Nanomedicine, Volume IIA: Biocompatibility
© 2003 Robert A. Freitas Jr. All Rights Reserved.
Robert A. Freitas Jr., Nanomedicine, Volume IIA: Biocompatibility, Landes Bioscience, Georgetown, TX, 2003
15.2.4 General and Nonspecific Inflammation
Inflammation  is a nonspecific physiological response to various forms of tissue damage including trauma (Chapter 24), infection (Chapter 23), intrusion of foreign material (Section 22.214.171.124, Chapter 24), local cell death (Section 10.4.1.1), or as an adjunct to immune system (Section 126.96.36.199), tissue remodeling (Chapter 24), or neoplastic responses . If vascular tissue has also been disrupted, then the complex process of blood coagulation (Section 15.2.5) may be superimposed on the inflammatory response, and if an infection is involved, the complement system (Section 188.8.131.52) may be activated.
The four classical clinical signs of inflammation, first reported by the ancient Roman medical writer Cornelius Celsus (Section 184.108.40.206), are redness (rubor), swelling (tumor), pain (dolor), and heat (calor). The magnitude of these initial events is related to the intensity and extent of the inflammatory stimulus, with cells involved in the inflammatory response (Section 220.127.116.11) producing more than 100 chemical mediators.
Redness or erythema reflects a higher local concentration of red blood cells in the vicinity of the inflammatory stimulus . This occurs because the first responses to such stimuli are (1) a rapid vasodilation of local capillaries (changing their local aspect ratio, leading to an increase in blood entry into the capillary beds), (2) an increase in the permeability of vascular endothelial cell linings (causing a loss of plasma through the capillary walls), and (3) a tendency for platelets and erythrocytes to become “sticky” (leading to slower flow and sludging). Vasodilation arises from the activation of Hageman factor (coagulation factor XII; Section 15.2.5) through contact with collagen or foreign proteins , biomedical polymers , or with glass , kaolin particles , or certain other insoluble negatively charged surfaces [1840-1845]. The intermediate contact activation of kallikrein, a polypeptide, leads to conversion of a group of additional molecules to kinins . Kinins are a group of strong vasoactive mediators that can affect blood pressure (e.g., induce hypotension), elevate blood flow throughout the body, increase the permeability of small blood capillaries, and stimulate pain receptors (see below).
Swelling or edema (see also Section 18.104.22.168) occurs in the vicinity of the inflammatory stimulus because the increased permeability of the capillary endothelium allows fluid to move into the surrounding tissue bed . Normally the endothelium is tight, permitting only a slow flow of water and small molecules into the surrounding tissues that is drained by local lymphatic vessels (Section 22.214.171.124). This slow flow maintains a constant tissue volume and a 10-15 mmHg pressure differential between the arteriole ends of capillaries and the external tissue bed . With increased vascular permeability, water and molecules such as plasma proteins and locally activated kinins enter tissues, causing them to distend or swell unless promptly balanced by increased lymphatic drainage.* However, local lymphatics may be constricted or blocked by the original trauma, or occluded by cell fragments or nanorobots (Section 126.96.36.199), or hydraulically compressed, and the elevated concentration of plasma proteins raises local osmotic pressure, tending to hold the fluid in place. In extreme cases, a fluid movement is blocked leading to the so-called “compartment syndrome”  (sometimes related to anatomic barriers such as fascial planes ) which, if not promptly relieved, results in cell death and tissue necrosis .
* Bradykinin, an end product of contact system activation (Section 15.2.5), is a tenfold more potent vasodilator than histamine.
Pain occurs proximal to the inflammatory stimulus in part because the local edema may activate local deep pain receptors, or nociceptors. Inflammatory pain is experienced by patients as a throbbing sensation repetitively pulsed by the peaks in systolic pressure . Kinins also produce pain by acting directly on nerve endings to induce both acute and persistent pain – the kinin B2 receptor predominates in acute inflammatory pain, the B1 receptor in persistent inflammation . Kinins may also be involved in the hyperalgesia associated with peripheral and central inflammatory insults to the CNS, and there are many interactions between kinins and other inflammatory mediators known to be involved in the genesis or maintenance of the accompanying hyperalgesia . Prostaglandins, cytokines, neuropeptides, and 5-HT have been implicated in the process of activation or sensitization of nociceptors. There is evidence that some of these mediators have powerful and complex interactions with kinins in the inflammatory pain process . As a possible analog with hard-material nanorobots, there is at least one report  of pain possibly caused by numerous small insoluble crystals in the renal tubules. Accordingly, care must be taken in nanorobot mission design to forestall nanorobot crystallization – crystal-like aggregates  or van der Waals solids  comprised of multiple individual nanorobots – which might form under certain conditions of dehydration or pH, especially among nanorobots purposely created to form space-filling aggregates (Section 5.2.5).
Heat in tissues near the site of inflammation is usually attributed to increased blood flows and to local disturbances of fluid flow in the presence of increased cellular metabolic activity by increasing numbers of cells. Pyrogens known to cause systemic fever (Section 15.2.7) might also be generated locally either by tissue necrosis or as a result of activation by bacterial or viral toxins (e.g., endotoxin) in the presence of infection .
These early events in the general inflammatory response are largely chemical in origin . Shortly afterwards, the affected tissue is invaded by a series of cells such as neutrophils, macrophages and fibroblasts. These cells are responsible for the removal of dead tissue, phagocytosis of foreign matter, damage repair (though sometimes creating additional damage), and tissue remodeling. The inflammatory cell response to foreign particles, and possibly to medical nanorobots, is described in Section 188.8.131.52.
Could medical nanorobots or nanoorgan surfaces trigger general inflammation in the human body? One early experiment  to determine the inflammatory effects of various implant substances placed subdermally into rat paws found that an injection of 2-10 mg/cm3 (10- to 20-micron particles at 105-106 particles/cm3) of natural diamond powder suspension caused a slight increase in volume of the treated paw relative to the control paw. However, the edematous effect subsided after 30-60 minutes at both concentrations of injected diamond powder that were tried. This swelling could have been wholly caused by mechanical trauma of the injection, not the diamond powder. Another experiment  at the same laboratory found that intraarticulate injection of diamond powder was not phlogistic (i.e., no erythematous or edematous changes) in rabbit bone joints and produced no inflammation. Diamond particles are traditionally regarded as biologically inert and noninflammatory for neutrophils [222, 605, 633, 639] and are typically used as experimental null controls . CVD (chemical vapor deposition) diamond  and DLC (diamond-like carbon) diamond  surfaces elicit minimal or no inflammatory response, and atomically smooth diamond may perform even better. Diamond particles are said to have little or no surface charge [633, 640] but unmodified graphene (Section 2.3.2) surfaces readily acquire negative charges in aqueous suspension [689, 690]. Adamantane-based compounds exist which enhance or inhibit the inflammatory response . Experiments are therefore needed to determine if negatively charged fullerenes or diamondoid substances can contact-activate Hageman factor or kallikrein and trigger an inflammation reaction. Carbon nanotubes and spherical fullerenes generally appear to be noninflammatory [2599, 5227].
The inflammatory properties of other possible nanorobot materials appear positive. For instance, vitreous carbon is mildly inflammatory  to inert . Pyrolytic carbon is mildly inflammatory [801, 902] to inert . Graphite is minimally inflammatory [820, 822, 823], though 1-micron particles apparently stimulate some nitric oxide production in rat cells, a possible indicator of inflammatory response . Carbon fiber elicits no significant tissue inflammation [224, 840] or foreign body reaction . Experiments with sapphire have generally found no serious inflammation in dental soft tissues [1006, 1018, 1021, 1031] or bony tissues [974, 1029, 1046], or only mild reactions . However, there are a few exceptions [1030, 1068] including brief acute inflammatory response in special cases [1050, 1055] so the noninflammatory character of sapphire has not yet been definitively established.
On the more negative side, carbon black is sometimes found to elicit moderate inflammatory responses in various soft tissues [852, 856, 887] and the lungs [769, 889-891], though there are some contrary reports [857, 893]. The performance of Teflon is mixed , depending on the form of the material used and the type of tissue in which it is implanted (Section 15.3.4). Inflammatory tissue reactions range from none [1168, 1171, 1173, 1195, 1344], to mild [1185, 1189, 1220, 1376], moderate [1191, 1277, 1350, 1368, 1391], or severe [900, 901, 1364, 1366]. Teflon activates fourfold more kallikrein than Hageman factor . Further details on these materials are in Chapter 15.3. Various natural crystalline substances can produce crystal-induced inflammation without any requirement for particle-bound opsonins . Examples include monosodium urate crystals in gout , silica crystals in pulmonary tissue disease , calcium oxalate  and calcium pyrophosphate dihydrate  crystals in kidney disease and arthritis, and hydroxyapatite and related basic calcium phosphates  in various crystal deposition diseases.
Since the general inflammatory reaction is chemically mediated, it may be possible to employ nanorobot surface-deployed molecular sorting rotors to selectively absorb kinins or other soluble activation factors such as HMGB1 , thus short-circuiting the inflammatory process. Active semaphores consisting of bound proteases such as gelatinase A could be deployed at the nanorobot surface to cleave and degrade monocyte chemoattractant molecules  or other chemokines, suppressing the cellular inflammatory response. Conversely, key inflammatory inhibitors could be locally released by nanorobots. For instance, Hageman factor contact activation inhibitors such as the 22.5-kD endothelial cell-secreted protein HMG-I , surface-immobilized unfractionated heparin , and C1 inhibitor  would probably require lower release dosages than for aspirin or steroids, and therapeutic blockade of factor XII activation has been demonstrated . Prekallikrein MAbs (antibodies) have been raised that inhibit prekallikrein activation by Hageman factor  and direct inhibitors of tissue kallikrein are known . One plasma protease inhibitor strongly inhibits both Hageman factor and kallikrein activation . Diclofenac sodium is a well-known nonsteroidal anti-inflammatory agent (NSAID) that competes with arachidonic acid for binding to cyclo-oxygenase, resulting in decreased formation of prostaglandins . A variety of antinociceptive agents have long been known [5814-5819]. The multivalent guanylhydrazone CNI-1493 inhibits macrophage activation, suppressing the acute inflammation reaction [2593-2595]. As yet another example, platelet activating factor (PAF) is a cytokine mediator of immediate hypersensitivity which produces inflammation. PAF is produced by many different kinds of stimulated cells such as basophils, endothelial cells, macrophages, monocytes, and neutrophils. It is 100-10,000 times more vasoactive than histamine and aggregates platelets at concentrations as low as 0.01 pmol/cm3 . Various PAF antagonists [2059-2062] and inhibitors [2062-2065] are known. These or related inhibitory molecules, if released or surface-displayed by medical nanorobots, may be useful in circumventing a general inflammatory response.
There is also a well-known nonspecific inflammatory response  that often, though not always , causes  or accompanies  mechanical injury or irritation. For example, angiogenesis may be induced by nonspecific inflammatory response to transmyocardial mechanical revascularization  or needle puncture mechanical injury ; nonspecific corneal inflammation has been reported in one case following a laser keratomileusis procedure ; incision of the skin during vascular surgery can induce local nonspecific cellular inflammation ; and inhalation of respirable fractions of fibrous glass particles by rats can produce a nonspecific inflammatory (macrophage) response similar to the effects of inhaling inert dusts . The possible induction of a nonspecific inflammatory response by properly designed and operated active mechanical surface components (e.g., sorting rotors, manipulatory appendages) of medical nanorobots seems avoidable but is an interesting issue that should be investigated further.
Last updated on 30 April 2004