RESUMEN
Purpose: This study aims to develop a mathematical model to elucidate fluid circulation in the retina, focusing on the movement of interstitial fluid (comprising water and albumin) to understand the mechanisms underlying exudative macular edema (EME). Methods: The model integrates physiological factors such as retinal pigment epithelium (RPE) pumping, osmotic pressure gradients, and tissue deformation. It accounts for spatial variability in hydraulic conductivity (HC) across the retina and incorporates the structural role of Müller cells (MCs) in maintaining retinal stability. Results: The model predicts that tissue deformation is maximal at the center of the fovea despite fluid exudation from blood capillaries occurring elsewhere, aligning with clinical observations. Additionally, the model suggests that spatial variability in HC across the thickness of the retina plays a protective role against fluid accumulation in the fovea. Conclusions: Despite inherent simplifications and uncertainties in parameter values, this study represents a step toward understanding the pathophysiology of EME. The findings provide insights into the mechanisms underlying fluid dynamics in the retina and fluid accumulation in the foveal region, showing that the specific conformation of Müller cells is likely to play a key role.
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Líquido Extracelular , Edema Macular , Epitelio Pigmentado de la Retina , Humanos , Edema Macular/fisiopatología , Edema Macular/metabolismo , Líquido Extracelular/metabolismo , Líquido Extracelular/fisiología , Epitelio Pigmentado de la Retina/patología , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/fisiopatología , Células Ependimogliales/metabolismo , Células Ependimogliales/patología , Modelos Teóricos , Retina/fisiopatología , Retina/metabolismo , Tomografía de Coherencia Óptica , Fóvea Central/patología , Presión OsmóticaRESUMEN
Adaptive elasticity in cortical bone has traditionally been modeled using Strain Energy Density (SED). Recent studies have highlighted the importance of interstitial fluid in bone adaptation, yet no research has quantified the role of interstitial fluid pressure and its effects, specifically incorporating both SED and interstitial fluid pressure in the adaptation process. This study introduces a novel formulation combining theory of porous media and theory of adaptive elasticity that considers both SED and interstitial fluid's pressure in cortical bone adaptation. The formulation is solved using ANSYS Fluent and a MATLAB script, and sensitivity analyses were conducted, analyzing various porosities, loading magnitudes, anisotropic properties of cortical bone, and involvement coefficients of interstitial fluid's pressure. This study reveals that bones with different vascular porosities (PV) tend to achieve similar density distributions under uniform loading over time. This highlights the significant role of interstitial fluid pressure in accelerating the convergence to optimal bone properties, especially in specimens with larger PV porosities. The findings emphasize the importance of fluid pressure in bone remodeling, aligning with previous studies. Furthermore, this study demonstrates that considering transversely isotropic material properties can significantly alter the remodeling configuration compared to isotropic material properties. This highlights the importance of accurately representing the anisotropic nature of cortical bone in models to better predict its adaptive responses. However, aspects such as fluid density variations and bone geometry changes remain unexplored, suggesting directions for future research. Overall, this research enhances the understanding of cortical bone adaptation and its mechanical interactions.
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Hueso Cortical , Líquido Extracelular , Modelos Biológicos , Líquido Extracelular/fisiología , Porosidad , Anisotropía , Humanos , Hueso Cortical/fisiología , Adaptación Fisiológica/fisiología , PresiónRESUMEN
Congestive heart failure (CHF) is a fatal disease with progressive severity and no cure; the heart's inability to adequately pump blood leads to fluid accumulation and frequent hospital readmissions after initial treatments. Therefore, it is imperative to continuously monitor CHF patients during its early stages to slow its progression and enable timely medical interventions for optimal treatment. An increase in interstitial fluid pressure (IFP) is indicative of acute CHF exacerbation, making IFP a viable biomarker for predicting upcoming CHF if continuously monitored. In this paper, we present an inductor-capacitor (LC) sensor for subcutaneous wireless and continuous IFP monitoring. The sensor is composed of inexpensive planar copper coils defined by a simple craft cutter, which serves as both the inductor and capacitor. Because of its sensing mechanism, the sensor does not require batteries and can wirelessly transmit pressure information. The sensor has a low-profile form factor for subcutaneous implantation and can communicate with a readout device through 4 layers of skin (12.7 mm thick in total). With a soft silicone rubber as the dielectric material between the copper coils, the sensor demonstrates an average sensitivity as high as -8.03 MHz/mmHg during in vitro simulations.
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Líquido Extracelular , Tecnología Inalámbrica , Tecnología Inalámbrica/instrumentación , Líquido Extracelular/química , Líquido Extracelular/fisiología , Humanos , Monitoreo Fisiológico/instrumentación , Monitoreo Fisiológico/métodos , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/fisiopatología , Presión , Técnicas Biosensibles/instrumentación , Técnicas Biosensibles/métodosRESUMEN
Physiological age-related alterations in the interstitial flow in the brain, which plays an important role in waste product removal, remain unclear. Using [15O]H2O positron emission tomography (PET), water dynamics were evaluated in 63 healthy adult participants aged between 20 and 80 years. Interstitial flow was assessed by influx ratio (IR) and drain rate (DR), using time-activity concentration data. Participants were divided into four age groups with 15-year ranges, to evaluate age-related functional alterations. At least one of the indices declined significantly with age across all groups. A significant linear negative correlation between age and both indicators was found in the scatter plots (IR: R2 = 0.54, DR: R2 = 0.44); both indicators were predominantly lower after age 50 years. These results suggest interstitial flow decreases with age, especially after 50 years. These important findings can contribute to devising therapeutic interventions for neurological diseases characterized by abnormal accumulation of waste products, and suggest the need for taking measures to maintain interstitial flow starting around the age of 50 years.
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Envejecimiento , Encéfalo , Líquido Extracelular , Tomografía de Emisión de Positrones , Humanos , Persona de Mediana Edad , Anciano , Adulto , Masculino , Femenino , Envejecimiento/fisiología , Líquido Extracelular/fisiología , Anciano de 80 o más Años , Adulto Joven , Encéfalo/diagnóstico por imagen , Encéfalo/fisiologíaRESUMEN
Flow in a porous medium can be driven by the deformations of the boundaries of the porous domain. Such boundary deformations locally change the volume fraction accessible by the fluid, creating non-uniform porosity and permeability throughout the medium. In this work, we construct a deformation-driven porous medium transport model with spatially and temporally varying porosity and permeability that are dependent on the boundary deformations imposed on the medium. We use this model to study the transport of interstitial fluid along the basement membranes in the arterial walls of the brain. The basement membrane is modeled as a deforming annular porous channel with the compressible pore space filled with an incompressible, Newtonian fluid. The role of a forward propagating peristaltic heart pulse wave and a reverse smooth muscle contraction wave on the flow within the basement membranes is investigated. Our results identify combinations of wave amplitudes that can induce either forward or reverse transport along these transport pathways in the brain. The magnitude and direction of fluid transport predicted by our model can help in understanding the clearance of fluids and solutes along the Intramural Periarterial Drainage route and the pathology of cerebral amyloid angiopathy.
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Encéfalo , Líquido Extracelular , Líquido Extracelular/metabolismo , Líquido Extracelular/fisiología , Porosidad , Humanos , Encéfalo/metabolismo , Encéfalo/irrigación sanguínea , Encéfalo/fisiología , Membrana Basal/metabolismo , Membrana Basal/fisiología , Conceptos Matemáticos , Transporte Biológico/fisiología , Modelos Biológicos , Simulación por Computador , Modelos Neurológicos , Animales , PermeabilidadRESUMEN
BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that has gained prominence recently. Clinical studies have explored tDCS as an adjunct to neurologic disease rehabilitation, with evidence suggesting its potential in modulating brain clearance mechanisms. The glymphatic system, a proposed brain waste clearance system, posits that cerebrospinal fluid-interstitial fluid (CSF-ISF) exchange aids in efficient metabolic waste removal. While some studies have linked tDCS to astrocytic inositol trisphosphate (IP3)/Ca2+ signaling, the impact of tDCS on CSF-ISF exchange dynamics remains unclear. HYPOTHESIS: tDCS influences the dynamics of CSF-ISF exchange through astrocytic IP3/Ca2+ signaling. METHODS: In this study, we administered tDCS (0.1 mA for 10 min) to C57BL/6N mice anesthetized with ketamine-xylazine (KX). The anode was positioned on the cranial bone above the cortex, and the cathode was inserted into the neck. Following tDCS, we directly assessed brain fluid dynamics by injecting biotinylated dextran amine (BDA) as a CSF tracer into the cisterna magna (CM). The brain was then extracted after either 30 or 60 min and fixed. After 24 h, the sectioned brain slices were stained with Alexa 594-conjugated streptavidin (SA) to visualize BDA using immunohistochemistry. We conducted Electroencephalography (EEG) recordings and aquaporin 4 (AQP4)/CD31 immunostaining to investigate the underlying mechanisms of tDCS. Additionally, we monitored the efflux of Evans blue, injected into the cisterna magna, using cervical lymph node imaging. Some experiments were subsequently repeated with inositol trisphosphate receptor type 2 (IP3R2) knockout (KO) mice. RESULTS: Post-tDCS, we observed an increased CSF tracer influx, indicating a modulation of CSF-ISF exchange by tDCS. Additionally, tDCS appeared to enhance the brain's metabolic waste efflux. EEG recordings showed an increase in delta wave post-tDCS. But no significant change in AQP4 expression was detected 30 min post-tDCS. Besides, we found no alteration in CSF-ISF exchange and delta wave activity in IP3R2 KO mice after tDCS. CONCLUSION: Our findings suggest that tDCS augments the glymphatic system's influx and efflux. Through astrocytic IP3/Ca2+ signaling, tDCS was found to modify the delta wave, which correlates positively with brain clearance. This study underscores the potential of tDCS in modulating brain metabolic waste clearance.
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Encéfalo , Líquido Extracelular , Ratones Endogámicos C57BL , Estimulación Transcraneal de Corriente Directa , Animales , Estimulación Transcraneal de Corriente Directa/métodos , Ratones , Encéfalo/fisiología , Encéfalo/metabolismo , Líquido Extracelular/fisiología , Líquido Extracelular/metabolismo , Masculino , Sistema Glinfático/fisiología , Líquido Cefalorraquídeo/fisiología , Líquido Cefalorraquídeo/metabolismo , Astrocitos/fisiología , Astrocitos/metabolismoRESUMEN
BACKGROUND: Under external loading, the fluid shear stress (FSS) in the porous structures of bones, such as trabecular or lacunar-canalicular cavity, can influence the biological response of bone cells. However, few studies have considered both cavities. The present study investigated the characteristics of fluid flow at different scales in cancellous bone in rat femurs, as well as the effects of osteoporosis and loading frequency. METHODS: Sprague Dawley rats (3 months old) were divided into normal and osteoporotic groups. A multiscale 3D fluid-solid coupling finite element model considering trabecular system and lacunar-canalicular system was established. Cyclic displacement loadings with frequencies of 1, 2, and 4 Hz were applied. FINDINGS: Results showed that the wall FSS around the adhesion complexes of osteocyte on the canaliculi was higher than that on the osteocyte body. Under the same loading conditions, the wall FSS of the osteoporotic group was smaller than that of the normal group. The fluid velocity and FSS in trabecular pores exhibited a linear relationship with loading frequency. Similarly, the FSS around osteocytes also showed the loading frequency-dependent phenomenon. INTERPRETATION: The high cadence in movement can effectively increase the FSS level on osteocytes for osteoporotic bone, i.e., expand the space within the bone with physiological load. This study might help in understanding the process of bone remodeling under cyclic loading and provide the fundamental data for the development of strategies for osteoporosis treatment.
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Remodelación Ósea , Hueso Esponjoso , Líquido Extracelular , Análisis Numérico Asistido por Computador , Osteocitos , Osteoporosis , Ratas Sprague-Dawley , Resistencia al Corte , Estrés Mecánico , Osteoporosis/fisiopatología , Hueso Esponjoso/fisiología , Osteocitos/fisiología , Femenino , Animales , Líquido Extracelular/fisiología , Imagenología Tridimensional , RatasRESUMEN
BACKGROUND AND OBJECTIVES: Physiological loading-induced mechanical environments regulate bone modeling and remodeling. Thus, loading-induced normal strain is typically considered a stimulus to osteogenesis. However, several studies noticed new bone formation near the sites of minimal normal strain, e.g., the neutral axis of bending in long bones, which raises a question on how bone mass is maintained near these sites. Secondary mechanical components such as shear strain and interstitial fluid flow also stimulate bone cells and regulate bone mass. However, the osteogenic potential of these components is not well established. Accordingly, the present study estimates the distribution of physiological muscle loading-induced mechanical environments such as normal strain, shear strain, pore pressure, and interstitial fluid flow in long bones. METHODS: A poroelastic finite element muscle standardized femur (MuscleSF) model is developed to compute the distribution of the mechanical environment as a function of bone porosities associated with osteoporotic and disuse bone loss. RESULTS: The results indicate the presence of higher shear strain and interstitial fluid motion near the minimal strain sites, i.e., the neutral axis of bending of femoral cross-sections. This suggests that secondary stimuli may maintain the bone mass at these locations. Pore pressure and interstitial fluid motion reduce with the increased porosity associated with bone disorders, possibly resulting in diminished skeletal mechano-sensitivity to exogenous loading. CONCLUSIONS: These outcomes present a better understanding of mechanical environment-mediated regulation of site-specific bone mass, which can be beneficial in developing prophylactic exercise to prevent bone loss in osteoporosis and muscle disuse.
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Líquido Extracelular , Osteoporosis , Humanos , Líquido Extracelular/fisiología , Huesos , Músculo Esquelético , Fémur , Estrés MecánicoRESUMEN
The physical microenvironment of cancer is characterized by elevated stiffness and tissue pressure, the main component of which is the interstitial fluid pressure (IFP). Elevated IFP is an established negative predictive and prognostic parameter, directly affecting malignant behavior and therapy response. As such, measurement of the IFP would allow to develop strategies aimed at engineering the physical microenvironment of cancer. Traditionally, IFP measurement required the use of invasive methods. Recent progress in dynamic and functional imaging methods such as dynamic contrast enhanced (DCE) magnetic resonance imaging and elastography, combined with numerical models and simulation, allows to comprehensively assess the biomechanical landscape of cancer, and may help to overcome physical barriers to drug delivery and immune cell infiltration. Here, we provide a comprehensive overview of the origin of elevated IFP, and its role in the malignant phenotype. Also, we review the methods used to measure IFP using invasive and imaging based methods, and highlight remaining obstacles and potential areas of progress in order to implement IFP measurement in clinical practice.
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Líquido Extracelular , Neoplasias , Biomarcadores , Líquido Extracelular/fisiología , Humanos , Imagen por Resonancia Magnética/métodos , Neoplasias/patología , Presión , Microambiente TumoralRESUMEN
The molecular signaling pathways that orchestrate angiogenesis have been widely studied, but the role of biophysical cues has received less attention. Interstitial flow is unavoidable in vivo, and has been shown to dramatically change the neovascular patterns, but the mechanisms by which flow regulates angiogenesis remain poorly understood. Here, we study the complex interactions between interstitial flow and the affinity for matrix binding of different chemokine isoforms. Using a computational model, we find that changing the matrix affinity of the chemokine isoform can invert the effect of interstitial flow on angiogenesis-from preferential growth in the direction of the flow when the chemokine is initially matrix-bound to preferential flow against the flow when it is unbound. Although fluid forces signal endothelial cells directly, our data suggests a mechanism for the inversion based on biotransport arguments only, and offers a potential explanation for experimental results in which interstitial flow produced preferential vessel growth with and against the flow. Our results point to a particularly intricate effect of interstitial flow on angiogenesis in the tumor microenvironment, where the vessel network geometry and the interstitial flow patterns are complex.
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Células Endoteliales , Líquido Extracelular , Líquido Extracelular/fisiología , Humanos , Morfogénesis , Neovascularización Patológica/patología , Microambiente TumoralRESUMEN
Living things comprise a typical hierarchical and porous medium, and their most fundamental logical architectures are interstitial structures encapsulating parenchymal structures. The recent discovery of the efficient transport mechanisms of interstitial streams has provided a new understanding of these complex activities. The substance transport of interstitial streams follows mesoscopic fluid behavior dynamics, which is intimately associated with material transfer in nanoconfined spaces and a unique signal transmission. Accordingly, the evaluation of interstitial stream transport behavior at the mesoscopic scale is essential. In this review, recent advances in physical and chemical properties, the substance transport model, and the characterization methods of interstitial streams at the mesoscopic scale, as well as the relationships between interstitial streams and disease are summarized. Interstitial stream transport can be used as a basis to fully mine hierarchal behavior in images to expand imaging behavior into an omics field. By starting from the perspective of soft matter, a new understanding can be gained of health and disease and quantitative physical markers for research, clinical diagnosis, and treatment can be provided, as well as prognosis evaluation in complex diseases such as cancer and Alzheimer's disease. This will provide a foundation for the development of medicine of soft matter.
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Enfermedades Cardiovasculares/patología , Líquido Extracelular/fisiología , Hidrodinámica , Neoplasias/patología , Enfermedades Neurodegenerativas/patología , Enfermedad Crónica , HumanosRESUMEN
Drainage of interstitial fluid and solutes from the brainstem has not been well studied. To map one drainage pathway in the human brainstem, we took advantage of the focal blood-brain barrier disruption occurring in a multiple sclerosis brainstem lesion, coupled with intravenous injection of gadolinium, which simulates an intraparenchymal injection of gadolinium tracer within the restricted confines of this small brain region. Using high-resolution MRI, we show how it is possible for interstitial fluid to drain into the adjacent trigeminal and oculomotor nerves, in keeping with a pathway of communication between the extracellular spaces of the brainstem and cranial nerve parenchyma.
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Barrera Hematoencefálica/fisiopatología , Tronco Encefálico/fisiología , Nervios Craneales/fisiología , Líquido Extracelular/fisiología , Esclerosis Múltiple/fisiopatología , Adulto , Barrera Hematoencefálica/diagnóstico por imagen , Nervios Craneales/diagnóstico por imagen , Gadolinio , Humanos , Imagen por Resonancia Magnética , MasculinoRESUMEN
The glymphatic system is a recently discovered network unique to the central nervous system that allows for dynamic exchange of interstitial fluid (ISF) and cerebrospinal fluid (CSF). As detailed in part I, ISF and CSF transport along paravascular channels of the penetrating arteries and possibly veins allow essential clearance of neurotoxic solutes from the interstitium to the CSF efflux pathways. Imaging tests to investigate this neurophysiologic function, although challenging, are being developed and are reviewed herein. These include direct visualization of CSF transport using postcontrast imaging techniques following intravenous or intrathecal administration of contrast material and indirect glymphatic assessment with detection of enlarged perivascular spaces. Application of MRI techniques, including intravoxel incoherent motion, diffusion tensor imaging, and chemical exchange saturation transfer, is also discussed, as are methods for imaging dural lymphatic channels involved with CSF efflux. Subsequently, glymphatic function is considered in the context of proteinopathies associated with neurodegenerative diseases and traumatic brain injury, cytotoxic edema following acute ischemic stroke, and chronic hydrocephalus after subarachnoid hemorrhage. These examples highlight the substantial role of the glymphatic system in neurophysiology and the development of certain neuropathologic abnormalities, stressing the importance of its consideration when interpreting neuroimaging investigations. © RSNA, 2021.
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Líquido Extracelular/diagnóstico por imagen , Líquido Extracelular/fisiología , Sistema Glinfático/diagnóstico por imagen , Sistema Glinfático/fisiología , Imagen por Resonancia Magnética/métodos , Neuroimagen/métodos , Animales , Humanos , RatonesRESUMEN
Normal physiologic function of organs requires a circulation of interstitial fluid to deliver nutrients and clear cellular waste products. Lymphatic vessels serve as collectors of this fluid in most organs; however, these vessels are absent in the central nervous system. How the central nervous system maintains tight control of extracellular conditions has been a fundamental question in neuroscience until recent discovery of the glial-lymphatic, or glymphatic, system was made this past decade. Networks of paravascular channels surrounding pial and parenchymal arteries and veins were found that extend into the walls of capillaries to allow fluid transport and exchange between the interstitial and cerebrospinal fluid spaces. The currently understood anatomy and physiology of the glymphatic system is reviewed, with the paravascular space presented as an intrinsic component of healthy pial and parenchymal cerebral blood vessels. Glymphatic system behavior in animal models of health and disease, and its enhanced function during sleep, are discussed. The evolving understanding of glymphatic system characteristics is then used to provide a current interpretation of its physiology that can be helpful for radiologists when interpreting neuroimaging investigations.
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Líquido Extracelular/fisiología , Sistema Glinfático/anatomía & histología , Sistema Glinfático/fisiología , Neuroimagen/métodos , HumanosRESUMEN
BACKGROUND: Mechanical interactions between tumor cells and microenvironments are frequent phenomena during breast cancer progression, however, it is not well understood how these interactions affect Epithelial-to-Mesenchymal Transition (EMT). EMT is associated with the progression of most carcinomas through induction of new transcriptional programs within affected epithelial cells, resulting in cells becoming more motile and adhesive to endothelial cells. METHODS: MDA-MB-231, SK-BR-3, BT-474, and MCF-7 cells and normal Human Mammary Epithelial Cells (HMECs) were exposed to fluid flow in a parallel-plate bioreactor system. Changes in expression were quantified using microarrays, qPCR, immunocytochemistry, and western blots. Gene-gene interactions were elucidated using network analysis, and key modified genes were examined in clinical datasets. Potential involvement of Smads was investigated using siRNA knockdown studies. Finally, the ability of flow-stimulated and unstimulated cancer cells to adhere to an endothelial monolayer, migrate and invade membrane pores was evaluated in flow and static adhesion experiments. RESULTS: Fluid flow stimulation resulted in upregulation of EMT inducers and downregulation of repressors. Specifically, Vimentin and Snail were upregulated both at the gene and protein expression levels in flow stimulated HMECs and MDA-MB-231 cells, suggesting progression towards an EMT phenotype. Flow-stimulated SNAI2 was abrogated with Smad3 siRNA. Flow-induced overexpression of a panel of cell adhesion genes was also observed. Network analysis revealed genes involved in cell flow responses including FN1, PLAU, and ALCAM. When evaluated in clinical datasets, overexpression of FN1, PLAU, and ALCAM was observed in patients with different subtypes of breast cancer. We also observed increased adhesion, migration and invasion of flow-stimulated breast cancer cells compared to unstimulated controls. CONCLUSIONS: This study shows that fluid forces on the order of 1 Pa promote EMT and adhesion of breast cancer cells to an endothelial monolayer and identified biomarkers were distinctly expressed in patient populations. A better understanding of how biophysical forces such as shear stress affect cellular processes involved in metastatic progression of breast cancer is important for identifying new molecular markers for disease progression, and for predicting metastatic risk.
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Neoplasias de la Mama/patología , Adhesión Celular , Transición Epitelial-Mesenquimal , Líquido Extracelular/fisiología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Adhesión Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Células Endoteliales/patología , Transición Epitelial-Mesenquimal/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Metástasis de la Neoplasia , Proteína smad3/genética , Proteína smad3/metabolismo , Factores de Transcripción de la Familia Snail/genética , Factores de Transcripción de la Familia Snail/metabolismo , Microambiente Tumoral , Vimentina/genética , Vimentina/metabolismoRESUMEN
BACKGROUND: Disruption of cerebrospinal fluid (CSF)/interstitial fluid (ISF) exchange in the spinal cord is likely to contribute to central nervous system (CNS) diseases that involve abnormal fluid accumulation, including spinal cord oedema and syringomyelia. However, the physiological factors that govern fluid transport in the spinal cord are poorly understood. The aims of this study were to determine the effects of cardiac pulsations and respiration on tracer signal increase, indicative of molecular movement following infusion into the spinal cord grey or white matter. METHODS: In Sprague Dawley rats, physiological parameters were manipulated such that the effects of spontaneous breathing (generating alternating positive and negative intrathoracic pressures), mechanical ventilation (positive intrathoracic pressure only), tachycardia (heart atrial pacing), as well as hypertension (pharmacologically induced) were separately studied. Since fluid outflow from the spinal cord cannot be directly measured, we assessed the molecular movement of fluorescent ovalbumin (AFO-647), visualised by an increase in tracer signal, following injection into the cervicothoracic spinal grey or white matter. RESULTS: Tachycardia and hypertension increased AFO-647 tracer efflux, while the concomitant negative and positive intrathoracic pressures generated during spontaneous breathing did not when compared to the positive-pressure ventilated controls. Following AFO-647 tracer injection into the spinal grey matter, increasing blood pressure and heart rate resulted in increased tracer movement away from the injection site compared to the hypotensive, bradycardic animals (hypertension: p = 0.05, tachycardia: p < 0.0001). Similarly, hypertension and tachycardia produced greater movement of AFO-647 tracer longitudinally along the spinal cord following injection into the spinal white matter (p < 0.0001 and p = 0.002, respectively). Tracer efflux was strongly associated with all blood vessel types. CONCLUSIONS: Arterial pulsations have profound effects on spinal cord interstitial fluid homeostasis, generating greater tracer efflux than intrathoracic pressure changes that occur over the respiratory cycle, demonstrated by increased craniocaudal CSF tracer movement in the spinal cord parenchyma.
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Líquido Cefalorraquídeo/fisiología , Líquido Extracelular/fisiología , Hipertensión/fisiopatología , Respiración , Médula Espinal/fisiopatología , Taquicardia/fisiopatología , Animales , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Interstitial fluid (ISF) flow through vascular adventitia has been discovered recently. However, its kinetic pattern was unclear. We used histological and topographical identification to observe ISF flow along venous vessels in rabbits. By magnetic resonance imaging (MRI) in live subjects, the inherent pathways of ISF flow from the ankle dermis through the legs, abdomen, and thorax were enhanced by paramagnetic contrast. By fluorescence stereomicroscopy and layer-by-layer dissection after the rabbits were sacrificed, the perivascular and adventitial connective tissues (PACTs) along the saphenous veins and inferior vena cava were found to be stained by sodium fluorescein from the ankle dermis, which coincided with the findings by MRI. The direction of ISF transport in a venous PACT pathway was the same as that of venous blood flow. By confocal microscopy and histological analysis, the stained PACT pathways were verified to be the fibrous connective tissues, consisting of longitudinally assembled fibers. Real-time observations by fluorescence stereomicroscopy revealed at least two types of spaces for ISF flow: one along adventitial fibers and another one between the vascular adventitia and its covering fascia. Using nanoparticles and surfactants, a PACT pathway was found to be accessible by a nanoparticle of <100 nm and contained two parts: a transport channel and an absorptive part. The calculated velocity of continuous ISF flow along fibers of the PACT pathway was 3.6â15.6 mm/s. These data revealed that a PACT pathway was a "slit-shaped" porous biomaterial, comprising a longitudinal transport channel and an absorptive part for imbibition. The use of surfactants suggested that interfacial tension might play an essential role in layers of continuous ISF flow along vascular vessels. A hypothetical "gel pump" is proposed based on interfacial tension and interactions to regulate ISF flow. These experimental findings may inspire future studies to explore the physiological and pathophysiological functions of vascular ISF or interfacial fluid flow among interstitial connective tissues throughout the body.
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Adventicia/fisiología , Líquido Extracelular/fisiología , Animales , Transporte Biológico , Vasos Linfáticos/fisiología , Imagen por Resonancia Magnética , ConejosRESUMEN
A biphasic computational model of a growing, vascularized glioma within brain tissue was developed to account for unique features of gliomas, including soft surrounding brain tissue, their low stiffness relative to brain tissue, and a lack of draining lymphatics. This model is the first to couple nonlinear tissue deformation with porosity and tissue hydraulic conductivity to study the mechanical interaction of leaky vasculature and solid growth in an embedded glioma. The present model showed that leaky vasculature and elevated interstitial fluid pressure produce tensile stress within the tumor in opposition to the compressive stress produced by tumor growth. This tensile effect was more pronounced in softer tissue and resulted in a compressive stress concentration at the tumor rim that increased when tumor was softer than host. Aside from generating solid stress, fluid pressure-driven tissue deformation decreased the effective stiffness of the tumor while growth increased it, potentially leading to elevated stiffness in the tumor rim. A novel prediction of reduced porosity at the tumor rim was corroborated by direct comparison with estimates from our in vivo imaging studies. Antiangiogenic and radiation therapy were simulated by varying vascular leakiness and tissue hydraulic conductivity. These led to greater solid compression and interstitial pressure in the tumor, respectively, the former of which may promote tumor infiltration of the host. Our findings suggest that vascular leakiness has an important influence on in vivo solid stress, stiffness, and porosity fields in gliomas given their unique mechanical microenvironment.
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Neoplasias Encefálicas/fisiopatología , Líquido Extracelular/fisiología , Glioma/fisiopatología , Microambiente Tumoral , Animales , Encéfalo , Fuerza Compresiva , Simulación por Computador , Humanos , Linfa/fisiología , Modelos Biológicos , Modelos Teóricos , Porosidad , Presión , Estrés Mecánico , Resistencia a la TracciónRESUMEN
Muscle paralysis induced with botulinum toxin (Botox) injection increases vascular porosity and reduces osteocyte lacunar density in the tibial cortical bone of skeletally mature rats. These morphological changes potentially affect interstitial fluid flow in the lacunar-canalicular porosity, which is thought to play a role in osteocyte mechanotransduction. The aim of this study was to investigate the effects of disuse-induced morphological changes on interstitial fluid velocity around osteocytes in the bone cortex. Micro-CT images from a previous study that quantified the effects of Botox-induced muscle paralysis on bone microarchitecture in skeletally mature rats were used to create high-resolution, animal-specific finite element models that included the vascular pores and osteocyte lacunae within the tibial metaphysis of Botox-injected (BTX, n = 8) and saline-injected control (CTRL, n = 8) groups. To quantify fluid flow, lacunar and canalicular porosities were modeled as fluid-saturated poroelastic materials, and boundary conditions were applied to simulate physiological loading. This modeling approach allowed a detailed quantification of the fluid flow velocities around osteocytes in a relatively large volume of bone tissue. The analysis demonstrated that interstitial fluid velocity at the vascular pore surfaces was significantly lower in BTX compared to CTRL because of the decreased vascular canal separation. No significant differences in average fluid velocity were observed at the osteocyte lacunae and no correlation was found between the fluid velocity and the lacunar density, which was significantly lower in BTX. Instead, the lacunar fluid velocity was dependent on the osteocyte's specific position in the bone cortex and its proximity to a vascular pore.
Asunto(s)
Hueso Cortical/fisiopatología , Líquido Extracelular/fisiología , Osteocitos/patología , Osteoporosis/patología , Osteoporosis/fisiopatología , Animales , Toxinas Botulínicas Tipo A , Modelos Animales de Enfermedad , Elasticidad , Femenino , Análisis de Elementos Finitos , Porosidad , Ratas Sprague-Dawley , Microtomografía por Rayos XRESUMEN
Cells within developing tissues rely on morphogens to assess positional information. Passive diffusion is the most parsimonious transport model for long-range morphogen gradient formation but does not, on its own, readily explain scaling, robustness and planar transport. Here, we argue that diffusion is sufficient to ensure robust morphogen gradient formation in a variety of tissues if the interactions between morphogens and their extracellular binders are considered. A current challenge is to assess how the affinity for extracellular binders, as well as other biophysical and cell biological parameters, determines gradient dynamics and shape in a diffusion-based transport system. Technological advances in genome editing, tissue engineering, live imaging and in vivo biophysics are now facilitating measurement of these parameters, paving the way for mathematical modelling and a quantitative understanding of morphogen gradient formation and modulation.