Interstitial fluid movement

The basic equations for mass transfer were derived in Chapter 3. The overall rate of change in local concentration depends on both the rate of diffusion and the rate of fluid flow (see Table 3.2)  

In the presence of fluid flow (v 7 0), changes in bulk fluid velocity with position and time must be included in the description of mass transfer. This discussion follows the approaches used in previously published analyses of convection in tissues [5, 6]. 

Fluid flow through a porous medium (such as the interstitial space of a tissue) can be analyzed using Darcy s law  

Chondroitin sulfate (deacetylated) Chondroitin sulfate in 1 M NaCI Chondroitin sulfate in PBS Hyaluronate 

Only a few experimental measurements of the rate of fluid movement in the interstitial space of tissues have been reported. Much is still to be discovered, but these initial studies are sufficient to provide guidance on the importance of convection in drug delivery to different tissues (Table 6.1). 

---

The basal metabolic rate for adults is 1 to 1.2 Calories/minute or 60 to 72 Calories/hour. This energy powers the movement of the chest during respiration and the beating of the heart—processes that are obviously necessary for life. However, a surprisingly large fraction of the BMR is used by cells to maintain ionic gradients between their interior and the fluid that surrnunds them (the interstitial fluid nr tissue fluid). 

Understanding the effects of colloid administration on circulating blood volume necessitates a review of those physiologic forces that determine fluid movement between capillaries and the interstitial space throughout the circulation (Fig. 10—5).4 Relative hydrostatic pressure between the capillary lumen and the interstitial space is one of the major determinants of net fluid flow into or out of the circulation. The other major determinant is the relative colloid osmotic pressure between the two spaces. Administration of exogenous colloids results in an increase in the intravascular colloid osmotic pressure. In the case of isosomotic colloids (5% albumin, 6% hetastarch, and dextran products), initial expansion of the intravascular space is essentially that of the volume of colloid administered. In the case of hyperoncotic solutions such as 25% albumin, fluid is pulled from the interstitial space into the vasculature... 

The movement of cutaneous interstitial fluids varies from a 3- to 4-fold range in normal individuals as determined by injecting riboflavin intradermally and recording the time required for one-half its fluorescence to disappear.31 When repeated tests were made on three individuals it was found that one gave relatively highly variable results. (S. D. 48.4), and the others gave relatively constant results (S.D. 9.5 and 5.8). 

The pressure that would be required to prevent the movement of water across a semipermeable membrane owing to the osmotic effect of interstitial fluid particles (jtj mmHg). 

The interstitial fluid content of the skin is higher than in the subcutaneous fat layer and normal fluid movement is intrinsically finked to lymphatic drainage as governed by mechanical stresses of the tissue. A model of temporal profiles of pressure, stress, and convective ISF velocity has been developed based on hydraulic conductivity, overall fluid drainage (lymphatic function and capillary absorption), and elasticity of the tissue.34 Measurements on excised tissue and in vivo measurement on the one-dimensional rat tail have defined bulk average values for key parameters of the model and the hydration dependence of the hydraulic flow conductivity. Numerous in vivo characterization studies with nanoparticles and vaccines are currently underway, so a more detailed understanding of the interstitial/lymphatic system will likely be forthcoming. 

Permeation of mAbs across the cells or tissues is accomplished by transcellular or paracellular transport, involving the processes of diffusion, convection, and cellular uptake. Due to their physico-chemical properties, the extent of passive diffusion of classical mAbs across cell membranes in transcellular transport is minimal. Convection as the transport of molecules within a fluid movement is the major means of paracellular passage. The driving forces of the moving fluid containing mAbs from (1) the blood to the interstitial space of tissue or (2) the interstitial space to the blood via the lymphatic system, are gradients in hydrostatic pressure and/or osmotic pressure. In addition, the size and nature of the paracellular pores determine the rate and extent of paracellular transport. The pores of the lymphatic system are larger than those in the vascular endothelium. Convection is also affected by tortuosity, which is a measure of hindrance posed to the diffusion process, and defined as the additional distance a molecule must travel in a particular human fluid (i. e., in vivo) compared to an aqueous solution (i. e., in vitro). 

Considerable losses of body water may occur rather suddenly via hemorrhage or more slowly via severe diarrhea or vomiting. Excessive losses of blood volume cause shock, which may set in when 25-30% of the blood volume is lost. The physiologic mechanism to correct for blood loss involves the rapid movement of interstitial fluid into the circulatory system, into which as much as 50% of the interstitial fluid may thus be transferred within a matter of a few hours. The interstitial fluid is, in turn, partially replaced by intracellular fluid however, this is a much slower process, and 1 or 2 days is required to reestablish a fluid equilibrium in the organism. The lost fluids and electrolytes must eventually be replaced through diet or intravenous feeding. 

Fig. 9 Cerebellar infarct with secondary hydrocephalus and transependymal fluid movement (interstitial edema), (a) Initial diffusion-weighted image with cerebellar infarct in the territory of the left posterior inferior cerebellar artery, (b) Echo-planar T2 axial image shows enlargement of the ventricles prior to surgery for hydrocephalus. Arrow shows transependymal movement of fluid...

The main advantage associated with the kinetic theory approach for dense suspensions is the appearance of two extra pressure terms in addition to the interstitial fluid phase pressure, one kinetic pressure tensor accounting for the transport phenomena due to the translational particle movement and one collisional pressure tensor accounting for the transport phenomena due to particle collisions. 

Fig. 2 Continued, (c) These macromolecules move toward the center by the slow process of diffusion (=>). In addition, interstitial fluid oozing from tumor carries macromolecules with it by convection (- ) into the normal tissue. Note that the interstitial movement may be further retarded by binding. Products of metabolism may be cleared rapidly by blood. (Reproduced with permission from Jain, 1989.) These transport processes have been mathematically modeled by Jain and Baxter (1988) and Baxter and Jain (1989, 1990, 1991a, b).

Oncotic pressure (or colloid osmotic pressure) is the osmotic pressure that results from the difference between the protein (mainly albumin) concentrations of plasma and the interstitial fluid. Water is lost from the body via feces, urine, salivation, insensible respiration, and through the skin, with sensible perspiration of sweat occurring in a few species. Although the movement of proteins between spaces is restricted, water and small ions can move across permeable membranes between the spaces. The volume of ECF is highly dependent on its sodium concentration and, under physiological conditions, the sodium ion concentrations of plasma and interstitial fluids are similar. 

In the capillary beds of most organs, a rapid passage of molecules occurs from the blood through the endothelial wall of the capillaries into the interstitial fluid. Thus, the composition of interstitial fluid resembles that of blood, and specific receptors or transporters in the plasma membrane of the cells being bathed by the interstitial fluid may directly interact with amino acids, hormones, or other compounds from the blood. In the brain, transcapillary movement of substrates in the peripheral circulation into the brain is highly restricted by the blood-brain barrier. This barrier hmits the accessibility of blood-borne toxins and other potentially harmful compounds to the neurons of the CNS. 

The rate of molecular movement by diffusion decreases dramatically with distance, and is generally inadequate for transport over distances greater than 100/rm (recall Table 4.8). The movement of molecules over distances greater than 100 jxro. occurs in specialized compartments in the body blood circulates through arteries and veins interstitial fluid collects in lymphatic vessels before returning to the blood cerebrospinal fluid (CSF) percolates through the central nervous system (CNS) in the brain ventricles and subarachnoid space. In these systems, molecules move primarily by bulk flow, or convection. 

Interstitial flows were measured by observing the motion of a spot bleached into fluorescent interstitial fluid in a tissue window preparation [10]. In this system, the fluid velocity was 0.2/ m/s parallel to the vessel and 0.75/xm/s perpendicular to the vessel. Convection was heterogeneous throughout the tissue region, but over a relatively small range (0.1 < u < 1 /xm/s). This rate of interstitial flow corresponds to a Peclet number (Pe) for BSA and IgG of 1, suggesting that convection and diffusion are equally important in the movement of macromolecules in the interstitial space. 

Distribution describes the movement of a compound from its site of absorption to other areas of the body. When a compound is absorbed it passes through absorptive cells into the interstitial fluid of the organ these body fluids (interstitial fluid, intracellular fluid, and blood plasma) are not isolated and separate, but represent one continuous pool. In contrast to fast-moving blood that allows mechanical transport to occur, interstitial- and intracellular fluids remain in place with a slow movement of components such as water and electrolytes into and out of cells. Any compound can leave the interstitial fluid by entering local tissue cells, the circulating blood, or the lymphatic system. After entry into... 

Transport of interstitial fluid toward the lymphatics requires convective flow, since it needs to be focused on relatively few channels in the interstitium. Diffusion cannot serve such a purpose because diffusion merely disperses fluid and proteins. Lymph formation and flow greatly depend upon tissue movement or activity related to muscle contraction and tissue deformations. It is also generally agreed that formation of initial lymph depends solely on the composition of nearby interstitial fluid and pressure gradients across the interstitial/lymphatic boundary [Zweifach and Lipowsky, 1984 Hargens, 1986]. For this reason, lymph formation and flow can be quantified by measuring disappearance of isotope-labeled albumin from subcutaneous tissue or skeletal muscle [Reed et al., 1985]. 

Substances ttansported by the blood to tissue cells move frtmi the blood, through capillary walls, into the interstitial fluid, then through cell membranes, and finally into the cytoplasm of the cells. Waste products of the cells move in the opposite direction. The movement of fluid through capillary walls is governed by the blood pressure against the capillary walls and by osmotic pressure differences that arise from protein concentration differences between blood and interstitial fluid. 

These movements of hydrogen and bicarbonate ions in opposite directions across the cell membrane of the tubular cells are of necessity accompanied by the movement of other charged particles to ensure that the net transfer of charge is zero. The principal contribution to provide this balance is by sodium ions, which move from tubular fluid to interstitial fluid as shown in Figure 1.4. 

Figure 3j5. A. The movements of hydrogen and potassium ions between intra- and extracellular fluid compartments produced by a fall in hydrogen ion concentration of the extracellular fluid. B. Similarly for a fall in potassium ion concentration of the extracellular fluid. C. Movements of ions between the renal tubular fluid and the renal interstitial fluid sodium, chloride and bicarbonate are reabsorbed, hydrogen and potassium ions are secreted.

The total transfer of charge across the tubular wall must be zero if this were not so, a large electrical potential would rapidly develop and prevent further net movement of charge. For every Mole of sodium ions transferred from tubular fluid to the renal interstitial fluid, there must be an accompanying Mole of charge to balance this. Whilst most of this is matched by chloride, the movement of other ions must make good the disparity. As shown by the... 

---