NATURE BIOTECHNOLOGY VOLUME 24 NUMBER 10 OCTOBER 2006 1211 The emerging nanomedicine landscape Volker Wagner, Anwyn Dullaart, Anne-Katrin Bock & Axel Zweck A global survey of companies pursuing ���nanomedicine��� indicates that nanotechnology is taking root in the drug and medical device industry. Thaspast he decade���s surge in research in what been termed ���nanomedicine��� is now translating into considerable commercializa- tion efforts around the world. Alerted by these developments, governmental agencies are planning funding programs to support this research, and roadmaps and foresight studies have been commissioned by various science administrations to analyze technological and commercial perspectives of this emerging field. The European Science Foundation���s report Scientific Forward Look on Nanomedicine, the culmination of a two-year study completed in 2005, warns that nanomedicine benefits will be lost without major investment and calls for a coordinated European strategy to deliver new nanotechnology-based medical tools for diag- nostics and therapeutics1. However, because of a lack of primary data on scientific and business activities in the field, discussions up until now have been largely qualitative. For this reason, the European Science and Technology Observatory (ESTO), a network of organizations operating under the European Commission���s leadership and funding, carried out a study focusing on gathering data2. This article presents data from the above study showing that commercialization efforts are significant, with more than 150 startups and small and medium enterprises (SMEs) pursuing focused nanomedicine R&D proj- ects and 38 nanotechnology-enabled products currently on the market with total sales valued at $6.8 billion. Drug delivery applications cur- rently dominate nanomedicine, accounting for three-quarters of the research activity and of the nanomedicine market. Commercialization efforts in Europe in this area are relatively weak, with only half as many companies as in the United States. What is nanomedicine? The term nanomedicine can be traced back to the late 1990s according to the Science Citation Volker Wagner and Axel Zweck are with VDI Technologiezentrum GmbH, The Association of German Engineers, Graf-Recke-Strasse 84, 40239 D��sseldorf, Germany Anwyn Dullaart is at the European Patent Office, Patentlaan 2, 2288 EE Rijswijk, The Netherlands and Anne- Katrin Bock is with the European Commission, Joint Research Centre, Institute for Prospective Technological Studies, Edificio Expo, Inca Garcilaso, E-41092 Seville, Spain. e-mail: wagner@vdi.de Box 1 Healthcare applications of nanomedicine We present below the definitions used within this article for the different applications of nanomedicine within healthcare. Drug delivery. Nanoscale particles/molecules developed to improve the bioavailability and pharmacokinetics of therapeutics. Examples are liposomes (and virosomes), polymer nanoparticles, nanosuspensions and polymer therapeutics. Drugs in which a protein is combined with a polymer nanoparticle or chemical nanostructure to improve its pharmacokinetic properties would be classified as nanomedicine-based drug delivery. Drugs and therapy. Nanoscale particles/molecules used in the treatment of diseases that according to their structure have unique medical effects and as such differ from traditional small-molecule drugs. Examples include drugs based on fullerenes or dendrimers. In vivo imaging. Nanoparticle contrast agents, particularly for MRI and ultrasound, that provide improved contrast and favorable biodistribution. For example, superparamagnetic iron oxide nanoparticles for use as MRI contrast agents. In vitro diagnostics. Novel sensor concepts based on nanotubes, nanowires, cantilevers or atomic force microscopy applied to diagnostic devices/sensors. The aim of these sensors is to improve the sensitivity, reduce production costs or measure novel analytes (e.g., Alzheimer plaques) that until recently could not be detected. For example, Nanomix (Emeryville, CA, USA) develops carbon nanotube���based sensors for monitoring respiratory functions and Bioforce���s Virichip (Ames, IA, USA) uses atomic force microscopy for the detection of whole viruses for early diagnosis of viral infections. Biomaterials. Self-assembling particles or other types of nanomaterial that improve the mechanical properties and the biocompatibility of biomaterials for medical implants. Examples include nanocomposite materials used as dental fillers and nano- hydroxyapatite used for implant coatings and bone substitutes. Also decoration of implant materials with biologically active signal molecules that stimulate, for example, cell growth or differentiation. Active implants. Particles/materials that improve electrode surfaces and biocompatibility of device housings. Examples include Biophan���s (Henrietta, NY, USA) magnetic nanoparticle���based coating that makes medical implants safe for use with MRI imaging and nanomaterials used for retina implants to improve the charge transfer at the electrode tissue interface (Retina Implantat AG, T��bingen, Germany). To address single cells on a submicron level is currently not an area of R&D at medical device companies. FEATURE �� 200 6 Nature Publishing Group http://www.nature.com/naturebiotechnology

1212 VOLUME 24 NUMBER 10 OCTOBER 2006 NATURE BIOTECHNOLOGY Index (Institute for Scientific Information, Thompson, Philadelphia, PA, USA) the first research publications that use this term appeared in the year 2000. With research pro- grams, conferences and journals focusing on nanomedicine for a number of years now, it has become clear that nanomedicine is more than a semantic fashion, though it was difficult to find a precise definition for this field with its blurred borderlines encompassing biotech and microsystems technology. In general, two concepts can be distin- guished. Some experts define nanomedicine very broadly as a technology that uses molecu- lar tools and knowledge of the human body for medical diagnosis and treatment3. Others prefer an emphasis on the original meaning of nanotechnology as one that makes use of physical effects occurring in nanoscale objects that exist at the interface between the molecu- lar and macroscopic world in which quantum mechanics still reigns4. We adopted the sec- ond concept and define nanomedicine as the use of nanoscale or nanostructured materials in medicine that according to their structure have unique medical effects (see Box 1), for example, the ability to cross biological barriers or the passive targeting of tissues. Such medi- cal effects are not strictly limited to a size range below 100 nanometers. Therefore, unlike the physical definition of nanotechnology, which is restricted to objects with dimensions in the range of 1 nm to 100 nm, we include struc- tures and objects up to 1,000 nm in size. Such a definition also seems to be justified from a technical point of view because the control of materials in this size range not only results in new medical effects but also requires novel, scientifically demanding chemistry and man- ufacturing techniques. This definition does not include traditional small-molecule drugs as they are not specifically engineered on the nanoscale to achieve therapeutic effects that relate to their nanosize dimension. Nanomedicine research A bibliometric analysis of documents (see Box 2 for methodology) in the Science Citation Index shows that nanomedicine has seen a surge in research activity over the past decade, with pub- lication numbers rising from some ten articles per year in the late 1980s to more than 1,200 in the year 2004 (Fig. 1). Patenting activities have skyrocketed since the beginning of the decade: a search by the European Patent Office reveals 2,000 patent filings in the nanomedicine sector in the year 2003, up from 220 in 1993. Drug delivery is the dominant research field with a share of 76% of the scientific papers and 59% of the patents (Figs. 2 and 3). In the field of nanomedicine research, the United States is leading, accounting for 32% of the publications and 54% of the patent filings. The EU country with the strongest nanomedicine activities is Germany, con- tributing 8% of the publications and 12% of the patent filings. Further, Japan has an internationally strong position with a share of 9% of the publications and 5% of the patents. A comparison between Europe as a whole with the United States shows that Europe is at the forefront of research with a publication share of 36%, compared with the United States��� share of 32%. However, the United States leads in the number of patent filings, with 54% compared with 25% from Europe. The strong patenting activity of US scientists and companies indicates a more advanced commercialization status in the United States. This contradicts the claim that nanomedicine is more advanced in Europe Currently, there is no generally agreed upon definition of nanomedicine, and comprehensive information resources are not yet available that allow quick and efficient data retrieval with regard to technological and commercial information. Therefore, we used a diverse set of information sources, such as internet forums, patent databases, business databases, proceedings of business conferences. Publications were searched in the Science Citation Index database (http://scientific.thomson.com/products/sci/), using discrete key words indicative for each of the defined nanomedicine application sectors (see Supplementary Methods online). A patent search was conducted by the European Patent Office using EPODOC, the internal European Patent Office Documentation database, which covers patents worldwide, using a combined keyword and patent classification search. Because industry codes for the classification of nanotechnology companies are not yet available in business databases, we identified nanomedicine companies using various internet nanotechnology databases (http://www.nanoforum.org/, http://www.nanovip.com/, http:// www.nano-map.de), booklets of nanotechnology fairs, agendas of business conferences and patent data. Companies were then profiled on the basis of publicly available information, such as web presentations, press releases and Security and Exchange Commission (SEC) filings. From an initial list of 400 companies, 207 were selected that have visible and openly communicated activities in the field of nanomedicine as we define it. Data on products on the market and in clinical trials were retrieved by analyzing review papers and business press as well as by searching in medical databases such as the Adis Newsletter and the Pharmaprojects Drug Development Status File. Information on product sales were retrieved by SEC filings, the Creditreform database and by expert interviews. In total, 46 questionnaire-guided interviews were conducted with scientists from academia, CEOs of startups and R&D managers of pharmaceutical and medical device companies, to provide more detailed insights into the structure of the emerging nanomedicine industry. Box 2 Methodology of data collection 0 500 1,000 1,500 2,000 2,500 Patents Publications 4 200200 3 2002 2001 1992000 9 1991998 7 1996 4 1991991995 3 1991992 1 1990 Year Number of documents Figure 1 Nanomedicine publications and patents worldwide. Sources: Science Citation Index, VDI Technologiezentrum GmbH, D��sseldorf, Germany and EPODOC patent database, European Patent Office, Rijswijk, The Netherlands. FEATURE �� 200 6 Nature Publishing Group http://www.nature.com/naturebiotechnology