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Interstitial Fluid

Keywords and Terms: interstitial fluid, extracellular fluid, transcellular fluid, intracellular fluid, tissue fluid, lymphedema, edema, osmosis, lymphatic capillary plexus, subcutaneous interstitial fluid

Everyone of us with lymphedema has heard that our swelling is due to the collection of interstitial fluid and the lymphatic system’s inability to remove it.

But, what exactly is interstitial fluid? What does it do and what is it made of?

Definition Tissue Fluid

Interstitial fluid (or tissue fluid, or intercellular fluid) is a solution which bathes and surrounds the cells of multicellular animals.

It is the main component of the extracellular fluid, which also includes plasma, lymph and transcellular fluid.

On average, a person has about 11 litres (2.4 imperial gallons) of interstitial fluid providing the cells of the body with nutrients and a means of waste removal. The hydrostatic pressure is generated by the pumping force of the heart. It pushes water out of the capillaries.

The water potential is created due to the inability of large solutes to pass through the capillary walls. This buildup of solutes induces osmosis. The water passes from a high concentration (of water) to a low concentration in an attempt to reach an equilibrium. This draws water back into the vessels. Because the blood in the capillaries is constantly flowing, equilibrium is never reached.

The balance between the two forces is different at different points in the capillaries. At the arterial end of the vessel, the hydrostatic pressure is greater than the water potential, so the net movement (see net flux) favors water and other solutes being passed into the tissue fluid. At the venous end, the water potential is greater, so the net movement favours substances being passed back into the capillary. This difference is created by the direction of the flow of blood, and the imbalance in solutes created by the net movement of water favoring the tissue fluid. (1)

Interstitial Fluid Collection Flow

Interstitial fluid, collected by the initial lymphatic capillary plexus, is transported by pre-collector lymphatic vessels to larger collecting lymphatic vessels and returned to the circulation through the thoracic duct. Collecting lymphatic vessels have smooth muscle cell coverage (red) and luminal valves to propel and maintain unidirectional lymph flow. Deep lymphatic vessels run along arteries and veins. b, Schematic cross-section of skin, showing the relative positions of blood and lymphatic vessels. c, Mechanism of interstitial tissue fluid uptake by a lymphatic capillary. Plasma components, extravasated white blood cells and particulate matter, such as bacteria, enter the lymphatic vessels through loose valve-like openings. Lymphatic vessels are linked to the extracellular matrix by anchoring filaments. The latter are very thin (4–10 nm) fibrillin-containing filaments, which are inserted into the endothelial cell plasma membrane. Anchoring filaments prevent vessel collapse in conditions of high interstitial pressure.(2)

Composition of Lymph Fluid and Interstitial Fluid


Each cell in the body of a multicellular organism is somewhat specialized and cannot survive independant from other cells. Because a cell is dependant on other cells it can only survive in a specific enviroment (milieu). This internal environment, also called cell milieu, is a thin layer of fluid, namely the tissue fluid or interstitial fluid which envelopes and bathes the living cells of the body.

Tissue fluid

Tissue fluid is basically blood plasma with a great reduced protein content, because the plasma proteins are too large to diffuse through the capillary walls. Like blood plasma, tissue fluid is a pale, straw-coloured tissue. Tissue is the medium in which the cells live. It therefore plays an important role in homeostasis, i.e. it helps to maintain a constant environment in which the cell can live. In order for the cells to remain alive and healthy, the tissue fluid must remain in a stable condition, i.e. it must receive a constant supply of oxygen and food, and the waste products must be removed from it.

Mammals have a special transport system made up of branching vessels that return fluids and their contents from the tissues to the blood. These vesels are known as lymph vessels. All the vessels together constitute the lymphatic system, which include lymph veins and {glossary:lymph capillary|lymph capillaries]]. The lymph capillaries are distributed throughout most of the body (except the nervous system). The lymph capillaries are closed at one end.


Composition of interstitial fluid

N Fogh-Andersen, BM Altura, BT Altura and O Siggaard-Andersen Department of Clinical Chemistry, Herlev Hospital, Denmark.

In several previous experiments to determine the composition of interstitial fluid, the results varied depending on the collecting technique, and the electrolyte concentrations differed from those of a hypothetical ultrafiltrate of plasma. In our approach, since a change of position from standing to supine is accompanied by hemodilution with interstitial fluid, we used the changes in hematocrit and composition of plasma in 20 subjects before and after lying down to calculate the composition of added interstitial fluid. The estimated protein concentration was 20.6 g/L, and the concentrations of total calcium and magnesium were low, in accord with a lower concentration of protein- bound calcium and magnesium. The activity of free cations was also lower, in agreement with a Donnan equilibrium potential of 1 mV across the endothelium. The concentration of leukocytes and platelets decreased according to the hemodilution, implying no escape or mobilization of these elements.

Clinical Chemistry

Fluid Physiology

Intracellular Fluid

The Intracellular Fluid is composed of at least 1014 separate tiny cellular packages. The concept of a single united “compartment” called intracellular fluid is clearly artificial. The ICF compartment is really a “virtual compartment” considered as the sum of this huge number of discontinuous small collections. How can the term ‘intracellular fluid’ be used as though it was a single body of fluid? The reason is that though not united physically, the collections have extremely important unifying similarities which make the ICF concept of practical usefulness in physiology. In particular, similarities of location, composition and behaviour:

Location: The distinction between ICF and ECF is clear and is easy to understand: they are separated by the cell membranes.

Composition: Intracellular fluids are high in potassium and magnesium and low in sodium and chloride ions.

Behaviour: Intracellular fluids behave similarly to tonicity changes in the ECF.

Because of this physiological usefulness, it is convenient to talk of an idealised ICF as though it were a single real entity. The use of this convention allows predictions to be made about what will happen with various interventions and within limits these are physiologically meaningful.

Extracellular Fluid

A similar argument applies to the Extracellular Fluid. The ECF is divided into several smaller compartments (eg plasma, Interstitial fluid, fluid of bone and dense connective tissue and transcellular fluid). These compartments are distinguished by different locations and different kinetic characteristics. The ECF compositional similarity is in some ways, the opposite of that for the ICF (ie low in potassium & magnesium and high in sodium and chloride).

Interstitial fluid (ISF) consists of all the bits of fluid which lie in the interstices of all body tissues. This is also a ‘virtual’ fluid (ie it exists in many separate small bits but is spoken about as though it was a pool of fluid of uniform composition in the one location). The ISF bathes all the cells in the body and is the link between the ICF and the intravascular compartment. Oxygen, nutrients, wastes and chemical messengers all pass through the ISF. ISF has the compositional characteristics of ECF (as mentioned above) but in addition it is distinguished by its usually low protein concentration (in comparison to plasma). Lymph is considered as a part of the ISF. The lymphatic system returns protein and excess ISF to the circulation. Lymph is more easily obtained for analysis than other parts of the ISF.

Plasma is the only major fluid compartment that exists as a real fluid collection all in one location. It differs from ISF in its much higher protein content and its high bulk flow (transport function). Blood contains suspended red and white cells so plasma has been called the ‘interstitial fluid of the blood’. The fluid compartment called the blood volume is interesting in that it is a composite compartment containing ECF (plasma) and ICF (red cell water).

The fluid of bone & dense connective tissue is significant because it contains about 15% of the total body water. This fluid is mobilised only very slowly and this lessens its importance when considering the effects of acute fluid interventions.

Transcellular fluid

Transcellular fluid is a small compartment that represents all those body fluids which are formed from the transport activities of cells. It is contained within epithelial lined spaces. It includes CSF, GIT fluids, bladder urine, aqueous humour and joint fluid. It is important because of the specialised functions involved. The fluid fluxes involved with GIT fluids can be quite significant. The electrolyte composition of the various transcellular fluids are quite dissimilar and typical values or ranges for some of these fluids are listed in the Table.

The total body water is divided into compartments and useful physiological insight and some measure of clinical predictability can be gained from this approach even though most of these fluid compartments do not exist as discrete real fluid collections.



Bates DO, Levick JR, Mortimer PS.

Department of Physiological Medicine, St George's Hospital Medical School, London, U.K.

1. The pathophysiology of chronic arm oedema after treatment of breast cancer was investigated by collecting serum and subcutaneous interstitial fluid from the affected and contralateral arms by the wick method (both arms) and by aspiration (oedematous arm). The fluids were analysed for total protein, albumin, glycosaminoglycan and viscosity, and arm volume was measured.

2. Total protein concentration in the aspirated oedema fluid was 32.4 +/- 7.5 g/l (mean +/- SD throughout; n = 39). Protein concentration in wick fluid from the oedematous arm (35.8 +/- 7.3 g/l, n = 14) was not significantly different from that in aspirated fluid. The oedema protein concentrations were significantly lower than in wick fluid from the non-swollen arm (41.4 +/- 6.7 cmH2O, n = 13, P < 0.01, analysis of variance). This was surprising in view of the common assumption that, the condition being of lymphatic origin, the oedema protein concentration should be raised.

3. The ratio of aspirate protein concentration to serum protein concentration showed a weak but highly significant negative correlation with the percentage increase in arm volume (r = -0.47, n = 35, P < 0.005), again in contrast to conventional expectation. The demonstration of a reduced protein concentration in the swollen arm did not therefore depend solely on a comparison with the wick control results. The volume increased by on average 33% and the ratio of aspirate protein concentration to serum protein concentration averaged 0.52 +/- 0.11 on the swollen side and 0.64 +/-0.13 on the unaffected side.

4. Serum protein concentration in the patients with arm swelling (61.2 +/- 4.9 g/l) was significantly lower than that in postmastectomy patients without this complication (65.0 +/- 6.2 g/l). Most of the decrease occurred in the albumin fraction (oedema patients, 38.3 +/- 5.1 g/l; control patients, 42.0 +/- 2.1 g/l). In oedema patients receiving the anti-oestrogen tamoxifen serum albumin concentration was on average 2.3 g/l lower than in oedema patients not under medication (P < 0.05, t-test).

5. Glycosaminoglycan concentration in oedema fluid was 0.8 +/- 0.14 g/l (n = 21) and 75% was sulphated. Along with the plasma protein this raised the relative viscosity of the fluid to 1.34 +/- 0.16 (n = 11). 6. The reduction in interstitial protein concentration in the swollen arm, contrary to expectation in lymphoedema, could be explained in several ways. One possible hypothesis in light of reported haemodynamic abnormalities in such arms is that capillary pressure rises, increasing capillary filtration rate.(ABSTRACT TRUNCATED AT 400 WORDS)

Publication Types: Clinical Trial Controlled Clinical Trial

MeSH Terms: Aged Albumins/analysis Anthropometry Arm Breast Neoplasms/drug therapy Breast Neoplasms/surgery* Extracellular Space/chemistry* Female Glycosaminoglycans/analysis Human Lymphedema/metabolism* Lymphedema/pathology Mastectomy Middle Aged Postoperative Complications/physiopathology* Proteins/analysis Support, Non-U.S. Gov't Tamoxifen/therapeutic use

Substances: Albumins Glycosaminoglycans Proteins Tamoxifen

PMID: 8287667 [PubMed - indexed for MEDLINE]


The concentration of protein-compounds in interstitial tissue of patients with chronic critical limb ischaemia and oedema

Anvar MD, Khiabani HZ, Lande K, Kroese AJ, Stranden E.

Departments of Vascular Diagnosis and Research, Aker Hospital, University of Oslo, Norway.


Many of chronic critical limb ischaemia (CLI) patients have distal leg and foot oedema. Previous electronmicroscopic studies have shown that chronic severe ischaemia may cause hypoxic damage of the capillary endothelium, including morphological changes i.e. multiplicated/thickened basal lamina, and formation of interendothelial gaps. To assess the functional consequences of these morphologic derangements, where proteins can leak through, we investigated the composition of the interstitial fluid in oedematous ischaemic limbs.


Nine female and 3 male patients with a mean age of 79 +/- 7.9 years were included. All had unilateral CLI and peripheral pitting oedema. Leg and foot volume was measured with water displacement volumetry. Blister suction technique was used to collect subcutaneous interstitial fluid. The concentration of albumin, transferrin, immunoglobulin G and alpha 2-macroglobulin in plasma and blister fluid was measured by immunoturbidimetry. Nine patients, 8 women and 1 man with a mean age of 83 +/- 5.5 years with a proximal femur fracture served as an age-matched control group.


The mean concentration of albumin in blister fluid was significantly lower in the patients, whereas the mean concentration of alpha 2-macroglobulin in blister fluid did not differ between patients and controls. Mean ratio between concentrations in blister and serum of albumin, transferrin and immunoglobulin G in the limbs with CLI and oedema were significantly lower than respective values in the control group. However, there was no significant difference in the ratio of alpha 2-macroglobulin between these groups. CONCLUSION: A higher transcapillary concentration gradient for proteins in CLI limbs signifies an increase in the net osmotic pressure gradient across the capillary wall, which may be a potential oedema limiting factor.

PMID: 11284084 [PubMed - indexed for MEDLINE]


Subcutaneous interstitial fluid pressure and arm volume in lymphoedema

Bates DO, Levick JR, Mortimer PS.

Department of Physiological Medicine, St. George's Hospital Medical School, London, United Kingdom.

Interstitial fluid pressures were measured by the wick in needle method in the swollen and normal arms of 38 patients with lymphoedema resulting from treatment for breast cancer. The mean increase in arm volume, calculated from sequential circumferential measurements, was 33% (range 0.25 to 85.9). Subcutis interstitial fluid pressure in the swollen arm (2.0 cmH2O range -4.5 cmH2O to 6.8 cmH2O) was significantly greater (p < 0.001) than in the contralateral, non-swollen arm (-2.6 cmH2O range -11 cmH2O to 0 cmH2O). Interstitial fluid pressure in the oedematous arm did not correlate with the duration of the swelling (1-324 months), but did correlate with the increase in volume relative to the normal arm (r = 0.38, p < 0.05), the slope ('apparent compliance') being 28 ml.dl-1.cmH2O-1. The pressure-volume curve was less steep than the classic curve for acute oedema of dog limbs (Guyton, 1965). Vascular pressures were normal. The interstitial fluid pressures were not as high as those reported for lymphoedema of the lower extremity (mean 17.9 mmHg, Christensen et al., 1985). Nevertheless, the rise in interstitial fluid pressure by an average of 4.6 cmH2O constitutes a force opposing further microvascular fluid filtration and perhaps promoting fluid drainage out of the arm.


A driving force for change: interstitial flow as a morphoregulator

Trends Cell Biol. 2007 Jan

Institute of Bioengineering, Ecole Polytechnique Federale de Lausanne (EPFL), 1015 Lausanne, Switzerland.

Dynamic stresses that are present in all living tissues drive small fluid flows, called interstitial flows, through the extracellular matrix. Interstitial flow not only helps to transport nutrients throughout the tissue, but also has important roles in tissue maintenance and pathobiology that have been, until recently, largely overlooked. Here, we present evidence for the various effects of interstitial flow on cell biology, including its roles in embryonic development, tissue morphogenesis and remodeling, inflammation and lymphedema, tumor biology and immune cell trafficking.

We also discuss possible mechanisms by which interstitial flow can induce morphoregulation, including direct shear stress, matrix-cell transduction (as has been proposed in the endothelial glycocalyx) and the newly emerging concept of autologous gradient formation.


External Links

(1)Biology Online


Interstitial Fluid Collection Flow


Interstitial fluid pressure in soft tissue as a result of an externally applied contact pressure

The relationship between interstitial fluid pressure and volume in rat trachea

Fluorescein Kinetics in Interstitial Fluid Harvested from Diabetic Skin during Fluorescein Angiography: Implications for Glucose Monitoring

Interstitial fluid flow induces myofibroblast differentiation and collagen alignment in vitro


Fibroblast alignment under interstitial fluid flow using a novel 3-D tissue culture model

Revision of the Starling principle: new views of tissue fluid balance

Extracellular fluid volume and glomerular filtration rate in 1878 healthy potential renal transplant donors: effects of age, gender, obesity and scaling.

Interstitial fluid pressure correlates with intravoxel incoherent motion imaging metrics in a mouse mammary carcinoma model Nov 2011

Body Fluid Dynamics: Back to the Future. Oct 2011

Exchanges through capillary membranes in the formation and removal of interstitial fluid

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