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

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

9.4.4.1 Nanorobot Diapedesis

The passage of formed blood elements, especially white cells, through the intact walls of blood vessels, is called transendothelial migration or diapedesis (Fig. 9.28). Diapedesis is a stereotyped behavior of certain motile cells that may occur everywhere in the human body except (usually) through the brain-blood barrier.

Normally, ~75% of circulating neutrophils are adherent to the endothelium at any time.¹⁴⁹¹ Following its rolling interaction (Section 9.4.3.6), a leukocyte may abruptly attach to the wall of a venule and leave the bloodstream by squeezing between adjacent endothelial cells. Prior to attachment, the leukocyte does not stop rolling until certain binding events occur between the vessel wall and the white cell plasma membrane. Rapid triggering (e.g., in a few seconds) of integrin-mediated adhesion is required for the arrest of bloodborne lymphocytes and neutrophils at sites of leukocyte recruitment from the blood. This adhesion is also mediated by pertussis toxin-sensitive Ga₁ protein-linked receptors of the rhodopsin-related seven-transmembrane or serpentine chemoattractant family.^982,1027 b2 integrin-mediated arrest of neutrophils can be triggered through stimulation of the formyl peptide, leukotriene B4, eotaxin, platelet activating factor, or interleukin-8 (IL-8) chemoattractant receptors in vivo.^982,1484 Particular chemokines (e.g., MIP-2b, SDF-1a, and 6-C-kine) induce flowing lymphocytes to decelerate and adhere to an integrin target protein within ~500 millisec.¹⁴⁸⁴ Adhesion is then followed by diapedesis, the final step in extravasation (exiting the blood vessel), given the presence of appropriate haptotactic (adhesion-gradient) or chemoattractant (0.0001-1 nanomolar^1512,1515 concentration-gradient) signals.

The same b₂ and a₄ integrins involved in lymphocyte arrest, in conjunction with other adhesion receptors, trigger the final steps in transendothelial migration.¹⁰²⁷ The junctions between adjacent endothelial cells in capillaries and venules are normally very narrow, with parallel plasma membranes forming an intercellular cleft of ~10-20 nm.^361,1493 The discontinuous-type endothelium found in the liver, spleen, and bone marrow (whose functions include the addition or extraction of whole cells from the blood) have resting gaps ~150 nm wide.¹⁴⁹² In the final step of diapedesis, biochemical mediators acting on capillary endothelial cells cause those cells to loosen their attachments to their neighbors.⁵³¹ The wall gaps in the capillaries open more widely, allowing diapedesis of white cells into the tissues.⁷¹ A wide range of pharmacologically active compounds (including prostaglandins, angiotensins, serotonin, histamine, epinephrine, and nicotine) have been observed to encourage the splitting of endothelial junctions along their symmetry plane, followed by cell separation and the appearance of gaps large enough to allow passage of whole cells -- especially in the postcapillary venules.¹⁴⁹³ It also appears that the emigration of neutrophils and monocytes from the vasculature is normally regulated by at least three distinct molecular signals -- selectin-carbohydrate, chemoattractant-receptor, and integrin-Ig interactions -- acting in sequence, not in parallel. This establishes a threedigit "area code" for cell localization in the body, "as if leukocytes carr[ied] cellular phones."¹⁴⁹⁵ The sequence in which these signals act on neutrophils and lymphocytes may differ. (A neutrophil surface typically has 5 x 10⁵ Mac-I integrin receptors and 2-4 x 10⁴ selectin receptors).^1509,1510 Properly configured medical nanorobots can undoubtedly read these "area codes" as well (Section 8.4.3).

Diapedesis typically requires ~3-10 minutes for the white cell to complete.^1488,1490 Leukocyte emigration occurs by insertion of a pseudopod into the enlarged gap between endothelial cells, followed by amoeboid-like migration of the white cell through the blood vessel wall (Fig. 9.28). Electron microscopic studies have demonstrated that an efficient protein-tight seal is maintained between endothelial cells and a migrating leukocyte during all stages of its escape.¹⁴⁸⁹ Endothelial cells are typically 0.5 microns thick, although in postcapillary venules they may be cuboidal and much thicker.

Nanorobots engaging in diapedesis may release a minute quantity (e.g., ~0.0005 micron³/micron³)¹⁴⁹⁶ of the RGDS tetrapeptide (a known adhesion inhibitor),¹⁴⁹⁴ cytoambulate through the widened endothelial gap possibly using a metamorphic surface to maintain a protein-tight seal if necessary, then release endothelial movement inhibitors such as cytochalasin B or endothelial growth inhibitor protein (EGIP)¹⁴⁹⁴ to encourage endothelial reattachment, returning the gap to its normal size. (Active chemokine concentrations are typically ~10 molecules/micron³; Section 7.4.5.2.) The actual transit of the gap should require only milliseconds assuming ~mm/sec ambulation velocities, but a time on the order of seconds could be required for biochemically-mediated endothelial cell gap width management. Physical force may be used to spread or to close a temporary gap much faster (Section 9.4.4.3) but may be inconsistent with endothelial cell homeostasis. As already noted in Section 8.2.1.3, the lymphatic endothelium can probably open gaps at least ~22.5 microns wide,⁸⁵¹ so micron-sized nanorobots should also find easy passage into and out of the lymphatic system.

Last updated on 21 February 2003