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

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

15.4.3.6.10 Systemic Phagocytic Blockade

Finally, there is the possibility of systemic phagocytic blockade [1391, 3631-3645]. It is well known that a large quantity of carbon particles present inside an alveolar macrophage will decrease its lysosomal enzyme concentrations and depress its phagocytic function [880]. At large enough whole-body particle loads, all professional phagocytic activity ceases. The phagocytic cells of the RES would be “full” of ingested medical nanorobots (Sections 15.4.3.1 and 15.6.3.4) and the RES is said to be blockaded, with the result that all subsequently arriving nanorobots will be ignored by a population of phagocytes overwhelmed beyond their functional capacitance. Acute blockade typically persists for 1-4 hours for metabolizable particles [2863, 3646], but may last 24-48 hours if nontoxic indigestible particles such as carbon [2863] or diamondoid nanorobots are used. RES blockade is sometimes employed clinically to improve graft survival in transplant recipients [3643, 3645]. Impaired particle clearance due to RES blockade by parvovirus particles has been observed in minks [3647], and the excessive use of hair spray has reportedly induced partial RES blockade [3639]. Blockade can also be chemically induced, as for example using GdCl₃ at ~0.005 gm/kg in rats [3383], or with cortisone [3648].

What volume of medical nanorobots might be needed to induce complete human RES blockade? There is some relevant experimental evidence from animal models:

(1) A 0.0025 cm³/kg test dose of radioiodinated colloidal albumin constituted an “appreciable phagocyte load” for human Kupffer cells but did not produce blockade [2845].

(2) 20 mg of colloidal carbon [872, 3644] produced complete RES blockade in rats (0.05 cm³/kg), though another similar experiment [875] found no blockade at a dose of 320 mg/kg (~0.16 cm³/kg). (Average rat weight is typically ~200 gm.)

(3) Particle loads of 1 mg of dextran sulfate [3649, 3650] (~0.03 cm³/kg body weight), or 5-10 mg of carbon [3641, 3645] or carrageenan [3638] (0.10-0.20 cm³/kg), or 2 x 10⁹ sheep erythrocyte cells [3650] (~3 cm³/kg), have produced RES blockade in mice.

(4) 1 gm/kg of carbon black injected IV in mice [873] produced complete macrophage blockade (0.5 cm³/kg).

Assuming 3.8 x 10⁶/cm³ granulocytes (volume ~700 micron³) and 0.4 x 10⁶/cm³ monocytes (volume ~1500 micron³) in the blood, and 200 x 10⁹ RES phagocytes [2863] (volume ~1500 micron³ [3651]) in the tissues, then the total human phagocyte volume is ~300 cm³. If the maximum particle storage capacity of each cell is ~10% (Section 15.6.3.4), then the maximum phagocytic capacity of the system – the maximum possible requirement for blockade – is ~30 cm³ of medical nanorobots, or ~0.4 cm³/kg, which is very roughly consistent with the rodent data, above. Since only ~2 cm³ of micron-sized particles may be harmlessly sequestered in lymph nodes and spleen (Section 15.4.3.4), safe blockade of the human RES with inert particles might not be feasible.* However, temporary blockade using biodegradable particles would enable a subsequent dose of medical nanorobots to operate for a time within the human body without risk of RES sequestration.

* Waste heat generated by blockade is not an issue. With <10¹² white cells in the human body (Section 8.5.1) whose power consumption may increase by 20-100 pW/cell when activated [2853] (Table 6.8), the entire human phagocytic system would generate <100 watts of excess thermal power during the blockade process, thus by itself producing no measurable increase in body temperature (Section 6.5.2).

Continuous systemic blockade is also undesirable because it can leave the body phagocytically defenseless against foreign particle accumulations and pathogenic invasions, can increase the lethality of certain infections [2863], and may contribute to the pathogenesis of inflammatory and autoimmune diseases [5769]. Normal adult human blood contains ~4 million neutrophils/cm³ (Appendix B). If the number of active neutrophils falls below ~0.5 million/cm³, the risk of infections increases markedly [361]. A sudden systemic cessation of phagocytic activity may produce symptoms similar to acute neutropenia and lymphocytopenia, with impaired immune defenses and susceptibility to a wide range of opportunistic infections such as aspergillosis, cytomegalovirus, mucormycosis and nocardiosis [361]. These symptoms should abate as the blockading particle mass is gradually cleared from the RES by the death of blockaded phagocytes, whose inert trapped particles are rephagocytized or permanently granulomatized, and the phagocytes are slowly replaced from storage pools (over many hours) or by accelerated granulopoiesis [3640] in bone marrow (over many days). However, the spleen’s ability to recycle aging red cells and platelets, and to filter particulate debris, may be compromised. There could be permanent lymph node swelling, chronic hepatosplenomegaly [3638], or even significant organ necrosis. Later, the widely dispersed sequestered particle load would have to be retrieved by injecting additional scavenger nanorobots (Chapter 19), compounding the problem. Experimentally-induced blockade of rat RES using carbon colloid also produces (1) marked reductions in terminal arteriolar lumen sizes, (2) curtailment of capillary inflow and outflow, (3) hyperreactivity to the constrictor (noradrenaline) and hyporeactivity to the dilator (acetylcholine), (4) arteriolar spasms, and (5) pronounced uptake of carbon particles in the endothelial cells with different degrees of endothelial cell swelling, often bulging into the microvessel lumens [872]. Intentional nonspecific blockade using inert particles probably should be avoided in most medical nanorobot mission designs.

Last updated on 30 April 2004