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
“Compatibility” most broadly refers to the suitability of two distinct systems or classes of things to be mixed or taken together without unfavorable results [2004]. 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 [234-243, 260, 6030-6048] 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 – and 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 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.
Classical biocompatibility refers to the assessment of the totality of nanorobot surface material-tissue/fluid interactions, both local and systemic. These interactions may include cellular adhesion, local biological effects, systemic and remote effects, and the effects of the host on the implant. Chapter 15.2 summarizes the current status of medical implant biocompatibility and then discusses the important future nanomedical issues of protein interactions with nanorobot surfaces, immunoreactivity, inflammation, coagulation and thrombosis, allergic reactions and shock, fever, mutagenicity and carcinogenicity.
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 – in both bulk and particulate forms.
The purposeful movement of solid bodies and particulate matter through the various systems of the human body is also of particular interest in nanomedicine. Chapter 15.4 examines the requirements for intact motile nanorobots that can locomote inside the human body while avoiding geometrical trapping, phagocytosis, and granulomatization, thus achieving controlled or indefinite persistence without clearance by the natural immune system. The analysis extends to the fate of free-floating nanorobots and their material ejecta, or fragments, as well as the fate of motile nanorobots that have malfunctioned and lost their mobility, or which are moving passively through the body, or are being driven by cell-mediated processes.
Unlike pharmaceutical agents whose interactions with biology are largely chemical in nature, medical nanorobots may interact both chemically and mechanically with human tissues and cells. Similarly, while traditional biomedical implants produce both chemical and bulk mechanical effects, nanoorgans and nanoaggregates may possess active nanoscale features and moving parts that can apply spatially heterogeneous mechanical forces at the molecular and microscopic scale. Thus any study of nanomedical biocompatibility must necessarily include an analysis of the mechanical biocompatibility, or mechanocompatibility, of nanorobotic systems as they interact with the tissues and cells of the human body. Accordingly, Chapter 15.5 describes the mechanical interactions of nanorobotic systems with human skin and other epithelial tissues, including mechanical tissue penetration and perforation leakage, as well as mechanical interactions with vascular systems, extracellular matrix and tissue cells, and nontissue cells such as erythrocytes, platelets, and leukocytes. The Chapter ends with a detailed review of cytomembrane and intracellular mechanocompatibility, and a brief consideration of electrocompatibility and nanorobot-nanorobot mechanocompatibility.
Finally, otherwise biocompatible medical nanodevices might provoke unwanted reactions by simple physical displacement of critical biological systems or fluids. Chapter 15.6 examines issues of volumetric intrusiveness – the degree to which artificial systems can safely displace natural systems volumetrically. The brief discussion includes a look at the acceptable limits of volumetric intrusiveness of macroscopic objects placed inside the human body (or its various organs), the bloodstream, and in individual human cells.
The discussion of nanorobot biocompatibility was originally intended to include just a single chapter, Chapter 15, in the Nanomedicine book series. However, during the course of this research it became clear that biocompatibility is a central issue in determining the feasibility, limitations, and technical requirements of medical nanorobotics. This recognition demanded additional investigations that resulted in the present book-length “Chapter 15.”
The primary intended audience of this Volume 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. Readers wishing to keep abreast of the latest developments can visit the author’s Nanomedicine Page website (http://www.foresight.org/Nanomedicine), hosted by the Foresight Institute; or may read the author’s most recent (2002) popular [23, 28] and technical [25, 30-32] summaries of the emerging field of nanomedicine; or may visit http://www.nanomedicine.com, the first commercial Internet domain exclusively devoted to nanomedicine and the online home of this document and related materials. Since 1994, the author has expended on the Nanomedicine project ~27,000 man-hours in total, including ~8000 man-hours on the present Volume IIA, a total of ~13 man-years of effort to date. Volume I [1] has been favorably reviewed [2-5]. The author’s Nanomedicine Art Gallery (http://www.foresight.org/Nanomedicine/Gallery/index.html), hosted by the Foresight Institute, also provides the largest online collection of original and previously-published nanomedicine-related images, graphics, artwork, animations, and relevant links.
References [####] are used in this book to denote the source
of: (1) a direct quotation (enclosed in quotes), (2) a paraphrased passage (footnoted
but not enclosed in quotes), or (3) a specific datum. Citations are also employed
to indicate sources of additional information on a given topic, especially collections
of literature review papers that would provide a suitable introduction to a
given field of study. The author apologizes in advance for any inadvertent instances
of unattributed usage of previously published material. Such events should be
few but should be brought to the author’s immediate attention for correction
in a future edition of this work. An attempt was made to cite primary sources
whenever possible, but some references are made to secondary sources believed
by the author to be reliable. Unreferenced in-text attributions to specific
named people generally refer to comments made by a technical reviewer of the
manuscript, usually as a personal communication.
I first must thank James R. Von Ehr II, the founder of Zyvex Corp., for his foresight, determination, and unwavering support of my efforts – without which the completion of this Volume would not have been possible. Jim founded Zyvex in April 1997 as the world’s first molecular nanotechnology company, with the explicit goal of creating a molecular assembler that would be capable of manufacturing medical nanodevices with the precision, and in the vast numbers, necessary to enable practical (economical) medical nanorobotic therapeutics. The company has recently broadened its objectives to include additional nearer-term goals, while never losing sight of the ultimate prize. I first met Jim in October 1996 and later joined Zyvex as a Research Scientist in March 2000, and am proud to be associated with this amazing company of brilliant and dedicated individuals.
Next, I would like to thank the following 114 people and organizations for providing useful references, preprints, publications or information, artwork or animations, helpful discussions, personal communications, positive media attention, encouragement, or other assistance to the Nanomedicine book project or to my other nanomedicine-related activities: Adriano Alippi, Alex M. Andrew, Amara D. Angelica, Rocky Angelucci, Igor Artyuhov, Kevin D. Ausman, James R. Baker, Jr., Peter E. Barker, Linda Bickerstaff, Robert J. Bradbury, Forrest Bishop, Renata G. Bushko, Barbara Carasso, Adriano Cavalcanti, Ken Clements, L. Stephen Coles, Carol Beck Crosby, K. Eric Drexler, William L. Dye, Extropy Institute, Gregory M. Fahy, Lars Lawrence Fields, Film Oasis, Arthur Fine, Stephen S. Flitman, Tim Fonseca, Foresight Institute, David R. Forrest, Frankfurter Allgemeine Zeitung, David Friedman, Katharine Green, Cecilia Haberzettl, J. Storrs Hall, James L. Halperin, Owen P. Hamill, John Hewitt, Hugh Hixon, Tad Hogg, Jan H. Hoh, C. Christopher Hook, Sue Houghton, Robert G. Hughes, Institute for Molecular Manufacturing, Neil A. Jacobstein, David A. Kekich, Markus Krummenacker, Aryavarta Kumar, Raymond Kurzweil, KurzweilAI.net, Eugene Kwon, Emily Laber, Ronald G. Landes, Landes Bioscience, Christophe Laurent, Eugene Leitl, Jerry B. Lemler, James B. Lewis, James Logajan, Patrick Mace, Roger E. Marchant, Elizabeth Mathews, Thomas McKendree, James McQuillan, Attila Meretei, Ralph C. Merkle, Gina “Nanogirl” Miller, Larry S. Millstein, Kelly Morris, Rajendrani Mukhopadhyay, Philippe Van Nedervelde, Vik Olliver, Brett Paatsch, Peter Passaro, Christine L. Peterson, Phlesch Bubble Productions, Christopher J. Phoenix, Sandra Pinkerton, Eugene Pinkhassik, Michael Prater, John N. Randall, Anil K. Rao, Rocky Rawstern, Edward M. Reifman, Carolyn Rogers, John D. Rootenberg, Jillian Rose, Lawrence Rosenberg, Uri Sagman, Niladri Neil Sarkar, Frank Schirrmacher, Titus L. Schleyer, Nadrian C. Seeman, Rafal Smigrodzki, Steven S. Smith, Heiko Spallek, Michael Sprintz, Charles Tandy, Richard P. Terra, Thomas Lucas Productions, Tihamer Toth-Fejel, Natasha Vita-More, James R. Von Ehr II, David O. Weber, Michael Weiner, Christopher Wiley, Stephen R. Wilson, Thomas G. Wilson, Paul K. Wolber, World Technology Network, World Transhumanist Association, Brian Wowk, Bai Xu, Eliezer S. Yudkowsky, and Zyvex Corp.; the Foresight Institute for hosting my Nanomedicine Page and Nanomedicine Art Gallery websites; several anonymous referees of published papers; and, finally, the one person whose name I have inadvertently but inexcusably omitted.
I extend my heartfelt thanks to the 36 individuals listed below who reviewed or commented on all or some part of various Chapters in Volume IIA (total number of chapters in parentheses): Kevin D. Ausman, Ph.D. (1), James R. Baker, Jr., M.D. (2), Peter E. Barker, Ph.D. (1), Robert J. Bradbury (5), Renata G. Bushko, M.S. (1), L. Stephen Coles, M.D., Ph.D. (6), William L. Dye (3), Gregory M. Fahy, Ph.D. (1), Arthur Fine, M.D. (2), Steven S. Flitman, M.D. (3), Cecilia Haberzettl, Ph.D. (2), Owen P. Hamill, Ph.D. (2), Aryavarta Kumar (3), Eugene Kwon, M.D. (2), Ronald G. Landes, M.D. (6), Christophe Laurent, M.D. (2), Roger E. Marchant, Ph.D. (1), Attila Meretei, M.D. (1), Rajendrani Mukhopadhyay (1), Eugene Pinkhassik, Ph.D. (1), Michael Prater, M.D. (1), Anil K. Rao, Ph.D. (2), Edward M. Reifman, D.D.S. (1), Carolyn Rogers, M.S. (4), John D. Rootenberg, M.D. (2), Lawrence Rosenberg, M.D., Ph.D. (2), Uri Sagman, M.D. (1), Nadrian C. Seeman, Ph.D. (1), Rafal Smigrodzki, M.D. (1), Steven S. Smith, Ph.D. (1), Michael Sprintz, D.O. (6), Christopher Wiley, M.D. (2), Thomas G. Wilson, Jr., D.D.S. (3), Paul K. Wolber, Ph.D. (2), Brian Wowk, Ph.D. (1), and Bai Xu, Ph.D. (1); number of reviews, by Chapter, are 15.1 (9), 15.2 (16), 15.3 (15), 15.4 (11), 15.5 (9), and 15.6 (8). These reviewers are to be lauded for undertaking a difficult task and should be held blameless for any errors that remain in the manuscript; the author is solely responsible for all errors of fact or judgment within these pages. Reports of errata may be transmitted electronically directly to the author at the following email address: rfreitas@rfreitas.com
My special thanks go to: Michael Sprintz, John Rootenberg, and Robert J. Bradbury for particularly lengthy and detailed Chapter reviews of the earliest and most imperfect drafts; Dr. Elizabeth Mathews of the San Joaquin Delta College Electron Microscopy Center, for generously making available research facilities and for assistance with my electron microscopy experiment with diamond grit, and also her laboratory supervisor, Carol Beck Crosby; Larry Millstein for his contribution to the financial support of Volume I which was never properly acknowledged, and for his continuing enthusiasm for this project; and especially Ralph C. Merkle for his longstanding friendship, collaboration, and unwavering encouragement of my progress, in all of its dimensions.
I again thank my publisher, Ronald G. Landes, M.D., for his trust, foresight, and persistence in publishing this book series. I also applaud Celeste Carlton, Cynthia Conomos, and the rest of the staff of Landes Bioscience for their excellent and professional work on this project, and Lars Lawrence Fields and Jillian Rose at Phlesch Bubble Productions for the wonderful cover art.
Finally, and most importantly, I wish to thank my wife, Nancy Ann Freitas, and my parents, Robert A. Freitas Sr. and Barbara Lee Freitas, without whose help, understanding, and encouragement this book could not have been written.
Robert A. Freitas Jr., J.D.
Research Scientist
Zyvex Corp.
6 December 2002
Last updated on 30 April 2004