Nanomedicine, Volume I: Basic Capabilities

© 1999 Robert A. Freitas Jr. All Rights Reserved.

Robert A. Freitas Jr., Nanomedicine, Volume I: Basic Capabilities, Landes Bioscience, Georgetown, TX, 1999 Lymphatic System

The lymphatic system consists of a branching series of closed endothelium-lined vessels. These vessels slowly drain lymph (composition discussed below) from the extracellular spaces and convey it back to the arteriovenous circulation, a sluggish current easily navigated by lymphborne medical nanodevices. The lymphatic vessels have a total capacity of ~2 liters of lymph,852 vs. ~3.7 liters of fluid capacity for all the veins. No detailed quantitative summation of the lymphatic system is readily available in the literature, so Table 8.5 must be regarded as an estimate consistent with data gleaned from a variety of sources363,838,848,850,853-860,874 but possibly still containing significant errors.

Lymphatic vessels resemble veins in structure but are greater in number. Compared to veins, lymphatics of similar size have thinner walls, more valves, much greater variation in their caliber but a less sinuous course through the tissue. They also contain lymph nodes at various intervals along their length. Lymph vessels are frequently connected with one another by short anastomotic branches.857 Lymphatics of the skin travel in loose subcutaneous tissue and generally follow veins and venules. Lymphatics of the viscera generally follow arterioles, forming plexuses (extensive two-dimensional meshworks) around them.

However, the lymph drainage system actually begins with the prelymphatics. The prelymphatics are a randomly interconnected network of non-endothelialized tissue channels 0.1-0.2 microns in diameter penetrating the cell masses of the body, although in certain regions where lymphatic capillaries are absent (e.g., the brain, eye, and bone), the prelymphatics take over the role of the capillaries and eventually discharge into them, outside the regions in question.861 In the viscera, these interstitial channels will normally be very short since there are frequent arteriovenous and lymphatic capillaries -- for example, ~30 microns long in the capsules of knee joints (~0.02-0.05 channels/micron3). In the muscles, the prelymphatics are longer since the lymphatic capillaries extend only into the larger regions of connective tissue. In the brain the channels may be 10-30 cm long since they must reach (in the case of the brain) from the depths of the cortex to the outside of the skull.861 Following injury, tissue channel volume may enlarge as much as ~400 times in a week, in response to a simple incision wound.1339

Drainage of the prelymphatics is done by the lymphatic capillaries, thin-walled irregularly-contoured valveless endothelial tubes varying in diameter from 15-75 microns. The lymphatic capillaries are blind sacs (Fig. 8.4) with an inferred mean separation of ~86 microns or ~4 tissue cell widths. Their walls are more porous than those of blood capillaries, so that larger molecules and particles may pass (Fig. 8.5). The resting gap of the open junction of adjoining lymphatic endothelial cells usually ranges from ~0.1 micron to several microns.361 However, Allen851 injected intraperitoneally a variety of particles of various sizes up to 22.5 microns in diameter, and all sizes later appeared in the diaphragmatic lymph. This suggests that the peritoneal mesothelium and the lymphatic endothelium on either side of the fenestrations of the basement membrane can open at least this wide, so micron-sized nanorobots should find easy passage into the lymphatic system through these pores.

Lymph capillaries originate throughout the body, though not in avascular tissue, the central nervous system, splenic pulp or bone marrow. They may occur singly or in plexuses, especially in regions where the connective tissue is lobulated (e.g., glands) or arranged in cylinders (e.g., muscles). Each lymphatic capillary plexus is typically 320-640 microns wide, encompassing 2-6 blood capillary loops. The terminal lymphatic network has different geometric patterns in different tissues. In the mesentery, it conforms to the modular configuration of the blood capillary network. In the skeletal muscle, lymphatics are found in the immediate neighborhood of the arterioles; in the dermis, near the venules. In the lung, the terminal lymphatics lie at the junctions of interalveolar septa.363 Simple observation of the local lymphocapillary topology (Section 8.3.4) might enable nanorobots to identify which tissue they are passing through.

The precollecting ducts are short vascular segments with valves (like all subsequent lymphatics) at intervals of 0.4-1.5 mm that connect the capillary plexuses to the larger collecting ducts. The lymphatic collecting ducts are denoted either prenodal or postnodal, though there are no morphological or structural differences between the two. Collecting ducts display many swellings and strictures along their course which alter their profile, due to the presence of valves. (Valve-counting may offer useful navigational information.) There is an inner and an outer muscular layer. The collecting ducts empty into the lymphatic trunks, larger and thicker-walled vessels which receive the lymph drained from entire regions of the body.

By their confluence, the lymphatics form progressively larger vessels, which ultimately converge at two cervical portals (Fig. 8.6). The first is the right lymphatic duct, which is relatively short and typically opens into the right brachiocephalic vein at the junction of the right internal jugular and right subclavian veins. It carries lymph drainage from the right upper portion of the body (Fig. 8.7). The second is the thoracic duct, which arises in the abdomen and courses upward along the anterior aspect of the vertebral column (with valves every ~3 cm along its length),857 through the thorax into the base of the neck, where it typically joins the venous system at the junction of the left jugular and subclavian veins. At its termination, a bicuspid valve faces into the vein to prevent or reduce reflux of blood, although after death blood regurgitates freely into the thoracic duct, which then looks like a vein.

The thoracic duct is ~5 mm in diameter at its abdominal commencement, but becomes narrower at midthoracic levels, then in ~50% of patients grows slightly wider again before its termination.854 There is a tremendous variation in structure from one patient to another. The duct may divide in its midcourse into two unequal vessels which soon reunite, or into several small branches which form a plexus before combining again to form one short wide trunk. Higher in the body, the duct occasionally bifurcates, the left branch ending as usual, the right branch diverging to join one of the right lymph trunks or even the right lymphatic duct, with the combined vessel opening into the right subclavian vein. After performing 529 human dissections, Kinnaert856 found that the thoracic duct terminated on the internal jugular vein in 36% of the cases, the subclavian vein in 17% of the cases, the jugulo-subclavian junction in 34% of the cases, both veins 8% of the time, and the transverse cervical vein in 2% of the cases where the thoracic duct terminated on the left. In 21% of the cases, the terminal openings were multiple; in the rest of the cases, the single thoracic duct terminus diameter ranged from 25 mm.856

Various lymphatic organs are located along the length of the lymphatic system (Fig. 8.8). A major function of these organs is the production of lymphocytes which are added to the lymph passing through the vessels. Lymphatic tissue is a loose-structured material consisting of a spongelike stroma and free cells in the meshes of the stroma, and is part of the reticuloendothelial system (RES). Phagocytic cells in the sinuses serve as filters that scavenge particles from the lymph and destroy them. Such particles include red blood cells, pathogenic bacteria, and larger dust particles imported by the respiratory tract and collected by macrophage cells of the bronchial nodes. Lymphborne nanorobots can avoid these traps (Section; the Reynolds number of lymph flow3303 is typically only ~0.0025.

The most numerous of the lymphatic organs is the lymph node, designed as a bacterial/particulate filter with channels, sinuses, valves, and fluid entering via 6-10 afferent lymph vessels (Fig. 8.9). Lymph nodes vary enormously in their size and structure, probably averaging ~4 mm in diameter but occasionally reaching 30-40 mm.857 A normal young adult body contains ~450 lymph nodes distributed as follows: ~30 nodes in the arm and superficial thoraco-abdominal wall down to the umbilicus; ~20 nodes in the legs and superficial buttocks, infraumbilical abdominal wall and perineum; 60-70 nodes in the head and neck; ~100 nodes in the thorax, including deep walls and contents; and ~230 nodes in the abdomen and pelvis, including deep walls and contents.854

There is also the 10 cm3 of lymphoid tissue in the bilobate thymus gland, and additional lymphoid tissue in the 80-300 cm3 spleen.854 (The spleen slowly enlarges during alimentary digestion and varies in size with the content of blood and state of nutrition, being large in well-fed patients and small in starved patients.) About 10% of the population has accessory spleens; these ~1 cm3 spleniculi may be numerous and widely scattered in the abdomen.854 Other lymphoid tissues include the lymph nodules or the lymph follicles in the intestines (Section 8.2.3), the subepithelial lymphoid aggregates including the palatine, lingual, and nasopharyngeal (e.g., adenoids, tonsils), and the lymphoid tissue in the submucosa of the appendix and in the bone marrow.

What, exactly, is lymph? Lymph is essentially an alkaline ultrafiltrate of the blood plasma formed by continual seepage of fluid constituents of the blood across the capillary walls and into the surrounding interstitial spaces. The lymph fluid has much the same composition as the interstitial fluid. Like blood, lymph consists of a plasmatic part and a corpuscular part (Table 8.6). Lymph contains almost no platelets but has about one-third the fibrinogen and five times the prothrombin as in blood serum, hence will thrombose spontaneously forming a yellowish clot. Lymph has 0.02-0.10% as many red cells as arterial blood, but most have passed near cells and become thoroughly deoxygenated, especially given the ~1 day transit time through the lymphatic system for cells. There is still some dissolved oxygen in the lymph water, however, roughly the same concentration as in blood plasma (see Appendix B). Glucose may be present in lymph at slightly higher concentration than in blood serum, so lymphoresident nanorobots have access to plenty of chemical fuel energy (Section 6.3.4). Lymph is slightly less viscous3304 than blood plasma, with specific gravity 0.016-1.023.2223

In a fasting patient, the lymph coming from the intestine is a clear, transparent fluid. After a meal containing fat has been ingested, the intestinal lymph becomes white or milky. This is termed chyle -- chyle is just lymph containing a surge (5-15% by volume) of emulsified fat which is transported in the form of chylomicrons measuring 0.5-0.75 microns in diameter.749 In ~65% of all patients, the intestinal trunk (which drains lymph from the stomach, intestines, pancreas, spleen, and visceral surface of the liver) empties separately into the thoracic duct immediately above the junction of the two lumbar trunks, and so the thoracic duct widens to a diameter of 8-13 mm, forming a cisterna chyli.857,874 In the other ~35% of cases, the intestinal trunk joins the left lumbar trunk and there is no cisterna chyli (Fig. 8.10), a navigationally distinctive characteristic.

The chemical composition of lymph plasma varies significantly at different locations in the lymphatic system, reflecting changes in source of drainage and variations in capillary permeabilities. This provides another ready source of useful navigational information for lymphborne medical nanorobots (Section 8.4.3). For example, thoracic lymph is rich in histaminase originating in the kidneys and gut, while cervical duct lymph contains only very low concentrations of histaminase, as in blood plasma.848 In humans, fibrinogen is 4.1 mg/cm3 in blood plasma, 1.1 mg/cm3 in thoracic duct lymph; in dogs, prothrombin concentration expressed as a percentage of serum concentration was measured experimentally as 93.2% in hepatic lymph, 51.2% in thoracic lymph, and 7.6% in leg lymph.848 The enzyme tributyrinase has high concentration in the intestinal lymph and significantly lower concentrations elsewhere.847 Insulin is more plentiful in pancreatic lymph.847

Cervical, leg, renal, and right duct lymph has 33%-50% of the protein concentration of blood plasma, while intestinal and thoracic duct lymph contains ~67% as much protein as the blood plasma.860 Protein is generally lowest in the capillary lymph, increasing in several steps with travel upstream toward the main trunks. Hepatic lymph has the highest protein content (about equal to blood plasma), as would be expected in view of the high permeability of the capillaries of the liver sinusoids.847,860 Central (trunk) lymph generally differs from blood plasma in having high concentrations of sodium, cholesterol, and tributyrinase, and significantly lower concentrations of total protein, albumen a-2 fraction, potassium, nitrogen, aldolase, pyruvic transaminases, choline esterase, amylase, and diastase.847

The cellular composition of lymph also changes dramatically with lymphatic location. Most of the prenodal duct lymph contains ~1 x 106 cells/cm3, except for hepatic lymph which has 4-6 x 106 cells/cm3. The majority of these cells are red cells, but a small proportion, perhaps 10-20%, are nucleated cells. Such cells include ~85% lymphocytes, ~13% monocytes and macrophages, and ~2% neutrophilic granulocytes. The postnodal duct lymph has ~12 times more nucleated cells than the peripheral lymph, perhaps ~3 x 106 nucleated cells/cm3. The central lymph has 8-11 x 106 nucleated cells/cm3.847

How fast does lymph move? Of the 20 liters/day of plasma water that leaves the blood circulation through ultrafiltration, 18 liters/day are reabsorbed862 by passing back out of the lymphatic capillaries and into the venous capillary loops; the remaining 2 liters/day returns to the circulation as lymph that passes through the entire lymphatic system. In other words, relatively little lymph reaches the collecting ducts compared with the total amount entering the lymphatic capillaries;850 much more lymph is formed in the periphery than ever reaches the main lymph ducts.849 Basal lymph flow rates are ~2 liters/day,847,848 rising to a 6-12 liter/day rate during heavy exercise.848 Summing the vessel crossing times (~length/velocity from Table 8.5), it takes ~24 hours for a node-inert particle entering a lymphatic capillary to drift to the final terminus of the thoracic duct and rejoin the venous flow.

What moves the lymph? Valves are essential to the function of the lymph vascular system, which has no pump comparable to the heart. In the collecting ducts, one-way valves are spaced roughly 2-3 mm apart857 and can oppose retrograde pressures of up to 20 mmHg.855 Lymph flow in the extremities depends largely on the massaging effect of movement of the surrounding tissues that results from muscle contraction. Such movements can be produced indirectly by the motion of nearby arterioles, or by the contraction of the skeletal muscles, or by movement of the organs (e.g., motion of the arms or legs, peristalsis of the intestine, or breathing of the lung). Arterial pulsations contribute 1.5-2.2 mmHg pressure variation to the lymphatic ducts between systole and diastole.848 Larger collecting lymphatics are innervated, so movement can also be induced by contractions of smooth muscles in the lymphatic vessel wall.848 The contractile activity seems to depend on the volume of lymph produced. If this is small, the vessel walls are quiescent, but slight distension initiates rhythmic contractions at ~0.1-0.2 Hz838,848,863 and can raise the lymphatic pressure by up to ~5 mmHg.855 By comparison, the mean interstitial hydrostatic pressure is ~1.4 mmHg and the mean intralymphatic pressure is ~0.9 mmHg.526,847,860

The minimum topological map required to reliably navigate the entire ~3500 kilometers of human lymphatic vasculature should be roughly comparable to that required for a comprehensive blood capillary map, or ~1 terabit (Section


Last updated on 16 April 2004