Hindered diffusion of dextran and ficoll in microporous membranes

Bohrer, M. P.; Patterson, G. D.; Carroll, Patrick J.

doi:10.1021/ma00136a011

Cited by 158 publications

(125 citation statements)

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“…23 Bohrer et al used light scattering techniques and suggested that ficoll was shaped more like a sphere than a rod. 24 Ohlson et al and Oliver et al reached the same conclusion. 25,26 Venturoli et al reviewed the literature and concluded that ficoll also exhibits "nonideal" properties due to an open, deformable structure and thus that it deviates from an ideally hard sphere in nature.…”

mentioning

confidence: 63%

Influence of molecular shape, conformability, net surface charge, and tissue interaction on transscleral macromolecular diffusion

Srikantha

Mourad

Suhling

et al. 2012

Experimental Eye Research

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Purpose: To study the influence of molecular shape, conformability, net surface charge and tissue interaction on transscleral diffusion.Methods: Unfixed, porcine sclera was clamped in an Ussing chamber. Fluorophore labelled, neutral, albumin, dextran, or ficoll were placed in one hemi-chamber and the rate of transscleral diffusion was measured over 24 hours using a spectrophotometer. Experiments were repeated using dextrans and ficoll with positive, or negative, net surface charges.Fluorescence recovery after photobleaching (FRAP) was undertaken to compare transscleral diffusion with diffusion through a solution.All molecules were 70 kDa.Results: Using FRAP, mean ± SD diffusion coefficient (D) was highest for albumin, followed by ficoll, then dextran (p = 0.0005). Positive dextrans diffused fastest, followed by negative, then neutral dextrans (p = 0.0005). Neutral ficoll diffused the fastest, followed by positive then negative ficoll (p = 0.0008). For the neutral molecules, transscleral D was highest for albumin, followed by dextran, then ficoll (p < 0.0001). D was highest for negative ficoll, followed by neutral, then positive ficoll (p < 0.0001). By contrast, D was highest for positive dextran, followed by neutral, then negative dextran (p = 0.0021).Conclusions: Diffusion in free solution does not predict transscleral diffusion and the molecular-tissue interaction is important. Molecular size, shape, and charge may all markedly influence transscleral diffusion, as may conformability to a lesser degree, but all need to be considered when selecting or designing drugs for transscleral delivery.Drugs directed against vascular endothelial growth factor (VEGF) have proven efficacy in some of the most common retinal diseases. The ANCHOR and MARINA studies demonstrated efficacy in wet age-related macular degeneration (AMD), 1,2 and studies such as CRUISE, BRAVO 3,4 and several from the DRCnet Group have shown favourable results in retinal vein occlusion and diabetic macular oedema. Whilst the data in these studies have led to improved clinical care, the need for regular intravitreal injections represents a burdensome regimen of treatment. A less invasive mode of delivery would have potential advantages in terms of reduced cost, discomfort, and complication rate.Systemic administration is impeded by the blood-aqueous and blood-retinal-barriers. High drug concentrations may be required to overcome these barriers to diffusion, with the attendant risk of systemic side effects. 5 A topical route would have obvious advantages. Delivery to the retina is however difficult for several reasons, such as lacrimation, low corneal permeability to large molecules, counter directional intraocular convection, and importantly the long diffusional distance. 53 Blood flow in the conjunctiva, episclera and choroid can also reduce drug concentration. 33,50 Notwithstanding these potential difficulties, transscleral delivery has a number of potential advantages. 6,7,8,9 The sclera has a large and accessible surface area, and a high d...

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mentioning

confidence: 63%

Influence of molecular shape, conformability, net surface charge, and tissue interaction on transscleral macromolecular diffusion

Srikantha

Mourad

Suhling

et al. 2012

Experimental Eye Research

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“…Studies in the rat have shown that, for a given value of molecular radius, dextran passes through the glomerular capillary wall more readily than does another uncharged test macromolecule, Ficoll (6,36). Diffusion studies with synthetic membranes suggest that Ficoll behaves like the neutral, spherical molecule envisioned in the theory of hindered transport through pores, whereas transmembrane diffusion of dextran is more rapid than expected from its molecular radius (37,38). This facilitation ofdextran transport implies that the use ofdextran data to evaluate membrane pore parameters will tend to overestimate the effective pore size (36).…”

Section: Discussionmentioning

confidence: 99%

Charge selectivity of the glomerular filtration barrier in healthy and nephrotic humans.

Guasch¹,

Deen²,

Myers³

1993

J. Clin. Invest.

138

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We used dextran sulfate (DS) to evaluate barrier charge selectivity in 11 nonproteinuric subjects and in 11 patients with the nephrotic syndrome due to either membranous nephropathy or minimal change nephropathy. The 3H-DS preparation spanned a molecular radius interval of 10-24A and exhibited size-dependent protein binding in vitro. Urine and ultrafiltrates of plasma were separated by size into narrow fractions using gel permeation chromatography. The sieving coefficient (0) for ultrafilterable DS of 15A radius averaged 0.68±0.03 in nonproteinuric vs. 0.95±0.05 in nephrotic subjects (P < 0.001). Uncharged dextrans of broad size distribution were used to evaluate barrier size-selectivity in separate groups of nonproteinuric subjects (n = 19) and nephrotic patients with either minimal change (n = 20) or membranous nephropathy (n = 27). The value of 0 for an uncharged dextran of similarly small radius (-18A) was significantly larger than that observed for DS in nonproteinuric subjects, but was similar in nephrotic individuals. Further, impaired barrier size-selectivity, as assessed by the sieving profile for uncharged dextrans (18-60A radius), failed to account fully for the observed level of albuminuria in almost half of the patients with either minimal change (9/20) or membranous nephropathy (12/27). Together these findings suggest that the human glomerular capillary wall normally provides an electrostatic barrier to filtration of negatively charged macromolecules such as albumin, and that impairment of this electrostatic barrier contributes to the magnitude of albuminuria in the nephrotic syndrome. (J. Clin. Invest. 1993.

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“…For artificial membranes with track-etched pores, the diffusion of dextran and Ficoll has been analyzed according to conventional hydrodynamic pore models for diffusion of hard spheres in cylindrical tubes (7). In experimental systems with such porous membranes, the agreement between data and theory was poor for dextran, whereas it was much better for Ficoll.…”

Section: In Vitro Polysaccharide Permeability Across Porous Membranesmentioning

confidence: 99%

“…In experimental systems with such porous membranes, the agreement between data and theory was poor for dextran, whereas it was much better for Ficoll. Dextran showed considerable hyperpermeability, and even when the ratio of molecular radius (a e ) to pore radius (r p ) (a e /r p ) approached unity, dextran was able to pass through the membrane (7). In other words, dextran molecules were able to pass through membrane pores with a smaller diameter than the molecule itself.…”

Section: In Vitro Polysaccharide Permeability Across Porous Membranesmentioning

confidence: 99%

Ficoll and dextran vs. globular proteins as probes for testing glomerular permselectivity: effects of molecular size, shape, charge, and deformability

Venturoli¹,

Rippe²

2005

American Journal of Physiology-Renal Physiology

393

408

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Venturoli, Daniele, and Bengt Rippe. Ficoll and dextran vs. globular proteins as probes for testing glomerular permselectivity: effects of molecular size, shape, charge, and deformability. Am J Physiol Renal Physiol 288: F605-F613, 2005; doi:10.1152/ajprenal.00171.2004.-Polydisperse mixtures of dextran or Ficoll have been frequently used as molecular probes for studies of glomerular permselectivity because they are largely inert and not processed (reabsorbed) by the proximal tubules. However, dextrans are linear, flexible molecules, which apparently are hyperpermeable across the glomerular barrier. By contrast, the Ficoll molecule is almost spherical. Still, there is ample evidence that Ficoll fractional clearances (sieving coefficients) across the glomerular capillary wall (GCW) are markedly higher than those for neutral globular proteins of an equivalent in vitro Stokes-Einstein (SE) radius. Physical data, obtained by "crowding" experiments or measurements of intrinsic viscosity, suggest that the Ficoll molecule exhibits a rather open, deformable structure and thus deviates from an ideally hard sphere. This is also indicated from the relationship between (log) in vitro SE radius and (log) molecular weight (MW). Whereas globular proteins seem to behave in a way similar to hydrated hard spheres, polydisperse dextran and Ficoll exhibit in vitro SE radii that are much larger than those for compact spherical molecules of equivalent MW. For dextran, this can be partially explained by a high-molecular-size asymmetry. However, for Ficoll the explanation may be that the Ficoll molecule is more flexible (deformable) than are globular proteins. An increased compressibility of Ficoll and an increased deformability and size asymmetry for dextran may be the explanation for the fact that the permeability of the GCW is significantly higher when assessed using polysaccharides such as Ficoll or dextran compared with that obtained using globular proteins as molecular size probes. We suggest that molecular deformability, besides molecular size, shape, and charge, plays a crucial role in determining the glomerular permeability to molecules of different species. capillary permeability; polysaccharides; macromolecules; reflection coefficient; transport POLYDISPERSE MIXTURES OF DEXTRAN, and more recently Ficoll, are frequently used as molecular probes in studies of glomerular permselectivity. After being filtered through the glomerular capillary wall (GCW), polysaccharides, unlike proteins, are left unreabsorbed by the proximal tubules. This implies that their sieving coefficients (), i.e., their filtrate-to-plasma concentration ratios, can be determined directly from their urinary clearances relative to that of a glomerular filtration rate marker (e.g., inulin). Infusing polydisperse mixtures of dextran or Ficoll and using chromatographic techniques to fractionate plasma and urine samples make it possible to simultaneously determine the for a wide spectrum of different-sized molecular probes, provided that proper size calibrations ...

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Hindered diffusion of dextran and ficoll in microporous membranes

Cited by 158 publications

References 4 publications

Influence of molecular shape, conformability, net surface charge, and tissue interaction on transscleral macromolecular diffusion

Influence of molecular shape, conformability, net surface charge, and tissue interaction on transscleral macromolecular diffusion

Charge selectivity of the glomerular filtration barrier in healthy and nephrotic humans.

Ficoll and dextran vs. globular proteins as probes for testing glomerular permselectivity: effects of molecular size, shape, charge, and deformability

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