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

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

9.4.4.3 Intercellular Passage

With just a few notable exceptions, virtually all tissue cells lie within ~2-3 cell widths of a capillary, or ~50 microns.^71,531 Thus a bloodborne nanorobot may reach any tissue cell by rapidly traveling most of the way by capillary, then exiting the capillary and crossing at most 1-2 cells to arrive at a given target cell. In cell-dense tissue, it may become necessary to crawl between adhering cells.

Tissue cells are not packed so tightly that adjacent cell surfaces are in direct contact with each other. There is usually a space of at least 20 nm between the opposing plasma membranes of adjacent cells, wide enough to admit a slender nanorobot manipulator arm (Section 9.3.1). This space is filled with extracellular fluid and provides a pathway for substances to pass between cells on their way to and from the blood in nearby capillaries. Most tissues employ desmosome or gap junctions²⁹²² wherein the opposing plasma membranes come within 2-4 nm of each other over a space of ~5 nm on the membrane surface, with these junctions spaced ~20 nm apart across the plasma membranes and opposing plasma membranes, retaining a fluid-filled 25-35 nm gap between them. Tight or "occluding" junctions (as in the endothelial blood-brain barrier and certain epithelial surfaces comprised of intestinal cells, bladder cells, and some exocrine cells) have <2.5 nm wide intermembrane gaps.³⁶¹ None of these spaces is wide enough to allow passage of whole (even metamorphic) medical nanorobots. To pass between cells in cell-rich tissue, it is necessary for an advancing nanorobot to disrupt some minimum number of cell-to-cell adhesive contacts that lie ahead in its path. After that, and with the objective of minimizing biointrusiveness, the nanorobot must reseal those adhesive contacts in its wake, after passage, crudely analogous to a burrowing mole.

A full treatment of all types of cell-cell contacts and anchoring mechanisms is beyond the scope of this book, but a few specific examples can be given. For instance, spot desmosomes (Section 5.4) are ~30-nm-long "spot weld" molecules linking neighboring cells, spaced ~8 nm apart across the apposed cellular surfaces. A force of 6-10 pN is required to separate each connexin-32 hepatic cell gap junction unit (Section 5.4.2). Integrins may average ~20 nm separation, and require ~2.1 pN to separate from a fibronectin molecule in the ECM,¹⁵⁰⁸ although direct cell-ECM connections are relatively scarce inside cell-cell junctions.

As a crude estimate, assume that intercellular adhesion molecules h_adhes ~ 30 nm in length are spaced X_adhes ~ 10 nm apart across the cell surfaces and require F_adhes ~ 10 pN to pull apart,¹²²³ and that an L_nano ~ 1 micron wide nanorobot wishes to pass through by dynamically clearing a path ahead that is L_nano wide and L_nano long. Along the leading edge, L_nano/X_adhes adhesive joints must be detached one by one, requiring a detachment energy of E_detach ~ L_nano F_adhes h_adhes / X_adhes ~ 30,000 zJ to advance a distance X_adhes. This gives a power requirement of P_travel ~ E_detach v_travel / X_adhes ~ 0.003 pW if the velocity of forward travel through the cell-cell junction is v_travel ~ 1 micron/sec, allowing transit between two adhered 20-micron cells in ~20 sec. Adding manipulator arm energy dissipation raises the total to ~0.01 pW (viscous drag power is ~10^-5 pW; Eqns. 9.74 and 9.75). Total detachment rate is n_detach ~ L_nano v_travel / X_adhes² ~ 10,000 detachments/sec, a burden which can be shared by more than one manipulatory appendage, each equipped with appropriate lytic end-effectors (e.g., trypsin-like tool tips; Section 9.3.2(11)). Rejoining the parted cell junctions astern requires, at worst, a similar energy expenditure; in the case of noncovalent bonds, unassisted rejoining may be energetically favorable if the edges have been left in relative proximity. Reattachment may be facilitated using a metamorphic nanorobot integument, together with a surfacial hydrophilic solvation wave drive system (Section 9.4.5.3), to establish a teardrop-shaped cross-section that can slowly adduct the separated plasma membrane faces and maneuver the detached stubs of parted anchor macromolecules into close proximity. Traffic density and frequency should be locally restricted to minimize mechanical stimulation of unwanted ECM and cytomatrical responses (Sections 9.4.3.2.1 and 9.4.4.2), and especially detachment-triggered apoptosis (Section 10.4.1.1), perhaps by restricting intercellular passage to nanorobots traveling single-file through a relatively small number of channels.

Last updated on 21 February 2003