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
8.2.2 Navigational Bronchography
Medical nanorobots may access the human body via the respiratory system. The airway begins at the mouth and nose, extends through the pharynx, larynx, the trachea and bronchial branchings, and ends at the alveoli. The conducting zone from the top of the trachea to the beginning of the respiratory bronchioles contains no alveoli, so gas exchange with the blood does not occur there. Gas exchange occurs only in the respiratory zone, which extends from the respiratory bronchioles down to the alveolar sacs.
Weibel864 provided the first quantitative measurements of the length, diameter, and area of successive segments of the human airway. Each branch gives rise to two narrower daughter branches which may vary considerably in length. However, the summary in Table 8.7 assumes mean values of length and diameter. Generations 0-16 are the conducting airways, while generations 17-23 constitute the respiratory airways which have alveoli on their walls. Generation 23 terminates in alveoli.
The respiratory airflow begins in the mouth and nose. In the nose are two nasal cavities (totalling ~160 cm2 in area,)863 one of which is illustrated in Figure 8.11. The nasal cavities are divided by a partition called the nasal septum, from which diverge three winglike projections called the conchae. The endings of the olfactory nerve lie in the mucosa in the cilia-free region near the ~1 cm2 olfactory bulb above the superior concha. The nasal passages are flanked by four sinuses which may swell up during infection or inflammation, closing off the air passages and necessitating breathing through the mouth. Lacrimal ducts drain tears and other secretions from the eyes into the nose via the nasolacrimal duct, requiring noseblowing after crying. The <~1 mm human vomeronasal organ, located near the base of the nasal septum in adults,1971 transduces pheromonal signals,1972 although apparently this organ is not present, is inactive, or is very insensitive in some people.
Air passing through the nasal cavities is warmed to within 1 K of body temperature by an extensive capillary vasculature, and is humidified by nasal mucous glands (e.g., goblet cells which secrete mucoid fluid) to within ~1% of full saturation, before the air enters the pharynx. Coarse particles are removed from incoming air by nose hairs. Smaller particles are removed by turbulent precipitation, wherein obstacles in the nasal passages force the airflow to execute many sharp turns which the particles are too heavy to negotiate. The particles hit the nasal mucous membrane and become embedded in the mucus. The nasal turbulence mechanism is so effective that almost no nasally-inhaled particles larger than 2-5 microns reach the lower airway.
Most of the surfaces of the nasal airway are covered by a layer of ciliated, pseudostratified columnar epithelium cells. Each epithelial surface cell has 25-100 cilia that beat forcefully and continually toward the pharynx at ~10 Hz.3556,3557 Respiratory cilia are ~0.2 microns in diameter and ~2-5 microns long (having a ~31 nm apical glycocalyx),3587 with a mean separation between cilia of ~2-5 microns. The film of particle-carrying nasal mucus >~200 microns thick 3167 is moved toward the pharynx by the cilia at a speed of ~1-3 cm/min,863,3167 where it is then swallowed down the esophagus. Mucus velocity increases with luminal depth. In unciliated areas such as the front of the nose, where temperatures fall below levels the cilia can tolerate, the mucous layer creeps along the surface solely through traction from neighboring ciliated areas. Swallowed mucus volume totals ~0.1 cm3/min. The absolute viscosity of normal mucus is typically ~1 kg/m-sec, rising as high as ~500 kg/msec in the thick sputum of cystic fibrosis patients.1081 Mucus rheology and mucociliary clearance mechanisms of the respiratory tract have been widely studied,3168 along with the energy dissipation per cilium in the periciliary fluid.3170 Airflow contributes little to mucus transport during normal breathing ,3168 except in patients with bronchial hypersecretions,3167 although high-frequency ventilation and coughing may make significant contributions.3167-3169
During inspiration, air passes through the nose or mouth into the pharynx (throat). The posterior wall of the pharynx rests against the cervical vertebrae; the lateral wall has openings communicating with the middle ear (auditory or eustachian tube). The pharynx branches into two tubes -- the esophagus (through which food passes to the stomach; Section 8.2.3) and the larynx (part of the airways). The larynx houses the vocal cords, two strong bands of elastic tissue (covered by stratified scalelike epithelium) stretched horizontally across its lumen. The flow of air past the vocal cords causes them to vibrate, producing sounds. The ventricular folds or false vocal cords (in mid-glottis) point downward. When closed by the action of sphincter muscles, the folds form an exit valve that permits the building up of abdominal pressure as in straining at stool or in expulsion of the fetus. Coughing involves releasing the air explosively through the folds.
After passing the larynx, air enters the trachea, a cylindrical tube with 16-20 circumferential cartilaginous rings shaped like horseshoes and embedded in an external fibroelastic membrane (Fig. 8.12). The trachea branches into two main bronchi, one of which enters each lung. The right bronchus is shorter, wider, and more nearly vertical in direction than the left bronchus; both (and subsequent branchings) are supported by complete rings of cartilage to prevent collapse under high levels of suction. There are more than 20 generations of branchings in the lungs, each resulting in narrower, shorter, and more numerous tubes (Table 8.7). When the bronchi become smaller than ~1 mm in diameter, they lose their cartilage, and become bronchioles.
The lungs themselves are cone-shaped organs which lie in the pleural cavities of the thorax. The base of each lung contacts with the upper surface of the diaphragm, extending to the level of the 7th rib anteriorly and the 11th rib posteriorly. The right and left pleural cavities are formed by two serous sacs into which the lungs are invaginated. Two layers of pleura are separated by a thin layer of fluid from ~20-80 microns thick. Pleural fluid is formed on the parietal pleural surface at a rate of 7-11 cm3/hr, with up to 20-25 cm3 normally present in the pleural space;2180,3305 glucose is present at serum levels (Appendix B) and there are topographic differences in pleural pressure.3402 The right lung, larger in size than the left, is divided into three lobes; the left lung has only two lobes (Fig. 8.12), presumably to make room for the heart. The interlobar surfaces are covered with visceral pleura where the lobes contact one another and are lubricated with the same thin mucoid pleural fluid that lubricates the outer surface of the lungs. The lobes slide against each other in the same way that the entire lungs slide within the thoracic cavity. The diaphragm is the principle respiratory muscle. Contraction of the diaphragm elongates the lungs, forcing them to inflate. Other muscles elevate the anterior thoracic wall or compress the abdomen, raising the ribs from an inferiorly slanting position to a horizontal position that increases the anteroposterior diameter of the chest.
Returning to the airflow, bronchiole walls are composed of smooth muscle and connective tissue. This smooth muscle normally remains relaxed so that the bronchioles stay open, although particles of irritating substances entering these passageways can cause bronchiolar spasms (as in patients with asthma). The bronchioles branch several times. The last bronchiolar branch that still has a complete muscular coat is the terminal bronchiole. This too branches into several respiratory bronchioles with sparse smooth muscle. These bronchioles are the entryways into the respiratory lobules, the final air spaces of the lungs (Fig. 8.13). The walls of all parts of the respiratory lobules form the respiratory membrane which totals ~70 m2 in total surface area in both lungs combined.361,863 The membrane is so thin (<~1 micron) that oxygen and carbon dioxide can diffuse freely between the air inside the lobule and the blood in the capillary surrounding the lobule.
As in the nasal passages, the bronchial tree from the lower pharynx down to the end of the respiratory bronchioles is lined with ciliated columnar epithelial cells. These cilia also wave constantly toward the pharynx, moving secreted mucus at ~1.4 cm/min which replaces the entire mucoid coating once every ~20 minutes. A second protective mechanism is provided by mobile phagocytes present in the airways and in the alveoli, that engulf inhaled particles and bacteria (<~100/cm2 in a healthy person360) and thus prevent this foreign matter from gaining access to other lung cells or from entering the blood by conveying this matter into the lymph system. Ciliary activity may be inhibited for several hours by smoking a single cigarette. Phagocytes are also injured by cigarette smoke, air pollution, and other noxious agents. Below the respiratory bronchioles, the ciliated columnar epithelium gives way to a nonciliated cuboidal epithelium.
Alveoli first begin to appear in the respiratory bronchioles, attached to the walls, and their frequency increases in the alveolar ducts until the airways end in grapelike clusters of alveoli (Fig. 8.13). The alveoli are tiny hollow sacs 100-300 microns in diameter that open onto the lumina of the airways (Fig. 8.14). Typically the air in two alveoli is separated by a single wall. The moist air-facing surfaces of the alveolar wall are lined by a continuous layer, one cell thick, of squamous type I epithelial cells (Fig. 8.15, enlargement of box in Figure 8.14). The alveolar surface contains smaller numbers of thicker specialized type II epithelial cells that secrete a detergent-like substance, or surfactant (a complex of protein with dipalmityl lecithin) in a fluid layer ~70 nm thick, which physically stabilizes alveoli of different sizes during inflation and deflation. (See also Section 9.2.3.)
The alveolar walls also contain capillaries, the endothelial linings of which are separated from the alveolar epithelial lining only by a basement membrane and a very thin interstitial space containing interstitial fluid and a loose meshwork of connective tissue (Fig. 8.15). In places, the interstitium is absent and the alveolar epithelium fuses with the capillary endothelium, with total thickness <~1 micron. In some of the alveolar walls there are pores that permit the flow of air between alveoli, an important route when the airway leading to an alveolus is occluded by disease.
At rest, ~4 liters/min of air enter and leave the alveoli, while 5.4 liters/min of blood, the entire cardiac output, flows through pulmonary capillaries which total ~2400 kilometers in length and ~150 cm3 in volume. During heavy exercise, the air flow to the alveoli can increase to 120-160 liters/min and the blood flow to 25-30 liters/min.866 The volume of air taken in with each breath (resting tidal volume) is ~0.4 liter/breath at a respiration rate of 18/min (12-15/min during sleep). Volume flow may rise to ~3.2 liters/breath at a respiration rate of up to 62/min during the most strenous exercise.780 The two human lungs hold a combined ~6 liters of gas, of which ~3.7 liters is the maximum inspirational capacity leaving ~2.3 liters as residual capacity or dead space.
Blood pressure in the pulmonary artery is only 15-30 mmHg systolic and 4-12 mmHg diastolic, compared to 100-150 mmHg systolic and 60-100 mmHg diastolic in the aorta.361 This low-pressure system allows pulmonary capillaries to be quite flexible and thin-walled -- they distend if higher blood pressures are applied to the pulmonary artery. Pulmonary blood vessels are richly supplied with nerve fibers but are largely free from neural and chemical control -- although they do respond to hypoxia and to pharmacological doses of catecholamines, histamine and serotonin.361
A navigational map of the airways can be surprisingly compact. Only log2(300 x 106) ~ 28 bits are needed to uniquely name each alveolus, requiring 8.4 x 109 bits to store all 300 million addresses. A complete bifurcation map of the airways down to the last generation of respiratory bronchioles (e.g., a lobule map for both lungs) can be stored in just ~107 bits. If numerous positions within each alveolus must be specified, for example during a scan seeking precancerous epithelial cells, the required map could be much larger. However, C. Phoenix notes that if nanorobots are given individual instructions to scan a certain set of cells for cancer, a contiguous (nonrandom) tissue volume could be searched, specified by a small number of partial addresses. For instance, if 107 nanorobots were tasked to scan 30 (unnamed) alveoli each, within the contiguous volume, then each nanorobot must store one ~23 bit hard-coded kernel address plus one ~5 bit alveolus extension address (total 28 bits/alveolus) and one 30-bit cell address for each cancerous cell discovered, a modest memory requirement. On the other hand, general surveyor nanorobots lacking individualized instructions can keep track of the forks they pass and the branches they take as they enter the lungs, assembling the final address (of any cancer cell they ultimately discover) as they go. Upon reaching the terminus of the bronchial system and encountering another nanorobot already at work, the newcomer moves on to another location, keeping track of its current address (~28 bits). Once a cancer is detected, treatment nanorobots can follow the surveyor's address to return to the specific cancer cell without requiring a comprehensive map of the rest of the lung. Thus a treatment protocol can be executed without any overall map of the lung, although the assignment of individual search territories may prove more efficient, and multiple connectivities within the bifurcation tree may demand storage of additional bits or require post-survey data compression.
Last updated on 19 February 2003