How does the body react to medical nanodevices?

November 19, 2003

Originally published in Foresight Update August 31, 2003. Published on November 18, 2003.

For the last 4 years, Robert Freitas has been teasing us with brief extracts from his forthcoming Nanomedicine, Volume IIA, in his quarterly nanomedicine articles for Foresight Update. The second installment of this famous series is in press and should be out by September 2003. A full online version will appear in the months to come, though an outline is available now at Robert’s nanomedicine site

There are now four books in the Nanomedicine trilogy&#8212what began as a single chapter in Volume II has grown into a book: Volume IIA. This is hardly surprising when we consider how critical biocompatibility is to the safety, effectiveness, and utility of medical nanorobotic devices, and the magnitude and complexity of the subject matter.

In his usual thorough fashion, Freitas gives us an overview of essentially the entire field of biocompatibility as it relates to medical nanorobots and the materials that might be used in their construction. While the target audience is "biomedical engineers, biocompatibility engineers, medical systems engineers, research physiologists, clinical laboratory analysts, and other technical and professional people who are seriously interested in the future of medical technology" this volume comes at a timely juncture: published concerns about the biocompatibility of nanotechnology are growing in the environmental community, and a solid foundation on which to base the discussion is greatly welcomed. This new book provides a technical tour-de-force and a treasure trove of facts, ideas, and recent research results, with an extensive 1400-entry glossary and over 6100 literature citations in the reference list, representing 8000 man-hours of effort by the author. This book should be the starting point for anyone planning a serious research program in medical nanorobot design.

Perhaps the best way to give the reader an overview of what Nanomedicine Volume IIA is all about is to quote a few words from Freitas describing just part of this Magnum Opus:

"Compatibility" most broadly refers to the suitability of two distinct systems or classes of things to be mixed or taken together without unfavorable results. More specifically, the safety, effectiveness, and utility of medical nanorobotic devices will critically depend upon their biocompatibility with human organs, tissues, cells, and biochemical systems. Classical biocompatibility has often focused on the immunological and thrombogenic reactions of the body to foreign substances placed within it. In this Volume, we broaden the definition of nanomedical biocompatibility to include all of the mechanical, physiological, immunological, cytological, and biochemical responses of the human body to the introduction of medical nanodevices, whether "particulate" or "bulk" in form. That is, medical nanodevices may include large doses of independent micron-sized individual nanorobots, or alternatively may include macroscale nanoorgans (nanorobotic organs) assembled either as solid objects or built up from trillions of smaller artificial cells or docked nanorobots inside the body. We also discuss the effects on the nanorobot of being placed inside the human body.

In most cases, the biocompatibility of nanomedical devices may be regarded as a problem of equivalent difficulty to finding biocompatible surfaces for implants and prostheses that will only be present in vivo for a relatively short time. That’s because fast-acting medical nanorobots will usually be removed from the body after their diagnostic or therapeutic purpose is complete. In these instances, special surface coatings along with arrays of active presentation semaphores may suffice. At the other extreme, very long-lived prostheses are already feasible with macroscale implants such as artificial knee joints, pins, and metal plates that are embedded in bone. As our control of material properties extends more completely into the molecular realm, surface characteristics can be modulated and reprogrammed, hopefully permitting long-term biocompatibility to be achieved. In some cases, nanoorgans may be coated with an adherent layer of immune-compatible natural or engineered cells in order to blend in and integrate thoroughly with their surroundings. Today (in 2002), the broad outlines of the general solutions to nanodevice biocompatibility are already apparent. However, data on the long-term effects of implants is at best incomplete and many important aspects of nanomedical biocompatibility are still unresolved&#8212and will remain unresolved until an active experimental program is undertaken to systematically investigate them.

Since a common building material for medical nanorobots is likely to be diamond or diamondoid substances, the first and most obvious question is whether diamondoid devices or their components are likely to be hazardous to the human body. Chapter 15.1 briefly explores the potential for crude mechanical damage to human tissues caused by the ingestion or inhalation of diamond or related particles. There are varying degrees of potential mechanical injury and these are probably ultimately dose-dependent. It will be part of any medical nanorobot research project to determine the actual amount of diamondoid particulate matter necessary to cause clinically significant injury.

A great deal of preliminary information is already available on the biocompatibility of various materials that are likely to find extensive use in medical nanorobots. Chapter 15.3 includes a review of the experimental literature describing the known overall biocompatibility of diamond, carbon fullerenes and nanotubes, nondiamondoid carbon, fluorinated carbon (e.g., Teflon), sapphire and alumina, and a few other possible nanomedical materials such as DNA and dendrimers&#8212in both bulk and particulate forms.

One of the more interesting issues is that medical nanorobots might be consumed by the body’s defenders, the white cells. Thus, nanorobots will have to dodge, pacify, or escape from their embrace. As Freitas observes: "… all nanorobots that are of a size capable of ingestion by phagocytic cells must incorporate physical mechanisms and operational protocols for avoiding and escaping from phagocytes. The basic strategy is first to avoid phagocytic contact, recognition, or binding and activation, and secondly, if this fails, then to inhibit phagocytic engulfment or enclosure and scission of the phagosome. If trapped, the medical nanorobot can induce exocytosis of the phagosomal vacuole in which it is lodged or inhibit both phagolysosomal fusion and phagosome metabolism. In rare circumstances, it may be necessary to kill the phagocyte or to blockade the entire phagocytic system. Of course, the most direct approach for a fully-functional medical nanorobot is to employ its motility mechanisms to locomote out of, or away from, the phagocytic cell that is attempting to engulf it. This may involve reverse cytopenetration, which must be done cautiously (e.g., the rapid exit of nonenveloped viruses from cells can be cytotoxic). It is possible that frustrated phagocytosis may induce a localized compensatory granulomatous reaction. Medical nanorobots therefore may also need to employ simple but active defensive strategies to forestall granuloma formation."

And, as always, Freitas is famous not just for his thorough coverage of the field, but also for the historical side lights that enliven his text. Pounded diamond dust, for example, was used by assassins through the ages&#8212an observation that inspired Freitas to investigate the issue more directly by examining pounded diamonds with a scanning electron microscope (SEM) and confirming that "even a single hammer blow produced numerous particles of a wide variety of sizes (0.1-100 micron), many possessing sharp ragged ‘fishhook’ edges, deep angular concavities, serrations, irregular holes, and other interesting features." No doubt of greater concern to his wife was his earlier report ( of self-experimentation with (albeit uncrushed) diamond powder, finding that "even irregularly-shaped diamondoid particles ~3 microns and smaller apparently roll smoothly out of the way when ground between the teeth, whereas particles larger than ~3 microns cannot roll sufficiently and retain a sensible grittiness."

This excellent volume provides us with yet another authoritative analysis of issues that are critical to the development of nanomedicine&#8212and again makes clear that, while there is much to do there are no insurmountable obstacles nor fundamental barriers that stand in our way.

To end with a question: do you expect to be alive in thirty years? If so&#8212and most people do&#8212then the development of nanomedicine within that time frame will benefit you directly. The medical nanorobots we are talking about could save your life, the lives of your loved ones and the lives of your friends. This is possible and even likely, but not inevitable. How long it takes to develop this life saving technology depends on what we do&#8212it is not happening according to some cosmic plan, with a date engraved in stone that neither you nor I can change&#8212but rather it will take as long as we let it take. Yes, thirty years is a long time. Yes, most people have a hard time thinking about the next year, let alone the next decade, let alone a few decades hence. But if we don’t act today, then we might one day wake up in a future where we are old and infirm and the promise of nanomedicine is still just that: a promise. To paraphrase a famous slogan: think long term, act short term.

© 2003 Foresight Institute. Reprinted with permission.