Growth and metastasis of Lewis' lung carcinoma in mice under the pharmacological action on metabolism and the effects of kinins

In experiments on C57 Bl mice the effects of growth and metastatic proliferation of Lewis lung carcinoma inoculated intramuscularly on metabolism and kinin activity have been studied during the application of pharmacologic agents (parmidin, cellulose sulphate, unithiol). Causing a weak inhibition of the primary tumour growth, parmidin if administered repeatedly in given doses, inhibits partially metastatic process, which is manifested in an essential decrease of the quantity, size and weight of lung metastases. Parmidin also inhibits an adverse effect of cellulose sulphate and unithiol on metastatic process. It is believed that the action of parmidin is of an indirect character and is mainly associated with the elimination of the kinin component of microcirculatory disorders in the lungs.     

Antiviral properties of various pharmacologic groups of drugs]

Currently used cardiovascular drugs such as nicotinamide, strophanthin, corglycon, curantyl, cavinton, papaverin hydrochloride, nicotinic acid, xantinole nicotinate, isoptin, parmidin and halidor were studied by the program of antiviral drug screening. The majority of them (9 out of 11) were shown to have antiviral activity which was rather individual by its specificity and level. Laboratory strains of 9 viruses inducing the most common infections in man and animals, i.e. Herpes simplex, poxvaccine, influenza, vesicular stomatitis, respiratory syncytial infection, VEE, ECHO. Lassa fever and rotavirus infection were tested. The characteristic feature of the drugs was their high specific activity against the DNA-containing viruses and rotavirus. The three drugs papaverin hydrochloride, strophanthin and corglycon proved to be the most promising. Their antiviral activity was confirmed on a model of herpes infection in mice. The paper discusses whether the phenomenon discovered in the official drugs is important in the therapy of somatic patients.     

Permeability analysis of scaffolds for bone tissue engineering

Porous artificial bone substitutes, especially bone scaffolds coupled with osteobiologics, have been developed as an alternative to the traditional bone grafts. The bone scaffold should have a set of properties to provide mechanical support and simultaneously promote tissue regeneration. Among these properties, scaffold permeability is a determinant factor as it plays a major role in the ability for cells to penetrate the porous media and for nutrients to diffuse. Thus, the aim of this work is to characterize the permeability of the scaffold microstructure, using both computational and experimental methods. Computationally, permeability was estimated by homogenization methods applied to the problem of a fluid flow through a porous media. These homogenized permeability properties are compared with those obtained experimentally. For this purpose a simple experimental setup was used to test scaffolds built using Solid Free Form techniques. The obtained results show a linear correlation between the computational and the experimental permeability. Also, this study showed that permeability encompasses the influence of both porosity and pore size on mass transport, thus indicating its importance as a design parameter. This work indicates that the mathematical approach used to determine permeability may be useful as a scaffold design tool.     

Action of 1-fluoro-2,4-dinitrobenzene on passive ion permeability of the human red blood cell

Summary Dinitrofluorobenzene (DNFB) inhibits the penetration of anions such as sulfate, phosphate, succinate, and lactate, and facilitates the penetration of cations such as K⁺ and Na⁺. The phlorizin-glucose insensitive fraction of erythritol permeability is not affected by the agent. The effects of DNFB on ion permeability are similar to those of more specific amino reactive agents like trinitrobenzene sulfonate and 2-methoxy-5-nitrotropone.Anion permeability reacts more sensitively to DNFB than cation permeability. At a given concentration of DNFB in the medium, the inhibition of anion permeability develops faster than the facilitation of cation permeability. At a given time of exposure, lower concentrations of DNFB are required to produce a nearly maximal response of anion permeability than are necessary for maximal effect on cation permeability.The response of anion and cation permeability to DNFB is augmented by increasing the pH at which dinitrophenylation is allowed to take place.DNFB binding to the cell membrane is about one order of magnitude lower than DNFB binding to the whole cell. In the cell membrane, proteins as well as lipids are dinitrophenylated. Among the lipids, only phosphatidylethanolamine binds significant amounts of DNFB. Phosphatidylserine does not seem to react with the agent under the experimental conditions under which DNFB produces its effects on ion permeability.The experimental results are compatible with the assumption that removal of uncharged NH₂-groups by dinitrophenylation of the membrane leads to a concomitant reduction of fixed NH ₃ ⁺ -groups and hence of the positive membrane charge. This leads to an acceleration of cation movements and an inhibition of anion permeability while nonelectrolyte permeability remains unaffected. However, other explanations of our observations cannot be ruled out.     

Numerical model for intraosseous infusion of the human calvarium for hydrocephalus shunting

Hydrocephaly is the defective absorption of cerebrospinal fluid (CSF) into the blood stream. This work is an experimental and computational fluid dynamic modelling study to determine the permeability of the diploë as a potential receptor for CSF. Human calvariae were studied by micro-CT to measure their porosity, the area of flow and develop model geometry. Pressure-flow measurements were conducted on specimens to determine their permeability in the physiological and transverse flow directions to compare with numerical results. The overall porosity and permeability of the calvaria were spatially variable. Results suggest an order of magnitude increase in permeability for a 14% increase in overall porosity based on a small number of samples. Numerical results fell within the experimental infusion tests results. Due to the difficulty and ethical considerations in obtaining adolescent skull samples to perform large-scale testing, the developed model will be invaluable.     

Effect of Experimental Temperature on the Permeation of Model Diffusants Across Porcine Buccal Mucosa

The influence of experimental temperature on the permeability of model diffusants across porcine buccal mucosa was investigated in vitro. The permeability increased significantly as the experimental temperature was increased in increments of approximately 7°C. It was observed that the apparent permeability and temperature were related by an exponential relationship that conformed to the Arrhenius equation. Diffusants with higher lipophilicities—buspirone and bupivacaine—had lower activation energies for diffusion when compared to hydrophilic diffusants—antipyrine and caffeine. The activation energy for diffusion of the model diffusants decreased linearly with increasing distribution coefficients across porcine buccal mucosa. The results suggested that the buccal mucosa acts as a stronger barrier to the diffusion of hydrophilic diffusants than the lipophilic ones. The log-linear relationship between permeability and temperature indicates that temperature should be carefully controlled in diffusion experiments. These results also point to the possibility of developing heat-generating buccal delivery devices, especially for hydrophobic diffusants.     

Quantitative study of aortic wall permeability

Fluorescent microscopy with trypan blue was used to assay aortal wall permeability. The dye permeation to the vascular wall was assayed by photometry with graphic data recording. The technique described enabled exploring aortal wall permeability in rabbits with experimental hypertension associated with induced atherosclerosis.     

Effect of convection in capillaries on oxygen removal from arterioles in striated muscle

Based on experimental data that show the presence of significant oxygen saturation gradients in precapillary arterioles, it has been suggested that the in vivo permeability to oxygen of resting striated muscle may be significantly higher than the corresponding in vitro value obtained in unperfused tissue samples (Popel et al., 1989b, Adv. expl. Med. Biol. 247, 215). The present study performs two analyses to further compare theoretical predictions with experimental data obtained under control conditions and during hemodilution and hemoconcentration. First, it is shown that, in principle, a capillary-perfused tissue layer with a thickness of a few hundred microns is necessary to convectively carry the experimentally determined amount of oxygen released by precapillary arterioles under control and hemodiluted conditions. This capacity to convect oxygen depends strongly on the resting tissue oxygen tension. Second, a more general version of a previous model (Weerappuli & Popel, 1989, J. Biomech. Eng. 111, 24) is used to examine whether changes made in the model parameters within the physiological range of values can explain the experimentally measured flux. The results show that the theoretical predictions can be made compatible with experimental observations if the in vivo permeability of perfused tissue to oxygen is assumed to be one to two orders of magnitude higher than the in vitro value. Furthermore, the predicted in vivo permeability for perfused tissue surrounding an arteriole varies with the arteriolar luminal oxygen tension and flow. This may be due to simplifying approximations made in the model or possible experimental artifacts. Alternatively, it could also be speculated that this variability indicates the flow dependency of the permeability of perfused tissue to oxygen.     

Experimental and numerical identification of cortical bone permeability

Bone is a complex system, and could be modeled as a poroelastic media. The aim of this paper is to identify the macroscopic value of the cortical bone permeability coefficient. A simple experimental method was designed in order to determine the permeability coefficient. Two bone samples taken from different ox femurs were filled with water, to place them under internal pressure. The measurements gave both the fluid flow through the lateral surfaces and the internal pressure. The originality of this work is the coupling between an experimental process and a structural computation performed with a finite element method. The mean cortical bone permeability coefficient identified was about k=1.1x10(-13)m(2). This value tends to confirm other values found in the literature, obtained by different methods and often at macroscopic scale. It confirms also the domination of vascular permeability (Haversian and Volkmann's canals).     

Predicting permeability of regular tissue engineering scaffolds: scaling analysis of pore architecture,scaffold length,and fluid flow rate effects

The main aim of this research is to numerically obtain the permeability coefficient in the cylindrical scaffolds. For this purpose, a mathematical analysis was performed to derive an equation for desired porosity in terms of morphological parameters. Then, the considered cylindrical geometries were modeled and the permeability coefficient was calculated according to the velocity and pressure drop values based on the Darcy’s law. In order to validate the accuracy of the present numerical solution, the obtained permeability coefficient was compared with the published experimental data. It was observed that this model can predict permeability with the utmost accuracy. Then, the effect of geometrical parameters including porosity, scaffold pore structure, unit cell size, and length of the scaffolds as well as entrance mass flow rate on the permeability of porous structures was studied. Furthermore, a parametric study with scaling laws analysis of sample length and mass flow rate effects on the permeability showed good fit to the obtained data. It can be concluded that the sensitivity of permeability is more noticeable at higher porosities. The present approach can be used to characterize and optimize the scaffold microstructure due to the necessity of cell growth and transferring considerations.     

Effect of fluid boundary conditions on joint contact mechanics and applications to the modeling of osteoarthritic joints

The long-term goal of our research is to understand the mechanism of osteoarthritis (OA) initiation and progress through experimental and theoretical approaches. In previous theoretical models, joint contact mechanics was implemented without consideration of the fluid boundary conditions and with constant permeability. The primary purpose of this study was to investigate the effect of fluid boundary conditions at the articular surfaces on the contact mechanics, in terms of load sharing and fluid flow properties using variable permeability. The tested conditions included totally sealed surfaces, open surfaces, and open surfaces with variable permeability. While the sealed surface model failed to predict relaxation times and load sharing properly, the class of open surface models (open surfaces with constant permeability, and surfaces with variable permeability) gave good agreement with experiments, in terms of relaxation time and load sharing between the solid and the fluid phase. In particular, the variable permeability model was judged to be the most realistic of the three models, from a biological and physical point of view. This model was then used to simulate joint contact in the early and late stages of OA. In the early stages of OA, the model predicted a decrease in peak contact pressure and an increase in contact area, while in the late stages of OA, peak pressures were increased and contact areas were decreased compared to normal. These findings agree well with experimental observations.     

The permeability of the barrier of the gastrointestinal tract for the macromolecules of polyethylene glycol-4000: an assessment of the mechanism and its reproducibility]

Polyethylene glycol (PEG)-4000 is proposed as a tracer of intestinal macromolecular permeability. The reproducibility of permeability testing with PEG-4000 and the mechanism of its penetration through intestinal mucosa were studied in adult rats. Permeability measurement for PEG-4000 was reproducible when repeated twice for 2 days. This makes it possible to repeat PEG-4000 permeability testing before and after any experimental impact on the intestine. I.p. administration of colchicine to rats (125 micrograms/100 g b. w.) significantly inhibited intestinal absorption of PEG-4000 fed to the animals 3 hours later. Hence, PEG-4000 penetration through the intestinal mucosa is mediated by the system of enterocyte cytoplasmic microtubules. Mucosal permeability for PEG-4000 may be consequently considered as a valuable model of permeability for protein macromolecules.     

Effects of small nonpolar molecules on membrane compressibility and permeability: A theoretical study of the effects of anesthetic gases

We explore from a theoretical perspective the effects of small nonpolar molecules, such as anesthetic gases, on membrane compressibility and permeability. As a model system we expand a previously proposed generalization of Nagle's model for biomembrane phase transitions. In this model anesthetic gases alter membrane compressibility, causing profound changes in membrane permeability. Anesthetics either increase or decrease membrane permeability, depending on whether the membrane lipid is originally in the solid or melted state, or in a two-phase region. These changes are reversed by high pressure, in agreement with experimental results. Anesthetic-induced changes in compressibility are predicted to inhibit fusion of phospholipid vesicles to each other and to planar bilayers, and thus might be expected to inhibit the fusion of presynaptic vesicles with the presynaptic nerve membrane. This work provides a detailed molecular theory for many of the effects of anesthetic gases on both synapse and axon, and provides a coherent framework for understanding diverse experimental results.     

A quantitative assay for experimental allergic encephalomyelitis in the rat based on permeability of spinal cords to 125I-human gamma-globulin.

We have developed a quantitative assay for experimental allergic encephalomyelitis (EAE) in the rat based on permeability of the spinal cord to 125I-human gamma-globulin (HGG). This assay is highly reproducible and eliminates many of the drawbacks of assaying for EAE on the basis of clinical and/or histologic criteria. Using the assay, we have shown a direct correlation between onset of histologic changes in the spinal cord and onset of permeability changes in the spinal cord. No rat without histologic lesions manifest permeability alterations, and all rats with histologic lesions did manifest increased permeability to 125I-HGG. Furthermore, strains of rats susceptible to EAE demonstrated permeability changes, whereas resistant rats did not. In addition, we demonstrated by permeability and histologic criteria that guinea pig myelin basic protein emulsified with incomplete Freund's adjuvant is encephalitogenic in the Lewis rat. We also demonstrated that recipients of passive transfer of sensitized cells develop permeability changes along with histologic lesions. We conclude that measuring permeability to 125I-HGG in the spinal cords of rats is a valid assay for EAE, and its improves upon current indices of EAE in that it is readily quantifiable.     

Improved characterization of cartilage mechanical properties using a combination of stress relaxation and creep

Mechanical characterization of cartilage, other soft tissues and gels has become a ubiquitous and essential aspect of biomechanics and biomaterials research. Current progress in theoretical modeling and tools for data analysis often exceed what is required for routine mechanical characterization assays in experimental studies, making selection of methodologies difficult for the nonspecialist. We have therefore developed an approach for measurement of confined compression modulus and hydraulic permeability based on simple poroelasticity theory and requiring only linear regression tools for data analysis. This technique involves a new application of an early-time solution for creep combined with stress relaxation measurements to characterize soft tissue mechanical parameters as a function of compressive strain or water content. This combined methodology allows measurement of hydraulic permeability by two different techniques with only a modest increase in experimental duration, providing a more precise assessment of permeability and associated measurement error.     

A simple theory regarding ambimobility of xenobiotics with special reference to the nematicide, oxamyl

A theory is presented to explain the phloem mobility of certain systemic xenobiotics that are not weak acids. It is shown that there is a theoretically optimum permeability that permits optimum circulation through the symplasm and apoplast (including the phloem and xylem) of Solanum tuberosum plants. The optimum permeability is large enough to permit substantial passive permeation into sieve cells in the source leaf and yet is small enough to permit phloem transport with some retention. The optimum permeability is a function of the velocity of sap flow in sieve tubes, the radius of the sieve tube, the over-all length of the plant, and the length of the carbohydrate and xenobiotic sources. It is argued that the nematicide, oxamyl, is near the optimum permeability under some experimental conditions. It is shown that depending on the strength of the carbohydrate sink in roots or growth points and depending on the permeability of the xenobiotic, there can be passive accumulation of xenobiotics in the sieve tubes in the carbohydrate sink regions.     

Local Partition Coefficients Govern Solute Permeability of Cholesterol-Containing Membranes

The permeability of lipid membranes for metabolic molecules or drugs is routinely estimated from the solute’s oil/water partition coefficient. However, the molecular determinants that modulate the permeability in different lipid compositions have remained unclear. Here, we combine scanning electrochemical microscopy and molecular-dynamics simulations to study the effect of cholesterol on membrane permeability, because cholesterol is abundant in all animal membranes. The permeability of membranes from natural lipid mixtures to both hydrophilic and hydrophobic solutes monotonously decreases with cholesterol concentration [Chol]. The same is true for hydrophilic solutes and planar bilayers composed of dioleoyl-phosphatidylcholine or dioleoyl-phosphatidyl-ethanolamine. However, these synthetic lipids give rise to a bell-shaped dependence of membrane permeability on [Chol] for very hydrophobic solutes. The simulations indicate that cholesterol does not affect the diffusion constant inside the membrane. Instead, local partition coefficients at the lipid headgroups and at the lipid tails are modulated oppositely by cholesterol, explaining the experimental findings. Structurally, these modulations are induced by looser packing at the lipid headgroups and tighter packing at the tails upon the addition of cholesterol.     

Local Partition Coefficients Govern Solute Permeability of Cholesterol-Containing Membranes

The permeability of lipid membranes for metabolic molecules or drugs is routinely estimated from the solute’s oil/water partition coefficient. However, the molecular determinants that modulate the permeability in different lipid compositions have remained unclear. Here, we combine scanning electrochemical microscopy and molecular-dynamics simulations to study the effect of cholesterol on membrane permeability, because cholesterol is abundant in all animal membranes. The permeability of membranes from natural lipid mixtures to both hydrophilic and hydrophobic solutes monotonously decreases with cholesterol concentration [Chol]. The same is true for hydrophilic solutes and planar bilayers composed of dioleoyl-phosphatidylcholine or dioleoyl-phosphatidyl-ethanolamine. However, these synthetic lipids give rise to a bell-shaped dependence of membrane permeability on [Chol] for very hydrophobic solutes. The simulations indicate that cholesterol does not affect the diffusion constant inside the membrane. Instead, local partition coefficients at the lipid headgroups and at the lipid tails are modulated oppositely by cholesterol, explaining the experimental findings. Structurally, these modulations are induced by looser packing at the lipid headgroups and tighter packing at the tails upon the addition of cholesterol.     

Finite element modelling of polymethylmethacrylate flow through cancellous bone

A mathematical model based on the Finite Element Method is developed to simulate the non-linear flow of acrylic bone cement through cancellous bone. The cancellous bone bed is modelled as a bed of parallel capillaries filled with equal spaced toroidal trabeculae. By manipulating the relative size of the torus and the capillary, the flow within bone of varying porosity is simulated. An apparent permeability based on the volume weighted average viscosity and Darcy's law is developed to describe the flow of the acrylic through the cancellous bone bed. The model predicts a cancellous bone permeability of 5.6 x 10(-9)-8.3 x 10(-9) m2 for linear flow. The non-linear behavior of the acrylic cement results in an increase of apparent permeability when compared to the permeability computed for linear flow. Estimates of penetration are achieved by running the model in a quasi-steady state fashion with pressure applied over a fixed time increment. Close agreement is shown between model predictions of penetration depth and experimental results available in the literature.     

The effect of biofilm permeability on bio-clogging of porous media

A 3D Biofilm model, appropriate for complex porous media support structures, is successfully modified such that non‐zero permeability of biofilms structures is enabled. A systematic study is then conducted into the influence of biofilm permeability on overall biomass growth rate. This reveals a significant influence at large biofilm concentrations; even when the permeability of the biomass is 1.25% of that of the free pore space, biomass accumulation increased by a factor of ～3 over 40 h. The effect is shown to be retained when allowing for biomass detachment or erosion as a consequence of adjacent velocity shear. We conclude that biofilm permeability should be included in biofilm models and that further experimental work is required to better describe the link between biofilm permeability and local microstructure. Biotechnol. Bioeng. 2012; 109:1031–1042. © 2011 Wiley Periodicals, Inc.