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PubMed1969

Permeability and structure of junctional membranes at an electrotonic synapse.

The dye Procion Yellow M4RS crosses junctional membranes from cytoplasm to cytoplasm at electrotonic synapses between segments of the crayfish septate axon. The dye does not enter the cells from extracellular space. Thus permeability of junctional membranes is qualitatively different from that of nonjunctional membranes. Electron microscopy after fixation in the presence of lanthanum hydroxide indicates that these synapses are "gap junctions" and that there is a network of channels continuous with extracellular space between apposed junctional membranes. These channels must be interlaced with intercytoplasmic channels that are not open to extracellular space.

Cell Membrane Permeability↗
PubMed1979

Ultrastructural and biochemical studies of the swelling of developing chick telencephalic slices.

An ultrastructural and biochemical study of the importance and localization of tissue swelling was performed on telencephalic slices of 1- and 30-day-old chicks incubated in an oxygenated or a non-oxygenated physiological medium. The swelling of slices is greater for 30-day-old chick material than for that from 1-day-old chicks. It also reaches higher values in the non-oxygenated than in the oxygenated medium. When the 30-day-old chick telencephalic slices are incubated in an oxygenated medium, swelling mainly affects astrocytes, and especially the astrocytic endfeet. When they are incubated in a non-oxygenated medium, the astrocytes and astrocytic endfeet are very swollen and in addition the swelling also affects the neurons and their organelles. Extracellular space is increased. When 1-day-old chick telencephalic slices are incubated in a non-oxygenated medium, the tissue structures are well preserved. Swelling predominantly affects astrocytes and astrocytic endfeet. Neurons are not affected and the extracellular space is reduced. However, when they are incubated in an oxygenated medium, tissue structures are greatly affected showing a high degree of disorganization. Extracellular space is greatly increased. This study thus indicates that the best incubation conditions are an oxygenated medium for 30-day-old chick telencephalic slices which are characterized by an aerobic metabolism, and a non-oxygenated medium for 1-day-old chick telencephalic slices which have a predominantly anaerobic metabolism.

Aerobiosis↗
PubMed2005

Microdialysis - an in vivo technique for studies of growth factors in breast cancer.

Changes in the microenvironment are important in the development of cancer and further tumor growth. Although landmark discoveries have been made regarding genetic alterations in cancer at a cellular level very little is known about protein regulation in the extracellular space. In the microenvironment many growth factors are activated at a post-translational level by interactions of different cell types such as epithelial cells, fibroblasts, adipose cells, and immune cells. The extracellular space is the bioactive site for the majority of growth factors and increased knowledge of protein activation in this compartment is of utmost importance for our comprehension of tumor biology. Microdialysis is a minimally invasive technique, which enables sampling of molecules in the extracellular space. It is applicable in human cancer as well as in experimental tumors. This review describes microdialysis, its application and the up to date literature of microdialysis for detection of growth factors in cancer with special emphasis on breast cancer.

Animals↗
PubMed1988

Increases in striatal and hippocampal impedance and extracellular levels of amino acids by cardiac arrest in freely moving rats.

The time course of changes in the tissue impedance and the levels of extracellular transmitter and non-transmitter amino acids was studied in the striatum and hippocampus of the unanesthetized rat after cardiac arrest. Electrodes were implanted for the continuous measurement of tissue impedance so that a measure of the volume of extracellular space was provided. Alternatively, bilateral dialysis probes were used for monitoring levels of extracellular amino acids in subsequent 30-s samples using an automated precolumn derivatization technique for reversed-phase HPLC analysis and fluorimetric detection. The impedance started to rise approximately 1.2 min following cardiac arrest, increased rapidly during the first 5 min, and increased almost linearly thereafter. After 15 min, a decrease of approximately 50% in the extracellular space was calculated. The impedance rose more steeply in the striatum than in the hippocampus. The extracellular levels of taurine, which increased greater than 300% within 5 min after cardiac arrest, most closely resembled the time course of the change in impedance. Glutamate and aspartate levels did not increase until 5 min after circulatory arrest, and at 15 min they had risen to a level of 465 and 265% for the striatum and 298 and 140% for the hippocampus of the resting release, respectively. The release of gamma-aminobutyric acid (GABA) was multiphasic and did not resemble that of any of the other--putative--transmitter amino acids. Fifteen minutes after cardiac arrest, the levels of GABA were 617 and 774% of the resting release in the striatum and hippocampus, respectively. Glycine and alanine efflux substantially increased (232 and 151% in striatum and 141 and 154% in hippocampus, respectively) 15 min postmortem, whereas the glutamine level was slightly increased and levels of asparagine, histidine, threonine, ethanolamine, serine, arginine, and tyrosine were inconsistently higher in the two brain regions. At this time, the extracellular levels of glutamate, GABA, and aspartate were only slightly lower, as expected from the tissue levels and from levels of the other amino acids, an observation indicating that all the amino acids may diffuse through postmortem brain tissue to a nearly similar extent.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acids↗
PubMed1993

Peptidases in the CNS: formation of biologically active, receptor-specific peptide fragments.

Peptides function as chemical signals between cells of multicellular organisms, or different organisms, via specific receptors on target cells. Many hormones, neuromodulators, and growth factors are peptides. Because there is no known reuptake system for peptides at the nerve terminal, the biological activity of peptides in the extracellular space is regulated by enzymatic degradation and extracellular metabolism. For example, angiotensin I is processed extracellularly in the lung by angiotensin-converting enzyme (ACE; E.C. 3.4.15.1), a peptidyl dipeptidase, to form the potent vasoconstrictor hormone angiotensin II. When neuropeptides are released from neurons into the extracellular space, specific peptidases also can modulate the peptidergic signal by generating smaller, biologically active fragments via products with similar or dissimilar characteristics of the parent peptide. Therefore, receptor-binding selectivity of a released peptide hormone can be regulated by peptidases. Because peptidases may play a key role in the extracellular regulation of peptidergic signaling, alterations in peptidase activities by drugs or disease states may lead to disruptions in biological homeostasis. The subject of this article is the role of peptidases in the central nervous system in the formation of biologically active, receptor-specific peptides from peptide E, beta-endorphin, neurotensin, and cholecystokinin.

Amino Acid Sequence↗
PubMed2000

Potassium ion recycling pathway via gap junction systems in the mammalian cochlea and its interruption in hereditary nonsyndromic deafness.

In the mammalian cochlea, there are two independent gap junction systems, the epithelial cell gap junction system and the connective tissue cell gap junction system. Thus far, four different connexin molecules, including connexin 26, 30, 31, and 43, have been reported in the cochlea. The two networks of gap junctions form the route by which K+ ions that pass through the sensory cells during mechanosensory transduction can be recycled back to the endolymphatic space, from which they reenter the sensory cells. Activation of hair cells by acoustic stimuli induces influx of K+ ions from the endolymph to sensory hair cells. These K+ ions are released basolaterally to the extracellular space of the organ of Corti, from which they enter the cochlear supporting cells. Once inside the supporting cells they move via the epithelial cell gap junction system laterally to the lower part of the spiral ligament. The K+ ions are released into the extracellular space of the spiral ligament by root cells and taken up by type II fibrocytes. This uptake incorporates K+ into the connective tissue gap junction system. Within this system, the K+ ions pass through the tight junctional barrier of the stria vascularis and are released within the intrastrial extracellular space. The marginal cells of the stria vascularis then take up K+ and return it to the endolymphatic space, where it can be used again in sensory transduction. It is highly probable that mutations of connexin genes that result in human nonsyndromic deafness cause dysfunction of cochlear gap junctions and thereby interrupt K+ ion recirculation pathways. In addition to connexin mutations, other conditions may disrupt gap junctions within the ear. For example, mice with a functionally significant mutation of Brain-4, which is expressed in the connective tissue cells within the cochlea, show marked depression of the endolymphatic potential and profound sensorineural hearing loss. It seems likely that disruption of connective tissue cells by this mutation disrupts K+ ion entry into the stria vascularis and thereby results in loss of endolymphatic potential. The association of sensorineural hearing loss with these genetic disorders provides strong evidence for the necessity of gap junction systems for the normal functioning of the cochlea.

Animals↗
PubMed1988

Cell death in suboptic necrotic centers of chick embryo diencephalon and their topographic relationship with the earliest optic fiber fascicles.

The structural features of suboptic necrotic centers (SONCs) in the floor of the chick embryo diencephalon were studied. These necrotic areas were observed lateral to the prospective zone of the optic chiasm through developmental stages 14 to 24. The relationship between SONCs and the earliest optic fiber fascicles also was studied in an attempt to determine the possible significance of these cell death areas in the mechanism of optic pathway development. In SONCs, healthy neuroepithelial cells contain primary lysosomes and phagocytose fragments of dead cells. Discrete regions within the cytoplasm of some cells show electron-transparent vacuoles in contact with dense contents of ruptured lytic bodies. The cytoplasm of dying cells and dead cell fragments are notably electron dense, with numerous secondary lysosomes and electron-transparent vacuoles. These observations are interpreted on the assumption that after autophagic processes, condensation and fragmentation take place in dying cells of the SONCs. In the ventricular lumen adjacent to the SONCs, numerous more or less spherical bodies are observed that appear to be shed from the tip of the cells constituting the SONCs. Three different types of intraventricular bodies can be distinguished: loose, moderately dense, and highly dense. The first type appears to originate from apical portions of cells that undergo autolytic processes. Moderately dense fragments are interpreted as originating from dying cells in which the cytoplasm is undergoing condensation. Finally, highly dense intraventricular bodies appear to be fragments of dead cells that are shed into the ventricular lumen. SONCs separate the prospective area of the optic chiasm from lateral regions of the diencephalic floor. Extracellular spaces are poorly developed within the wall of the SONCs, whereas the neuroepithelium of the presumptive optic chiasm and regions located rostral and caudal to SONCs show abundant and extensive extracellular spaces. These are bounded by long marginal processes of neuroepithelial cells. Sagittal sections of embryonic heads at stages 22-24 reveal optic fiber fascicles penetrating the SONCs asymmetrically, as they are found only in its caudal half. These observations suggest that the SONCs function as doorways made of compact neuroepithelium, to be traversed by the earliest optic fibers before they reach the middle zone of the floor of the diencephalon through which they travel to the contralateral optic tract within large extracellular spaces.

Animals↗
PubMed1994

Astrocytes and axon regeneration in the central nervous system.

The failure of axons to regenerate in the central nervous system is mainly due to inhibition by the environment, made up of astrocytes and oligodendrocytes, which surrounds regions of damage. Both cell types are inhibitory to axon regeneration, and it seems likely that each will have to be neutralised before significant axon regeneration is achieved. Axons regenerate over the surface of astrocytes grown in normal monolayer culture but not through three-dimensional astrocyte cultures. Astrocyte cell lines have been created, some of which resemble embryonic astrocytes and form a loose tissue with extensive extracellular space which permits axon regeneration, and others which model astrocytes in the damaged brain having little extracellular space and much extracellular matrix material. There is no correlation between the inhibitory effect on axons and the expression of cell adhesion molecules, proteases, protease inhibitors, and a variety of extracellular matrix molecules. However, extracellular matrix produced by inhibitory cell lines is inhibitory to axon regeneration, while that produced by permissive cell lines is not. This difference depends on the production of a chondroitinase-sensitive proteoglycan which can block the neurite-inducing effects of laminin so that treatment of inhibitory extracellular matrix with chondroitinase renders it more permissive to axon regeneration.

Animals↗
PubMed1991

[Methodological considerations in microdialysis].

Microdialysis has rapidly become popular in recent years as an in vivo technique to monitor endogenous substances in the extracellular space of the local brain region. The combination of this technique with a variety of highly sensitive detection methods has enabled us to measure in vivo release of various neurotransmitters. However, the technique involves several methodological problems. The first is that the concentrations of substances in the dialysate only partially reflect their true concentrations in the extracellular space. Therefore, neurotransmitters such as neuropeptides that are present at very low concentrations in the extracellular space are still difficult to detect. The second problem is the effects of tissue damage by the microdialysis probe. Though the probe has been miniaturized, severe disturbance in tissue metabolism cannot be neglected. Histological examination suggests that the most suitable time for commencing microdialysis is between 24 and 48 h after probe implantation. The third problem is that neurotransmitters recovered in the dialysate are sometimes not involved in neurotransmission. It is suggested that the dialysate concentration of a neurotransmitter which reflects neuronal activity should be both tetrodotoxin-sensitive and calcium-dependent. In the case of a neurotransmitter in the dialysate which does not show these characteristics, its concentration may be related to metabolic rather than neurogenic events. The fourth problem is that microdialysis has poor time resolution. Therefore, the method is not suitable for measurement of neurochemical events that rapidly change in short intervals such as milliseconds or seconds. Thus careful consideration has to be given to these problems in the actual laboratory use of microdialysis technique.

Animals↗
PubMed1977

Changes in the cell coat at the onset of gastrulation in Xenopus laevis embryos.

Four developmental stages of Xenopus laevis embryos were fixed in standard electron microscopic fixatives with 1% lanthanum nitrate added. This treatment reveals a lanthanum staining material (LSM) on the cell surface and in extracellular spaces. Morula and blastula stage cells have a small amount of LSM; in blastulae, 3 +/- 3 SD % of the cell surface is coated with LSM. In early gastrulae, 29 +/- 6 SD % of the cell periphery is covered with LSM. In late gastrulae, 82 +/- 13 SD % of the cell periphery is either coated with LSM or faces a space with LSM in it. There is also an appreciable accumulation of LSM within extracellular spaces during gastrulation.

Animals↗
PubMed1990

The metabolism of low density lipoproteins by rat serosal mast cells.

Rat serosal mast cells contain secretory granules composed of a heparin proteoglycan matrix in which neutral proteases are embedded. Stimulation of the mast cells leads to granule exocytosis and formation of two pools of granules located extracellularly, firstly, granules expelled into the 'free' extracellular space and ultimately phagocytosed by the scavenging cells in the vicinity of mast cells and, secondly, granules which remain associated with their parent mast cells, and become internalized by them during recovery from stimulation. If mast cells are stimulated in the presence of macrophages in a low density lipoprotein (LDL)-containing medium, LDL is bound to the heparin proteoglycan component of the exocytosed granules whether they are expelled into the 'free' extracellular space or remain associated with the mast cells. The granules located in the 'free' extracellular space degrade, by the action of their neutral proteases, the apolipoprotein B component of the bound LDL. The proteolytic degradation of the granule-bound LDL results in its modification such that large fused LDL particles are formed on the granule surface. Phagocytosis, by macrophages, of the granules containing fused LDL particles leads to lysosomal degradation of LDL and cholesterol accumulation in macrophages as non-membrane-bound cholesteryl ester droplets, typical of foam cells. In contrast, the rapid internalization of the LDL-bearing, mast-cell-associated granules by recovering mast cells is not followed by lysosomal processing of LDL. Instead, it leads to cholesterol accumulation in mast cells, in the form of large, partially degraded, modified LDL particles, in the granule compartment.

Animals↗
PubMedDate not supplied

Reduced glutamate uptake by retinal glial cells under ischemic/hypoxic conditions.

The high-affinity uptake of glutamate by glial cells and neurons of the central nervous system, including the retina, serves to inactivate synaptically released glutamate and maintains glutamate at low concentrations in the extracellular space. This uptake prevents accumulation of glutamate extracellularly and thus minimizes the possibility of glutamate neurotoxicity secondary to ischemic insult. One mechanism whereby glutamate neurotoxicity may occur in ischemic/hypoxic insult is through increased extracellular K+ reversing the electrogenic glutamate uptake into retinal glial (Müller) cells. We investigated glial uptake of the amino acids glutamate, GABA, and D-aspartate in the intact isolated rat retina under high extracellular K+ conditions and under conditions simulating ischemia. Immunocytochemical findings showed that uptake of glutamate and GABA by MIller cells in the intact isolated rat retina continues under conditions simulating ischemia and high extracellular K+ conditions, and uptake of D-aspartate also continues under high K+ conditions. However, under high K+ conditions, the glutamate uptake system saturates at a lower concentration of exogenous glutamate than in the normal K+ condition. These findings provide evidence that disruption of glutamate uptake by Müller cells is likely to be a significant contributing factor to excess glutamate accumulation in the extracellular space which can lead to neurotoxicity.

Animals↗
PubMed1991

Extracellular volume decreases while cell volume is maintained by ion uptake in rat brain during acute hypernatremia.

1. Regulation of brain extracellular and intracellular water content, regarded as volume, and electrolytes in response to 90 min of hypernatremia has been studied in the cerebral cortex of rats under urethane anaesthetic. 2. Total tissue electrolytes and water were partitioned between extracellular and intracellular compartments based on measurements made in two series of experiments. In one, tissue samples were collected and analysed for total water, Na+, K+ and Cl-. In the other, tissue extracellular volume fraction, [Na+] and [K+] were measured in situ using ion-selective microelectrodes. 3. Osmotically induced water loss from cerebral cortex was less than that predicted for ideal osmotic behaviour, revealing a degree of volume regulation, and this regulation was associated with net tissue uptake of Na+, Cl- and K+. 4. Total water content was 3.77 g H2O (g dry weight)-1 in control cortex and this decreased by 7% after 30 min of hypernatremia and then remained relatively stable at this value. Control extracellular water content, based on an extracellular volume fraction of 0.18, was 0.88 g H2O (g dry weight)-1. Control intracellular water content, estimated as the difference between total and extracellular water contents, was 2.89 g H2O (g dry weight)-1. After 30 min of hypernatremia, extracellular water content decreased by an average of 27% but intracellular water did not change. This indicates selective regulation of cell volume. By 90 min the extracellular water content had decreased by 47% and the loss in extracellular water content appeared to be accompanied by a roughly equivalent increase in intracellular water content. The intracellular volume increase, however, was not statistically significant. The tortuosity of the extracellular space averaged 1.57 and increased to 1.65 during the hypernatremia. 5. Brain extracellular fluid and plasma [Na+] were roughly equal in control tissue. Both increased by 30 mu equiv (g H2O)-1 as a result of the hypernatremia, although extracellular [Na+] lagged behind the plasma value during much of the first 60 min of hypernatremia. Extracellular [K+] was homeostatically regulated at 3 mu equiv (g H2O)-1 independent of changes in plasma electrolytes. 6. Estimates of extracellular and intracellular ion content (mu equiv (g dry weight)-1) indicate that extracellular Na+, Cl- and K+ content decreased during hypernatremia, by 32, 21 and 42% respectively, whereas intracellular ion content increased by 100, 169 and 5% respectively. 7. It is concluded that during acute hypernatremia the extracellular space decreases in volume through the loss of water and electrolytes while the intracellular compartment maintains its water content and gains electrolytes.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2004

Anatomical remodelling of the supraoptic nucleus: changes in synaptic and extrasynaptic transmission.

The adult hypothalamic-neurohypophysial system undergoes activity-dependent morphological plasticity that modifies the astrocytic enwrapping of its magnocellular neurones. For a long time, the functional consequences of such changes have remained hypothetical. Modifications in the glial environment of neurones are expected to have important physiological repercussions in view of the various functions played by astrocytes in the central nervous system. In particular, glial cells are essential for uptake of neurotransmitters, including glutamate, and for physically and functionally restricting diffusion of neuroactive substances within the extracellular space. Recent studies performed in the supraoptic nucleus of lactating and chronically dehydrated animals, in conditions where astrocytic coverage of neurones is reduced, have revealed a significant impairment of glutamate clearance. The resulting accumulation of the excitatory amino acid in the extracellular space around glutamatergic inputs causes an enhanced activation of presynaptic metabotropic glutamate receptors that inhibit transmitter release. In the supraoptic nucleus of lactating rats, neuroglial remodelling is accompanied by modification of the geometry, size and diffusion properties of the extracellular space. The latter observations suggest that, in the activated supraoptic nucleus, the range of action and the concentration of released neuroactive substances may be significantly enhanced. Overall, our observations indicate that the glial environment of supraoptic neurones influences synaptic glutamatergic transmission, as well as extrasynaptic forms of communication.

Animals↗
PubMedDate not supplied

Glucose consumption and lactate production of human placental tissue under different conditions of in vitro incubation.

OBJECTIVE: To assess the glycolytic activity of human placental tissue in the third trimester as measured by glucose consumption and lactate production under different conditions of in vitro incubation. METHOD: An incubation technique was used to study the metabolic activity of the human placenta by comparing large blocks (0.3 cm3, T1) and small fragments (explants, 0.03 cm3, T2). Placentas were obtained from premature (28-33 weeks) and term (39-41 weeks) deliveries. In addition, different experimental conditions were used to investigate the influence of incubation medium (Earle's buffer and cell culture medium NCTC = 135), medium oxygen pressure (PO2) (400 and 30 mmHg), and regional sampling of placental tissue (central, intermediate, and peripheral). All media contained glucose (1 g/L). The tissue (2-3 g/25 mL medium, pH 7.2-7.4) was incubated for 3 hours at 37C. 3H-inulin was used for the determination of the extracellular space. RESULTS: Incubation of both tissue forms yielded a higher metabolic activity as measured by glucose consumption and lactate production when incubated with Earle's buffer compared with incubations with NCTC medium. In general, the metabolic activity was consistently higher for small fragments compared with the large blocks. Extracellular space values found for large fragments (25-31%) were significantly lower than for small pieces (39-46%), indicating that an equilibration of the medium with the extracellular space is inadequate with large fragments. Incubation with small fragments showed that 1) there is a tendency for higher metabolic activity during incubation with lower PO2, 2) the metabolically most active part of the placenta is the intermediate tissue region, and 3) placental metabolic activity was significantly higher at 28-33 weeks (n = 5) than at term (n = 6). These differences were not seen with large fragment incubations. CONCLUSION: The smaller tissue fragments are preferable for the in vitro incubation study of placental glucose metabolism. Apparently, there are differences in the metabolic activity with regard to the placental tissue region and gestational age.

Culture Media↗
PubMed1991

Time course of intracellular edema and epileptiform activity following prenatal cerebral ischemia in sheep.

The role of edema in the pathogenesis of hypoxic-ischemic injury in the immature brain is controversial. We studied 15 chronically instrumented fetal sheep following transient cerebral ischemia, to estimate changes in extracellular space using an impedance technique, to quantify the electroencephalogram with real-time spectral analysis, and to assess histologic outcome 3 days after the insult. These measurements were made in the parasagittal cortex. There was a rapid loss of extracellular space from 5 +/- 2 minutes after the onset of ischemia. Following 10 minutes of ischemia (n = 7) the intracellular edema peaked but then quickly resolved (6 +/- 4 minutes), and mild selective neuronal loss was seen. In contrast, the swelling was biphasic after 30-40 minutes of ischemia (n = 8). The early edema resolved slowly (28 +/- 12 minutes) but incompletely, and secondary swelling began at 7 +/- 2 hours and peaked at 28 +/- 6 hours. The early swelling was the more severe. Postinsult epileptiform activity began at 8 +/- 2 hours and peaked at 10 +/- 3 hours; later there was laminar necrosis of the underlying cortex. The secondary decrease of extracellular space indicates that a progressive loss of membrane function started with the onset of postischemic epileptiform activity. The increased metabolic load of the epileptiform activity may have worsened this delayed deterioration.

Animals↗
PubMed1994

Morphogenesis of amyloid plaques in 87V murine scrapie.

Amyloid plaques of scrapie-infected mouse brains are composed of fibrillar forms of a host coded, cell surface sialoglycoprotein called PrP (prion protein). Serial ultrastructural immunogold staining was performed on plaques identified by light microscopic immunocytochemistry of brains of VM mice infected with the 87V strain of scrapie. Classical plaques, of a kuru-type morphology, were composed of a central core of bundles of amyloid fibrils. Amyloid fibrils of classical plaques were immunoreactive for PrP. In addition, PrP was also found at the plaque periphery, in the absence of fibrils, at the plasmalemma of cell processes and in the associated extracellular spaces. Frequent microglial cells and occasional astrocytes contained PrP within lysosomes. Other plaques with few or no recognizable amyloid fibrils were frequent and were termed primitive plaques. PrP could be demonstrated in a non-fibrillar form at the plasmalemma and in the extracellular spaces between neurites of such plaques. Many primitive plaques showed little or no sub-cellular pathology associated with the PrP accumulation. PrP was closely associated with the plasmalemma of occasional dendrites passing towards the centre of primitive plaques. These results suggest that plaques are formed around one or more PrP releasing dendrites. PrP accumulates in the extracellular spaces adjacent to such processes prior to its spontaneous aggregation into fibrils. Lysosomal accumulation of PrP in microglia and astrocytes located at the periphery of plaques suggest that these cells are involved in the phagocytosis of excess or abnormal PrP.

Amyloid↗
PubMed2001

Available space and extracellular transport of macromolecules: effects of pore size and connectedness.

Molecular exclusion in tumor tissues is one of the limiting factors for drug delivery to tumor cells. It can be quantified by the available volume fraction of solutes (K(AV)). We found in a previous study that K(AV) of dextran in tumor tissues decreased sharply when the molecular weight (MW) of dextran was increased from 40,000 to 70,000. Outside this range, K(AV) was less sensitive to the MW of dextran. To understand the mechanisms of the MW dependence of K(AV), we investigated K(AV) in tissue phantoms composed of tumor cells in 1% agarose gels, and performed numerical simulations of the available volume fraction in pore networks. We found that the MW dependence of K(AV) in tissue phantoms was similar to that in tumor tissues when the volume fraction of cells in the former was approximately 30%. Our numerical simulations revealed that the sharp decrease in K(AV) required two necessary conditions: (i) the existence of at least two populations of pores and (ii) the lack of connectedness of available pores in the interstitial space. Furthermore, results in this study suggest that it is important to consider not only the local structures of pores but also their connectedness in analyses of molecular transport in tissues.

Biological Transport, Active↗