma excludes actin and incorporates only changes in microtubules and intermediate filaments. Actin is excluded in part because it is difficult to image with conventional techniques. However, recent innovations in fluorescent microscopy provide an opportunity to image the actin cytoskeleton at super-resolution resolution in living cells. This study applied these innovations to an in vitro model of neurotrauma. NEW METHOD: New methods are introduced for traumatizing neurons before imaging them with high speed structured illumination microscopy or lattice light sheet microscopy. Also, methods for analyzing structured illumination microscopy images to quantify post-traumatic neurite dystrophy are presented. RESULTS: Human induced pluripotent stem cell-derived neurons exhibited actin organization typical of immature neurons. Neurite dystrophy increased after trauma but was not influenced by jasplakinolide treatment. The F-actin content of dystrophies varied greatly from one dystrophy to another. COMPARISON WITH EXISTING METHODS: In contrast to fixation dependent methods, these methods capture the evolution of the actin cytoskeleton over time in a living cell. In contrast to prior methods based on counting dystrophies, this quantification scheme parameterizes the severity of a given dystrophy as it evolves from a local swelling to an almost-perfect spheroid that threatens to transect the neurite. CONCLUSIONS: These methods can be used to investigate genetic factors and therapeutic interventions that modulate the course of neurite dystrophy after trauma.


Assuntos
Lesões Encefálicas/diagnóstico por imagem , Microscopia de Fluorescência/instrumentação , Microscopia de Fluorescência/métodos , Neuritos/patologia , Neurônios/patologia , Citoesqueleto de Actina/patologia , Lesões Encefálicas/patologia , Humanos , Células-Tronco Pluripotentes Induzidas
10.
J Alzheimers Dis ; 65(4): 1055-1064, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30149456

RESUMO

Functional outcomes after traumatic brain injury (TBI) vary widely across patients with apparently similar injuries. This variability hinders prognosis, therapy, and clinical innovation. Recently, single nucleotide polymorphism (SNPs) that influence outcome after TBI have been identified. These discoveries create opportunities to personalize therapy and stratify clinical trials. Both of these changes would propel clinical innovation in the field. This review focuses on one of most well-characterized of these SNPs, the Val66Met SNP in the brain-derived neurotrophic factor (BDNF) gene. This SNP influences neurological function in healthy subjects as well as TBI patients and patients with similar acute insults to the central nervous system. A host of other patient-specific factors including ethnicity, age, gender, injury severity, and post-injury time point modulate this influence. These interactions confound efforts to define a simple relationship between this SNP and TBI outcomes. The opportunities and challenges associated with personalizing TBI therapy around this SNP and other similar SNPs are discussed in light of these results.


Assuntos
Lesões Encefálicas Traumáticas/complicações , Fator Neurotrófico Derivado do Encéfalo/genética , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/genética , Polimorfismo de Nucleotídeo Único/genética , Lesões Encefálicas Traumáticas/terapia , Humanos , Medicina de Precisão/métodos
11.
J Vis Exp ; (134)2018 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-29733307

RESUMO

Traumatic brain injury (TBI) is a major clinical challenge with high morbidity and mortality. Despite decades of pre-clinical research, no proven therapies for TBI have been developed. This paper presents a novel method for pre-clinical neurotrauma research intended to complement existing pre-clinical models. It introduces human pathophysiology through the use of human induced pluripotent stem cell-derived neurons (hiPSCNs). It achieves loading pulse duration similar to the loading durations of clinical closed head impact injury. It employs a 96-well format that facilitates high throughput experiments and makes efficient use of expensive cells and culture reagents. Silicone membranes are first treated to remove neurotoxic uncured polymer and then bonded to commercial 96-well plate bodies to create stretchable 96-well plates. A custom-built device is used to indent some or all of the well bottoms from beneath, inducing equibiaxial mechanical strain that mechanically injures cells in culture in the wells. The relationship between indentation depth and mechanical strain is determined empirically using high speed videography of well bottoms during indentation. Cells, including hiPSCNs, can be cultured on these silicone membranes using modified versions of conventional cell culture protocols. Fluorescent microscopic images of cell cultures are acquired and analyzed after injury in a semi-automated fashion to quantify the level of injury in each well. The model presented is optimized for hiPSCNs but could in theory be applied to other cell types.


Assuntos
Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Neurais/citologia , Neurônios/citologia , Técnicas de Cultura de Células/métodos , Humanos , Microscopia de Fluorescência , Estresse Mecânico
12.
Otol Neurotol ; 38(8): 1205-1212, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28692592

RESUMO

HYPOTHESIS: Internal jugular vein (IJV) compression influences not only intracranial but also intracochlear physiology and has demonstrated preclinical effectiveness in reducing acute audiological injury in a rodent blast model. However, the long-term effects in this model are unknown. BACKGROUND: Blast wave-induced audiological injury from an improvised explosive device is a leading cause of morbidity among service members in theater but there are limitations to the current protective measures. METHODS: For this study, we exposed 20 Sprague Dawley rats to a 16.8 ±â€Š0.3 PSI (195.3 dB SPL) right-sided shock wave in which 10 had application of a custom IJV compression collar in place at the time of injury. RESULTS: IJV compression at the time of injury was shown acutely to significantly reduce the incidence of tympanic membrane rupture and the initial temporary threshold shift on otoacoustic emissions in both the right and left ears of animals who had collar application immediately after and 7 days post injury. At 28 days from injury, collared animals demonstrated a return to baseline of otoacoustic emission values while the noncollared animals had persistent threshold shifts, signifying the presence of a permanent threshold shift only in those animals without collar application. IJV compression was also found to significantly reduce hair cell loss at the base of the cochlea secondary to mechanical trauma from the blast wind. CONCLUSION: Previously observed acute protective effects of IJV compression are sustained at chronic time points. IJV compression can potentially be used to reduce long-term permanent morbidity from blast-induced audiological trauma.


Assuntos
Traumatismos por Explosões/complicações , Transtornos da Audição/etiologia , Transtornos da Audição/prevenção & controle , Veias Jugulares/lesões , Emissões Otoacústicas Espontâneas/fisiologia , Animais , Cóclea/efeitos dos fármacos , Modelos Animais de Doenças , Células Ciliadas Auditivas , Veias Jugulares/fisiopatologia , Masculino , Pressão , Ratos , Ratos Sprague-Dawley , Roedores , Fatores de Tempo , Membrana Timpânica/patologia , Perfuração da Membrana Timpânica
13.
Acta Biomater ; 55: 333-339, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28351681

RESUMO

To determine viscoelastic shear moduli, stress relaxation indentation tests were performed on samples of human brain tissue resected in the course of epilepsy surgery. Through the use of a 500µm diameter indenter, regional mechanical properties were measured in cortical grey and white matter and subregions of the hippocampus. All regions were highly viscoelastic. Cortical grey matter was significantly more compliant than the white matter or hippocampus which were similar in modulus. Although shear modulus was not correlated with the age of the donor, cortex from male donors was significantly stiffer than from female donors. The presented material properties will help to populate finite element models of the brain as they become more anatomically detailed. STATEMENT OF SIGNIFICANCE: We present the first mechanical characterization of fresh, post-operative human brain tissue using an indentation loading mode. Indentation generates highly localized data, allowing structure-specific mechanical properties to be determined from small tissue samples resected during surgery. It also avoids pitfalls of cadaveric tissue and allows data to be collected before degenerative processes alter mechanical properties. To correctly predict traumatic brain injury, finite element models must calculate intracranial deformation during head impact. The functional consequences of injury depend on the anatomical structures injured. Therefore, morbidity depends on the distribution of deformation across structures. Accurate prediction of structure-specific deformation requires structure-specific mechanical properties. This data will facilitate deeper understanding of the physical mechanisms that lead to traumatic brain injury.


Assuntos
Lesões Encefálicas Traumáticas , Simulação por Computador , Hipocampo , Modelos Neurológicos , Substância Branca , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/fisiopatologia , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Humanos , Substância Branca/metabolismo , Substância Branca/patologia , Substância Branca/fisiopatologia
14.
Sci Rep ; 6: 34097, 2016 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-27671211

RESUMO

Traumatic brain injury (TBI) is a major cause of mortality and morbidity with limited therapeutic options. Traumatic axonal injury (TAI) is an important component of TBI pathology. It is difficult to reproduce TAI in animal models of closed head injury, but in vitro stretch injury models reproduce clinical TAI pathology. Existing in vitro models employ primary rodent neurons or human cancer cell line cells in low throughput formats. This in vitro neuronal stretch injury model employs human induced pluripotent stem cell-derived neurons (hiPSCNs) in a 96 well format. Silicone membranes were attached to 96 well plate tops to create stretchable, culture substrates. A custom-built device was designed and validated to apply repeatable, biofidelic strains and strain rates to these plates. A high content approach was used to measure injury in a hypothesis-free manner. These measurements are shown to provide a sensitive, dose-dependent, multi-modal description of the response to mechanical insult. hiPSCNs transition from healthy to injured phenotype at approximately 35% Lagrangian strain. Continued development of this model may create novel opportunities for drug discovery and exploration of the role of human genotype in TAI pathology.

15.
BMC Res Notes ; 9: 160, 2016 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-26969621

RESUMO

BACKGROUND: Brain edema is a significant challenge facing clinicians managing severe traumatic brain injury (TBI) in the acute period. If edema reaches a critical point, it leads to runaway intracranial hypertension that, in turn, leads to severe morbidity or death if left untreated. Clinical data on the efficacy of standard interventions is mixed. The goal of this study was to validate a novel therapeutic strategy for reducing post-traumatic brain edema in a mouse model. Prior in vitro work reported that the brain swells due to coupled electrostatic and osmotic forces generated by large, negatively charged, immobile molecules in the matrix that comprises brain tissue. Chondroitinase ABC (ChABC) digests chondroitin sulfate proteoglycan, a molecule that contributes to this negative charge. Therefore, we administered ChABC by intracerebroventricular (ICV) injection after controlled cortical impact TBI in the mouse and measured associated changes in edema. RESULTS: Almost half of the edema induced by injury was eliminated by ChABC treatment. CONCLUSIONS: ICV administration of ChABC may be a novel and effective method of treating post-traumatic brain edema in the acute period.


Assuntos
Edema Encefálico/complicações , Edema Encefálico/tratamento farmacológico , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/tratamento farmacológico , Condroitina ABC Liase/administração & dosagem , Condroitina ABC Liase/uso terapêutico , Doença Aguda , Animais , Injeções Intraventriculares , Camundongos Endogâmicos C57BL , Água/metabolismo
16.
Biomech Model Mechanobiol ; 13(3): 573-84, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23928858

RESUMO

Indentation has several advantages as a loading mode for determining constitutive behavior of soft, biological tissues. However, indentation induces a complex, spatially heterogeneous deformation field that creates analytical challenges for the calculation of constitutive parameters. As a result, investigators commonly assume small indentation depths and large sample thicknesses to simplify analysis and then restrict indentation depth and sample geometry to satisfy these assumptions. These restrictions limit experimental resolution in some fields, such as brain biomechanics. However, recent experimental evidence suggests that conventionally applied limits are in fact excessively conservative. We conducted a parametric study of indentation loading with various indenter geometries, surface interface conditions, sample compressibility, sample geometry and indentation depth to quantitatively describe the deviation from previous treatments that results from violation of the assumptions of small indentation depth and large sample thickness. We found that the classical solution was surprisingly robust to violation of the assumption of small strain but highly sensitive to violation of the assumption of large sample thickness, particularly if the indenter was cylindrical. The ramifications of these findings for design of indentation experiments are discussed and correction factors are presented to allow future investigators to account for these effects without recreating our finite element models.


Assuntos
Tecido Conjuntivo/fisiologia , Análise de Elementos Finitos , Humanos
17.
Artigo em Inglês | MEDLINE | ID: mdl-23475918

RESUMO

To fully assess contrast-enhanced acoustic bioeffects in diagnostic and therapeutic procedures, the mechanical properties of microbubbles need to be considered. In the present study, direct measurements of the microbubble stiffness were performed using atomic force microscopy by applying nanoscale compressions (up to 25 nN/s) on size-isolated, lipidcoated microbubbles (diameter ranges of 4 to 6 µm and 6 to 8 µm). The stiffness was found to lie between 4 and 22 mN/m and to decrease exponentially with the microbubble size within the diameter range investigated. No cantilever spring constant effect was found on the measured stiffness. The Young's modulus of the size-isolated microbubbles used in our study ranged between 0.4 and 2 MPa. Microstructures on the surface of the microbubbles were found to influence the overall microbubble elasticity. Our results indicated that more detailed theoretical models are needed to account for the size-dependent microbubble mechanical properties to accurately predict their acoustic behavior. The findings provided useful insights into guidance of cavitation-induced drug and gene delivery and could be used as part of the framework in studies on the shear stresses induced on the blood vessel walls by oscillating microbubbles.


Assuntos
Microbolhas , Microscopia de Força Atômica/métodos , Nanopartículas/química , Módulo de Elasticidade , Nanotecnologia , Tamanho da Partícula
18.
Annu Rev Biomed Eng ; 14: 431-55, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22655599

RESUMO

Mechanical loading induces both nuclear distortion and alterations in gene expression in a variety of cell types. Mechanotransduction is the process by which extracellular mechanical forces can activate a number of well-studied cytoplasmic signaling cascades. Inevitably, such signals are transduced to the nucleus and induce transcription factor-mediated changes in gene expression. However, gene expression also can be regulated through alterations in nuclear architecture, providing direct control of genome function. One putative transduction mechanism for this phenomenon involves alterations in nuclear architecture that result from the mechanical perturbation of the cell. This perturbation is associated with direct mechanical strain or osmotic stress, which is transferred to the nucleus. This review describes the current state of knowledge relating the nuclear architecture and the transfer of mechanical forces to the nucleus mediated by the cytoskeleton, the nucleoskeleton, and the LINC (linker of the nucleoskeleton and cytoskeleton) complex. Moreover, remodeling of the nucleus induces alterations in nuclear stiffness, which may be associated with cell differentiation. These phenomena are discussed in relation to the potential influence of nuclear architecture-mediated mechanoregulation of transcription and cell fate.


Assuntos
Engenharia Biomédica/métodos , Núcleo Celular/metabolismo , Animais , Núcleo Celular/fisiologia , Cromatina/metabolismo , Cromossomos/ultraestrutura , Citoplasma/metabolismo , Citoesqueleto/metabolismo , Matriz Extracelular/metabolismo , Histonas/metabolismo , Humanos , Mitose , Modelos Biológicos , Osmose , Transdução de Sinais , Estresse Mecânico
19.
Ann Biomed Eng ; 40(1): 70-8, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22012082

RESUMO

Rat is the most commonly used animal model for the study of traumatic brain injury. Recent advances in imaging and computational modeling technology offer the promise of biomechanical models capable of resolving individual brain structures and offering greater insight into the causes and consequences of brain injury. However, there is insufficient data on the mechanical properties of brain structures available to populate these models. In this study, we used microindentation to determine viscoelastic properties of different anatomical structures in sagittal slices of juvenile and adult rat brain. We find that the rat brain is spatially heterogeneous in this anatomical plane supporting previous results in the coronal plane. In addition, the brain becomes stiffer and more heterogeneous as the animal matures. This dynamic, region-specific data will support the development of more biofidelic computational models of brain injury biomechanics and the testing of hypotheses about the manner in which different anatomical structures are injured in a head impact.


Assuntos
Encéfalo/anatomia & histologia , Modelos Biológicos , Fatores Etários , Animais , Fenômenos Biomecânicos , Elasticidade , Feminino , Ratos
20.
Biochem Biophys Res Commun ; 408(2): 230-5, 2011 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-21463604

RESUMO

Osmotic stress is a potent regulator of biological function in many cell types, but its mechanism of action is only partially understood. In this study, we examined whether changes in extracellular osmolality can alter chromatin condensation and the rate of nucleocytoplasmic transport, as potential mechanisms by which osmotic stress can act. Transport of 10 kDa dextran was measured both within and between the nucleus and the cytoplasm using two different photobleaching methods. A mathematical model was developed to describe fluorescence recovery via nucleocytoplasmic transport. As osmolality increased, the diffusion coefficient of dextran decreased in the cytoplasm, but not the nucleus. Hyper-osmotic stress decreased nuclear size and increased nuclear lacunarity, indicating that while the nucleus was getting smaller, the pores and channels interdigitating the chromatin had expanded. The rate of nucleocytoplasmic transport was increased under hyper-osmotic stress but was insensitive to hypo-osmotic stress, consistent with the nonlinear osmotic properties of the nucleus. The mechanism of this osmotic sensitivity appears to be a change in the size and geometry of the nucleus, resulting in a shorter effective diffusion distance for the nucleus. These results may explain physical mechanisms by which osmotic stress can influence intracellular signaling pathways that rely on nucleocytoplasmic transport.


Assuntos
Núcleo Celular/metabolismo , Cromatina/metabolismo , Citoplasma/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Células Cultivadas , Cromatina/química , Pressão Osmótica , Suínos
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