Effects of hydration on steric and electric charge-induced interstitial volume exclusion--a model

Abstract

The presence of collagen and charged macromolecules like glycosaminoglycans (GAGs) in the interstitial space limits the space available for plasma proteins and other macromolecules. This phenomenon, known as interstitial exclusion, is of importance for interstitial fluid volume regulation. Physical/mathematical models are presented for calculating the exclusion of electrically charged and neutral macromolecules that equilibrate in the interstitium under various degrees of hydration. Here, a central hypothesis is that the swelling of highly electrically charged GAGs with increased hydration shields parts of the neutral collagen of the interstitial matrix from interacting with electrically charged macromolecules, such that exclusion of charged macromolecules exhibits change due to steric and charge effects. GAGs are also thought to allow relatively small neutral, but also charged macromolecules neutralized by a very high ionic strength, diffuse into the interior of GAGs, whereas larger macromolecules may not. Thus, in the model, relatively small electrically charged macromolecules, such as human serum albumin, and larger neutral macromolecules such as IgG, will have quite similar total volume exclusion properties in the interstitium. Our results are in agreement with ex vivo and in vivo experiments, and suggest that the charge of GAGs or macromolecular drugs may be targeted to increase the tissue uptake of macromolecular therapeutic agents.

Keywords: 1-particles; 2-particles; 3-particles; A; A [as subscript]; DCL(z); Debye length; GAGs, glycosaminoclycans [also as subscript]; H(z); L; N1in; O; Q(1), Q(2); T; VO; VT; albumin- or macromolecules in general [also as subscript]; available; available volume of charged particle; available volume of small neutral macroparticle; available volume per unit volume for large neutral macroparticles; average volume density of macromolecules, as albumin, in cell; axial length of equilibration cell; charge part per unit volume of excluded volume; circular cross-section area of equilibration cell; collagen particles [also as subscript]; core radius of GAG; d1, d2 = 2H(z), d3; dCL; diameters of 1-, 2-, and 3-particles; distance between two side-by-side GAGs- or collagen particle centers; distance of closest approach in GAG-albumin interactions; distance of closest approach in albumin-albumin interactions; effective density of collagen particles; electrical charge on particle I; excluded volume per unit volume for large neutral macroparticles; excluded volume per unit volume of charged macroparticle; excluded volume per unit volume of small neutral macroparticle; highest thickness value; hydration; inside cell tissue [also as subscript]; l; lowest thickness value; n1T(z), n1O(z); n1in; n2, n3; n3eff(z); number densities of 2- and 3-particles; number of macromolecules, as albumin, poured into cell; outside cell tissue [also as subscript]; outside tissue-cell volume; p1; pressure of 1-particles; r; radial distance; radius of GAGs as function of tissue thickness; rmin; thickness of tissue sample; tissue-cell volume; volume density of 1-particles in tissue, outside tissue; volume of collagen-, GAG- and macroparticle material per unit volume of tissue; volume of water per unit volume of tissue (water content); z; z1; z2; ζ; λD; νA; νA0G; νAO; νE; νE00; νE0G; νEO; νH2O; νQ.