© 2003 Robert A. Freitas Jr. All Rights Reserved.

Robert A. Freitas Jr., Nanomedicine, Volume IIA: Biocompatibility, Landes Bioscience, Georgetown, TX, 2003

15.5.5.3.3 Leukocyte Margination and Migration

When aggregated in low shear conditions, red cells preferentially take up axial flow which induces margination of platelets and leukocytes (Section 9.4.1.3), increasing endothelial adhesion and other cell-wall vascular interactions for these non-RBC elements [4130]. Medical nanorobots seem unlikely to disturb this aggregation and axial migration of red cells, or the resulting peripheral migration of white cells, platelets, and smaller blood components including bloodborne nanorobots (Section 15.5.5.1.3). This is important because without white cell margination, natural phagocytic defense mechanisms could be greatly impaired.

Given that free-flowing nanorobots will likely be marginated toward the vascular walls (Section 9.4.1.3) along with platelets and white cells at low shear rates, could nanorobots interfere with the wall-related functions of those cells? For example, nanorobots may share the plasmatic layer or plasmatic zone (Sections 9.4.1.4 and 9.4.2.6; aka. Poiseuille’s space) closest to the vessel walls with leukocytes and platelets. Collisions there will involve shear stresses of at most <0.1 N/m² (Section 9.4.2.2), hence should not significantly affect leukocyte morphology or function. At the highest shear rates in the vasculature, red cell aggregates break up and the erythrocytes distribute more uniformly, with white cell concentration becoming highest along the tube axis (Section 9.4.1.3). Nanorobots the size of platelets or smaller remain marginated to the periphery. Under these flow conditions the white cells and nanorobots should interact only infrequently. There is some evidence for margination of chylomicrons [4131-4133], the only major particle population in human blood having smaller dimensions than medical nanorobots and hence theoretically capable of at least partially displacing free-floating nanorobots from the periphery.

Vasculomobile nanorobots also may collide with slow-moving leukocytes that are rolling along the local endothelium. The microvillus “feet” upon which a leukocyte rolls across endothelium are present on the white cell surface at a number density of ~1.1/micron² [4122]. The equilibrium length of a microvillus ranges from 0.35 microns (untethered, at equilibrium) to 1.75 microns (tethered, at full stretch), and the step sizes range from 1.25 microns (extrapolated to zero rolling velocity) to 2-5 microns for continuous-contact locomotion [4122]. Thus it is likely that a rolling leukocyte could simply step over an isolated unmoving endothelium-anchored low-aspect-ratio nanorobot of lateral diameter ~1-2 microns.

More commonly, vasculomobile nanorobot ambulation velocities may be as high as 10,000 microns/sec (Section 9.4.3.5) compared to a maximum of 10-80 microns/sec for a rolling leukocyte [4122]. The locomotive force envisioned for vasculomobile nanorobots using legged ambulation is on the order of ~200 pN (Section 9.4.3.5). Distributed over a 1-10 micron² nanorobot-leukocyte contact area, this force induces a shear stress of 20-200 N/m², probably sufficient to dislodge a rolling white cell. Vasculomobile nanorobot control systems thus must include specific leukocyte (and platelet) encounter protocols. These operational protocols would provide that the forces or speeds generated by nanorobots are to be greatly reduced in the vicinity of a rolling white cell, or else the nanorobot is detoured either around or over the larger but much slower-moving motile blood cell. Crawling over the leukocytic obstacle may be a good option for isolated nanorobots or narrow nanoaggregates that can maintain low levels of applied shear stress during the transit, thus avoiding any unwanted activation of leukocyte morphological or functional changes. Achieving this objective when large numbers of nanorobots are in transit for extended periods of time across the same leukocyte may prove challenging. The mean number of marginated leukocytes in venous blood vessels in rat and mouse spleens has been observed to range from 0.1-4.5 WBCs per 1000 micron² of wall surface (a mean center-to-center separation of 15-100 microns), with rolling speeds from 11-20 microns/sec [2869]. Adherence times of leukocytes to vessel walls are log-normally distributed, with median values 30 sec, 130 sec, and 560 sec for lymphocytes, PMNs, and macrophages, respectively [2869].

Nanorobot diapedesis should require only milliseconds for gap passage, plus possibly several seconds for gap management (Section 9.4.4.1). Leukocytes have been observed to migrate through the venous wall as fast as 1-2 minutes [2869] or as slow as 3-10 minutes [4134, 4135] – roughly 100 times slower than medical nanorobots. Even a major convoy (Section 15.5.2.3) involving ~10⁹ medical nanorobots can complete its extravasation in the shortest possible time required for a single WBC transit. As long as such passages are infrequent, they should not interfere with or impair normal leukocytic activities.*

* Extravasating leukocytes [4136] preferentially migrate around endothelial tight junctions or zonula occludens by crossing at tricellular corners where the borders of three endothelial cells meet, rather than by passing through the tight junctions that lie between two endothelial cells, thus preserving the barrier properties of the endothelium and avoiding widespread disruption of endothelial tight junctions [4137].

Last updated on 30 April 2004