Translational nanomedicine: status assessment and opportunities

Article Outline

• Abstract
• Health care needs with promising nano-enabled technology impact
• Nanoscale science and engineering research needed to enable more effective technology
  • In vivo and in vitro diagnostics
    • In vivo imaging—contrast agents
    • In vivo diagnostics (nonimaging)
    • In vitro miniaturized diagnostics
  • Drugs, delivery, and therapy
    • New approaches to drug development
    • Innovative drug delivery
    • Innovative therapy
  • Implants and tissue regeneration
    • Tissue engineering
    • Orthopedic implants
    • Implanted drug dispenser/factory
    • Implants interacting with the central nervous system
  • Biological systems engineering
  • Innovations in medical instrumentation and devices
• Present federal programs
  • National Institutes of Health
    • Nanomedicine initiative
    • National Institute of Biomedical Imaging and Bioengineering
    • National Cancer Institute
    • National Heart Lung and Blood Institute
    • National Institute of Environmental Health Sciences/National Toxicology Program
    • National Institute of General Medical Sciences
    • National Center for Research Resources
    • NanoHealth Enterprise, public-private partnerships
    • Small Business Innovative Research/Small Business Technology Transfer Research
  • National Science Foundation
  • US Food and Drug Administration
  • Department of Defense
  • Department of Energy
  • European Union
• Recommendations
• References
• Copyright

Abstract 

Nano-enabled technologies hold great promise for medicine and health. The rapid progress by the physical sciences/engineering communities in synthesizing nanostructures and characterizing their properties must be rapidly exploited in medicine and health toward reducing mortality rate, morbidity an illness imposes on a patient, disease prevalence, and general societal burden. A National Science Foundation–funded workshop, “Re-Engineering Basic and Clinical Research to Catalyze Translational Nanoscience,” was held 16–19 March 2008 at the University of Southern California. Based on that workshop and literature review, this article briefly explores scientific, economic, and societal drivers for nanomedicine initiatives; examines the science, engineering, and medical research needs; succinctly reviews the US federal investment directly germane to medicine and health, with brief mention of the European Union (EU) effort; and presents recommendations to accelerate the translation of nano-enabled technologies from laboratory discovery into clinical practice.

From the Clinical Editor

An excellent review paper based on the NSF funded workshop “Re-Engineering Basic and Clinical Research to Catalyze Translational Nanoscience” (16-19 March 2008) and extensive literature search, this paper briefly explores the current state and future perspectives of nanomedicine.

Key words: Nanomedicine, Translational, Nanotechnology, Medicine, Nanobio

Nanostructures and their properties are critical to understand and develop innovations in biological systems, therapeutic agents, and medicine and health. However, it has only been in the last 5 years that “nanomedicine” as a field has been created and has rapidly accelerated. This article explores the reasons behind that fact, examines the science and engineering issues that remain to be addressed if one is to more rapidly translate nanoscience discovery into nano-enabled medical technology, and suggests federal agency actions that could accelerate that eventuality.

The US National Nanotechnology Initiative (NNI) was instituted in 2001 to accelerate and exploit progress in the science and engineering of nanostructures. As evident in Figure 1, exponential growth in literature addressing the nanoscale began about 1990. Interest in the nanoscale has been driven by the commercial availability of nanoscale manipulation and characterization tools, the expectation of new physical, chemical, and biological properties of nanostructures, the expectation that nanostructures will provide new building blocks for innovative new materials with novel properties, the miniaturization into the nanoscale by the semiconductor industry, and the recognition that the molecular machinery in a biological cell functions at the nanoscale. Historically, aspects of chemistry and biology—such as colloids, protein engineering, and molecular virology—have involved nanostructures but on a largely empirical basis. Finally, there is an expectation that a better understanding of the 1- to 100-nm materials size scale (the nanoscale) will lead to a seamless integration of theory and models across the size scales that encompass atomic-molecular-nanostructure-microstructure behavior and thereby enable the a priori prediction and design of a material's properties.

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• Figure 1. 

  Publication counts derived from the Thompson ISI Web of Science database on 15 March 2009 using the indicated key words. The vertical axis is the natural logarithm of the number of publications. There is a clear change in slope for the publications associated with biology and medicine around the year 2000.

The nanoscale literature in the 1990s is dominated by investigations of “hard” materials—ceramics, metals, semiconductors—only in small part resulting from the keen interest in nanoelectronics devices. Many of the new nanoscale analytical tools depend on proximity between a tip and the sample under investigation. This requirement was not overly onerous for relatively stiff materials, the primary focus of nanotechnology in the 1990s. In contrast, soft materials, those of predominant interest in the biology and medical communities, are more readily deformed by a proximal probe and are thereby more difficult to analyze quantitatively. It was not until roughly 2000 that improvements in commercially available instrumentation made the analysis of soft material more viable. Not coincidentally, the literature reporting nanostructures in biology, medicine, and health began to increase more rapidly at that point (Figure 1).

The increase in research activity has to be complemented by programs in the various funding entities. For example, in the United States there are 11 agencies with nanoscale research and development programs reported by the US NNI (Table 1).¹, ² The reported funding for nanoscale science and technology has grown by nearly a factor of 4 since the initiation of the NNI in 2001.

Table 1. US federal agency research and development funding in the NNI (US$ million)

CSREES, Cooperative State Research, Education, and Extension Service; DHS, Department of Homeland Security; DOC, Department of Commerce; DOD, US Department of Defense; DOE, US Department of Energy; DOJ, Department of Justice; DOT, Department of Transportation; EPA, Environmental Protection Agency; FHWA, Federal Highway Administration; FS, Forest Service; HHS, US Department of Health and Human Services; NASA, National Aeronautics and Space Administration; NIH, National Institutes of Health; NIOSH, National Institute of Occupational Safety and Health; NIST, National Institute of Science and Technology; TSA, Transportation Security Administration; USDA, US Department of Agriculture.

At the beginning of the NNI, the National Institutes of Health (NIH) investment at the nanoscale was modest. The NIH hosted two workshops—Nanoscience and Nanotechnology: Shaping Biomedical Research, June 2000³ and Nanobiotechnology, October 2003⁴—to better understand the potential impact of nanostructures on medicine and health, and the knowledge deficiencies inhibiting progress. These workshops, along with promising results from research,⁵ led to major increases in the NIH investment in nanoscale research. The nanoscale investment by NIH has more than doubled since 2005 (sextupled since 2001—Table 1).

As part of the NIH investment to exploit the nanoscale, nanomedicine was incorporated into the NIH Roadmap for Medical Research in 2004.⁶ Understanding nanoscale properties permits engineers to build new materials structures and use these materials in new ways. The same holds true for the biological structures inside living cells of the body. To meet the challenges and to complement its Institute-based programs, the NIH established a national network of eight Nanomedicine Development Centers. These collaborative centers are staffed by multidisciplinary research teams including biologists, physicians, mathematicians, engineers, and computer scientists. In the initial phase of the program (FY2005–FY2010), research has been primarily directed toward gathering extensive information about the chemical and physical properties of nanoscale biological structures.

The European Science Foundation launched a Scientific Forward Look on Nanomedicine in 2004, which involved a series of five workshops and a Consensus Conference (November 2004). This was followed in November 2006 by a report with a strategic research agenda for nanomedicine.⁷ A proceedings from the 2006 NATO Advanced Research Workshop on Nanomaterials for Application in Medicine and Health has been published.⁸ Founded in 2007, the European Society for Nanomedicine (ESNAM)⁹ shares office space with the European Foundation for Clinical Nanomedicine (CLINAM foundation).¹⁰ The first European Conference for Clinical Nanomedicine was organized by CLINAM in May 2008 and had sessions on unsolved problems waiting for nanomedical solutions, nanotechnologies at hand for solving medical problems, clinical trials in nanomedicine, and building bridges between clinicians and nanoscientists.

The growing attention to nanostructures in medicine and health is also reflected in other professional science and engineering communities. A Handbook of Nanomedicine is being implemented.¹¹ The American Academy of Nanomedicine was founded in 2005. The nonprofit American Society for Nanomedicine (http://www.amsocnanomed.org/) was launched in 2008, and—in collaboration with ESNAM—has recently founded the International Society of Nanomedicine at the second CLINAM meeting in April 2009. In 2005 Elsevier launched a journal—Nanomedicine: Nanotechnology, Biology and Medicine (ISSN 1549-9634). Additional journals, the International Journal of Nanomedicine (ISSN 1176-9114) and Nanomedicine (ISSN 1743-5889)—were both launched in 2006. The Institute of Nanotechnology, founded in the United Kingdom in 1994, began its nanomednet¹² in 2007. Though not strictly “nano,” another relevant journal initiated is the Royal Society of Chemistry's Lab on a Chip,¹³ which was initiated in 2001. The American Physical Society PACs classification scheme has been modified to include “nanotechnology design” (87.85.Qr) and “nanotechnology application” (87.85.Rs) under Biomedical Engineering (87.85). Recurrent professional forums addressing aspects of nanomedicine are The International Nanomedicine and Drug Delivery Symposium (NanoDDS, begun in 2003),¹⁴ the Annual Meetings of the American Academy of Nanomedicine (2005–2008),¹⁵ the Society for Biomaterials meeting,¹⁶ the AVS International Symposium and Exhibition,¹⁷ the European Science Foundation conference Nanomedicine 2008,¹⁸ and the International Conference on Biomedical Applications of Nanotechnology.¹⁹

The paucity of knowledge for nanostructure impact on environment, safety, and health (ESH), coupled with the growing prevalence and diversity of, and especially the novel engineered properties in, nano-enabled technologies continues to raise ESH concerns.²⁰ Knowledge of nanostructure ESH risks and their amelioration will be symbiotic with health and medicine applications, in that understanding how to avoid health problems can potentially be used to guide therapy and vice versa. Workshop and task force reports on ESH issues include “Nanotechnology: A Report of the US Food and Drug Administration”²¹ and “Environmental, Health, and Safety Research Needs for Engineered Nanoscale Materials,”²² a UK report on Nanomaterials risk,²³ an International Council on Nanotechnology (ICON) report,²⁴ and a European Commission article.²⁵

Conventional wisdom, buttressed by observation, posits a 20-year gestation period between science discovery and its exploitation in the market. Figure 2 illustrates this point for several major twentieth-century technologies and suggests imminent emergence of nano-enabled technologies. In practice, nanostructures have been used in selected technologies for some time, including carbon black in tires, colorants in stained glass windows, colloidal silver as a disinfectant, colloids and colorants in cosmetics, and many catalysts. Small particles have also been in use for biomedical research and in vitro diagnostic protocols during the last 50 years.²⁶, ²⁷ Most of these applications are based on technology derived empirically from macroscopic observations.

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• Figure 2. 

  Time required for maturation of science discoveries into commercial products. Courtesy of Lux Research Inc., One Liberty Square, Suite 210, Boston, Massachusetts, USA 02109.

There is a database with a listing of products in the market that are (or claim to be) nano-enabled²⁸; there are also specific listings of nano-enabled products in medicine and health.²⁹, ³⁰ As the capability to make, measure, and manipulate individual nanostructures continues to progress, one can expect more extensive entry of nano-enabled and nano-enhanced products and technologies into the marketplace in the coming years.

Although 20 years might be the generic interval for transition of science discovery to innovative technology to translation of these technologies into medical applications, a thoughtfully crafted investment strategy might shorten this time frame. To improve human health, scientific discoveries must be translated into practical applications. Such discoveries typically begin at “the bench” with basic research—in which scientists study disease at a molecular or cellular level—then progress to the clinical level, or the patient's “bedside”. Scientists/engineers are increasingly aware that this bench-to-bedside approach to translational research is really a two-way street.³¹ Basic scientists provide clinicians with new tools for use with patients and for assessment of their impact; clinical researchers make new observations about the nature and progression of disease that often stimulate basic investigations. Translational research has proven to be a powerful process that drives the clinical research engine.³² However, a stronger research infrastructure could strengthen and accelerate this critical part of the clinical research enterprise. Through discussions with deans of academic health centers, recommendations from the Institute of Medicine, and meetings with the research community, the NIH recognized that a broad re-engineering effort is needed to create greater opportunity to catalyze the development of a new discipline of clinical and translational science. An outcome was the launch of the Clinical and Translational Science Awards (CTSAs) Consortium in October 2006.

Accelerating discovery into technological devices is certainly a goal for the US Department of Defense (DOD) hierarchy of research and development funds (evolving from basic (6.1), applied (6.2), advanced technology development (6.3), advanced component development and prototypes (6.4), to system development and demonstration (6.5), and the National Aeronautic and Space Administration (NASA) research and development funds evolving from technology readiness levels 1–6. One might consider the NIH equivalent as R01 programs to explore new concepts (basic), the R21 programs to demonstrate feasibility (applied research), the R33 programs to further develop the idea toward a technological/methodological goal, and the CTSAs providing translation into the clinic (which might be considered the equivalent of initial field testing by the DOD or NASA).

Many agencies, NIH included, also utilize small business innovative research/small business technology transfer (SBIR/STTR) and public-private partnerships as a bridge into commercialization. In contrast to many DOD/NASA technologies, because there are large public markets for medical and health technologies, commercialization does not have to rely as predominantly on additional federal funding.

The April 2008 report on the NNI by the President's Council of Advisors on Science and Technology emphasizes the central role the NNI must play in overcoming the barriers to nanotechnology development and commercialization.³³ The 2009 US NNI reauthorization draft bill (HR554, 111th Congress) also places greater emphasis on applications. As a key supporter of nano-bio basic research, the National Science Foundation (NSF) sponsored a workshop on “Re-Engineering Basic and Clinical Research to Catalyze Translational Nanoscience” on 16–19 March 2008, hosted by the University of Southern California, with a goal to provide insights toward a federal government nanomedicine investment strategy. The workshop participants, listed in Table 2, were carefully chosen to reflect both individuals working in nanoscience and nanoengineering and those working in clinical settings. The NIH Institute of Biomedical Imaging and Bioengineering (NIBIB) sponsored a conference (20–21 March 2008) to present the preliminary findings.

Table 2. Participants in the USC workshop “Re-Engineering Basic and Clinical Research to Catalyze Translational Nanoscience”

NHGRI, National Human Genome Research Institute; NIEHS, National Institute of Environmental Health Sciences; NIH, National Institutes of Health.

Based on information derived from the workshop and other resources, the succeeding sections of this report will examine opportunities to accelerate the development and optimization of nanostructures for impact on medicine and health. The next section briefly explores economic and societal drivers for nanomedicine initiatives. The third section will examine the science, engineering, and medical research needs. The fourth section succinctly examines the US federal investment directly germane to medicine and health, with brief mention of the EU effort. The final section presents recommendations to accelerate the translation from laboratory discovery into clinical practice.

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Health care needs with promising nano-enabled technology impact 

An investment strategy to accelerate nanoscience into nano-enabled technology for medicine and health should reflect both health need (technology pull) as well as science push. Within this context, science and engineering of nanoscale structures is expected to make major contributions across the entire medicine and health spectrum ranging from mortality rate, morbidity an illness imposes on a patient, disease prevalence, and general societal burden.^29,34, ³⁵, ³⁶ The following examples illustrate potential economic and therapeutic impacts, even if nano-enabled technologies only contribute partial solutions:

The 2006 “Nanomedicine: Nanotechnology for Health” publication of the European Technology Platform–Strategic Research Agenda for Nanomedicine presents additional examples of expected nanomedicine impact.⁷

The workshop participants were polled for their opinion of pressing clinical needs amenable to nano-enabled technology and identified the following as illustrating the wealth of opportunities:

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Nanoscale science and engineering research needed to enable more effective technology 

The considerable investment in nanoscience across the world has been leading to many new discoveries. In the second 5 years of the US NNI there is growing effort to identify potential applications for those discoveries and to accelerate their transition into innovative technology solutions to societal problems. Medicine and health provide fertile ground for this goal. For convenience this section is organized about the headings of “In Vivo and in Vitro Diagnostics”; “Drugs, Delivery, and Therapy”; “Implants and Tissue Regeneration”; “Biological Systems Engineering”; and “Innovations in Medical Instrumentation and Devices”. The amount of published work is growing rapidly; this article's intent is not to be exhaustive but instead to be illustrative of these topics.

In vivo and in vitro diagnostics 

Several noninvasive medical imaging approaches—such as computed tomography (CT), magnetic resonance (MR), positron emission tomography (PET), single-photon-emission CT (SPECT), ultrasound (US), and optical imaging (OI)—are currently being used. The emergence of nanosized contrast agents for these tools has been the subject of several recent reviews⁴⁵, ⁴⁶, ⁴⁷, ⁶⁷, ⁶⁸ and is anticipated to lead to advancements in imaging for understanding biological processes at the molecular level. Examples of these nanoparticles are biocompatible polymer-based nanogels/nanospheres/nanoemulsions, carbon nanotubes, dendrimers, gold nanoparticles, liposomes, microbubbles, semiconductor quantum dots, silica nanoparticles with enclosed fluorescers, and superparamagnetic iron oxide particles. Generic goals for these contrast agents include:

Nanostructured imaging contrast agents are overcoming many limitations of conventional contrast agents such as poor photostability, low quantum yield, and insufficient in vitro and in vivo stability. They are small enough to be taken up by single cells—via processes such as phagocytosis, pinocytosis, or vector-mediated transport—as labels for in vivo imaging.⁴², ⁴³ Because the nanostructures are sufficiently small, one can envision linking them to provide multiple functions, opening possibilities for multimodal imaging, high payload of imaging reporter, activatable “on-off” systems, and chemical information. For instance, human oral cancer cells have been found to assemble and align gold nanorods conjugated to antibodies specific to epidermal growth factor receptor (EGFR).⁶⁹ Molecules near the nanorods on the cancer cells gave a Raman spectrum that was enhanced, sharp, and polarized; those spectral features could be used for diagnostic signatures.

Research issues and opportunities include:

As microelectromechanical systems (MEMS) become more sophisticated and miniaturization continues into the nanoscale (MEMS evolving into nanoelectromechanical systems, NEMS), it will become possible to incorporate ever more sophisticated analytical capability onto and into the human body.⁷³, ⁷⁴ There are already a growing number of miniaturized devices for transdermal sensing. Examples include the SCRAM system, which is a high-tech bracelet that samples a person's sweat to monitor alcohol ingestion⁷⁵; Echo's Symphony tCGM System (Franklin, Massachusetts), which is a noninvasive (needle-free), wireless, transdermal continuous glucose monitoring system⁷⁶; and Flexible Medical Systems (Rockville, Maryland), which is testing a MEMS chip with readable via radiofrequency (RF) identification technology that could be applied to the skin via a bandage to sense body fluid constituents.⁷⁷ As miniaturization continues, allowing greater sophistication per unit volume, the variety of measured analytes (and other properties such as temperature and tissue turgidity) will certainly increase. It is also within the realm of possibility that “spectrometers-on-a-chip” will be developed for insertion beneath the skin.

Research issues and opportunities include:

Current approaches to medical diagnostics are usually high-cost, benchtop laboratory analyzers, or disposable kits that only test for a single analyte. The challenges are considerable when determining whether sophisticated chemical/physical laboratory instrumentation can be reduced in size, while retaining adequate capabilities. For instance, there are 10⁴–10⁵ different proteins in blood with concentration ranges from 10^–3 to 10^–17 M. Miniaturized chip-based array detection methods, known as microarrays, have been prevalent in almost all areas of health-related research for some time; continued miniaturization into nanoarrays will generate many orders of magnitude increase in multiplexed detection.⁷⁸, ⁷⁹ Furthermore, as noted in the section on contrast agents, nanoparticles are already incorporated into some diagnostics to provide greater selectivity, sensitivity, and practicality as compared with conventional systems.

Beyond the arrays, an alluring potential for microdevices and nanodevices is to harness the concept of laboratory-on-a-chip for medical diagnostics⁸⁰, ⁸¹, ⁸², ⁸³, ⁸⁴, ⁸⁵, ⁸⁶, ⁸⁷, ⁸⁸, ⁸⁹, ⁹⁰, ⁹¹; analytical microchips are considered to be a fast-growing technology.⁹² The lab-on-a-chip concept (incorporating microfluidics) has several features that have attracted users in biology, chemistry, engineering, and medicine. It requires only small volumes of samples and reagents, produces little waste, offers short reaction and analysis times, is relatively cheap, and has reduced dimensions compared with other analytical devices. Potential applications include point-of-care measurements of saliva for periodontitis,⁴¹ heart disease,⁹³ hemacrit determination,⁹⁴ insulin detection.⁹⁵ and improving health care accessibility.⁹⁶ In addition to improving established diagnostics, new approaches—such as mechanical analysis to distinguish cancerous cells from normal ones even when they show similar shapes⁹⁷—will be discovered and implemented. The lab-on-a-chip concept is particularly attractive as an approach to providing inexpensive, effective medical care especially in underserved populations.⁴⁰, ⁹⁸, ⁹⁹

Research issues and opportunities include:

Drugs, delivery, and therapy 

There is a need to analyze potential drug candidates in a more rapid and accurate manner, a need that provides an opportunity to develop new tools for that purpose. Ideally, to provide specific information, quantification of single-cell pharmacokinetics/dynamics is desired but requires the detection of minute quantities of proteins and other molecules.¹⁰¹ One must identify and evaluate types of drug targets (including proteins, polysaccharides, lipids, and nucleic acids) that can interact with small-molecule therapeutic agents. Polysaccharides, lipids, and nucleic acids have been investigated less frequently than proteins because of a lack of understanding of the involvement of these molecules in disease and a lack of small-molecule therapeutic agents.

Traditional high-throughput systems perform by using multiple-well plates. Microfluidic technologies, and their nano-enabled enhancements, have great potential in high-throughput studies involving target selection, lead compound generation, identification, and dosage design.

In general, in vivo imaging has been focused at the diagnostics level and has not been an inherent component of drug discovery. In the past decade a paradigm shift has occurred; imaging is now adding a new dimension to our understanding of basic biological and pharmacological mechanisms.¹⁰² Many aspects of drug development can be facilitated using molecular imaging as an integrative tool to discover new “druggable” targets, to identify new drug candidates, and to validate their potency, sensitivity, specificity, pharmacokinetics, pharmacodynamics, and toxicity, metabolism, and adverse drug-drug interactions in living systems. Clinical, epidemiological, and bioinformatics data suggest that population-wide genetic polymorphism may dictate the responsiveness to molecular therapy. Novel drugs are envisioned to be specifically tailored to selected patients.

Although the greatest use of nanotechnology thus far has largely been in passive carriers for drug delivery (see next section), nanoparticles themselves hold potential as therapeutic agents.¹⁰³, ¹⁰⁴ Thus far, about 10 years after the regulatory approval of liposomally encapsulated doxorubicin to treat various forms of cancer, “higher functionality” nanoparticles such as gene transfer vectors are in the Investigational New Drug stage of clinical research.¹⁰⁵ On the horizon is the use of nanoparticles themselves as drugs—as truly active “nanomedicines”.

Research issues and opportunities include:

Nanotechnology advances are the cornerstone of a paradigm shift in targeting and safely delivering agents—thereby improving controlled drug release, improving patient safety and compliance, and reducing side effects.¹⁰⁶, ¹⁰⁷, ¹⁰⁸, ¹⁰⁹, ¹¹⁰, ¹¹¹ Through the use of colloid chemistry (e.g., liposome and micelle encapsulation) nanoparticles have been used for drug delivery for decades. Examples of nanoscale delivery vehicles now under investigation include polymeric particles,¹¹², ¹¹³ dendrimers,⁴⁸, ¹¹⁴ nanoshells,¹¹⁵, ¹¹⁶ liposomes,⁵¹, ¹¹⁷ and magnetic nanoparticles.²⁶, ¹¹⁸ There are a number of new delivery platforms in clinical trial including a dendrimer-derived microbiocide (i.e., VivaGel; Starpharma, Melbourne, Australia) for HIV or genital herpes in its final stage of US Food and Drug Administration (FDA) approval,⁴⁸ and a dendrimer-based targeted delivery of chemotherapeutic drugs and an apoptotic sensor in cancer cells.¹¹⁹ Nanoparticles also show considerable promise for drug delivery to the retina and for powering prosthetic “artificial retinas”.¹²⁰ Various gene delivery systems based on nanoparticles have been developed, and different polymers have been tested as gene delivery agents.¹²¹ Going beyond simply carrying a drug, the development of “smart” nanoparticles is an exciting and promising area of investigation.³⁹, ⁴⁹, ⁵², ¹²², ¹²³, ¹²⁴

Delivering intravenous agents to their intended targets is no easy task. For intravenous infusion it is estimated that only approximately 1 of every 100,000 molecules of agent reaches its desired destination. The generic requirements of delivery systems are⁴⁹:

Nanoscale building blocks provide opportunity for multifunctional packaging small enough to navigate body vessels and membranes. A multifunctional approach is needed to circumvent the body's natural defenses or biobarriers, which act as obstacles to foreign objects injected in the bloodstream. One must avoid them being removed from circulation by monocytes and macrophages or accumulated in the organs of the reticuloendothelial system, especially the liver and spleen. For instance, for many cancers endothelial gaps in tumor vasculature are measured in hundreds of nanometers instead of in tens of nanometers. In this case nanocarriers in the appropriate size range could more selectively extravasate into a tumor and provide a passive means for selective delivery.¹²⁵ Other factors influencing the magnitude and pattern of tumoral distribution are in vivo stability, particle size, surface charge, and intracellular uptake.¹²⁶

In most cases active selectivity will be desirable. Targeted drug delivery carriers are being functionalized with antibodies or antibody fragments to provide active localization. It is well accepted that the binding affinity, stability, and size of the ligand play a critical role for successful targeting. The conjugation of multiple antibodies to each nanocarrier enhances their avidity, and nanocarriers can be surface-functionalized with multiple distinct antibodies to overcome tumor heterogeneity. Peptides and antibody fragments have been developed to overcome some of the shortcomings of antibodies, and several examples of these ligands are now under clinical development. Functional, single-domain heavy-chain antibodies, referred to as nanobodies, have been raised against cancer targets which either antagonize receptor function or deliver an enzyme for prodrug activation.¹²⁷ Affibodies against a variety of cancer-related targets have been developed and are now commercially available, including: EGFR, HER2 (official symbol HERBB2), and transferrin.²⁷

Cancer stem cells are characterized to be a quiescent and small cell subpopulation with different surface markers than bulk differentiated tumor cells, and to present well-developed drug resistance. Although there is considerable emphasis on specific cell markers in the current cancer targeting paradigm, one must also recognize cases where cell-nonspecific approaches may be necessary for more effective and consistent therapeutic output.¹²⁸

For more sophisticated applications, where greater dosage and/or actively controlled time release is needed, MEMS/NEMS-based devices are envisioned that can incorporate both local sensing and mechanisms to dispense drugs (see below, “Implanted Drug Dispenser/Factory”).

Research issues and opportunities include:

The possibilities for innovative therapies are limitless. As one example, hyperthermia has been explored as a treatment for cancer for a couple of decades, but with limited success. Nanostructure-enabled innovation has rejuvenated hyperthermia with the nanoparticles extracting energy from NIR¹³⁰, ¹³¹ or RF⁵³, ¹³² electromagnetic fields. Lack of knowledge on the fundamental mechanisms involved has slowed the implementation of clinical protocols. For instance, recent efforts²⁶ for elucidating the mechanisms have demonstrated that cell membrane and cytoskeleton are important loci of cell damage by both ionizing radiation and hyperthermia. Technical difficulties in developing magnetic field applicators at the frequencies and field values with concurrent compliance of the safety regulations demanded for clinical use will have to be addressed.

As a second example, photodynamic therapy is also an innovative, evolving approach for treating neovascular diseases of the eye where nanostructures can play an important role¹³³; two-photon IR, nanoplatform phototoxicity has been demonstrated for rat glioma cells.¹³⁴ A third example is magnetic nanoparticles to remove toxins from the blood; however, a magnetic separator suitable for real-time clearing of magnetic nanospheres has to be improved.¹³⁵ As a final example, self-assembling nanofibers have been shown to promote neural healing after spinal cord injury.⁶¹

Research issues and opportunities include the following:

Implants and tissue regeneration 

Tissue engineering, or regenerative medicine, is an interdisciplinary field that merges principles and innovations from the physical and chemical sciences, engineering, and the life sciences. The focus is on the improvement, repair, or replacement of tissue and organ function.¹³⁶, ¹³⁷, ¹³⁸, ¹³⁹ The ultimate goal is to enable the body to heal itself by introducing an engineered scaffold—that is, substitute extracellular matrix (ECM)—that the body recognizes as “self.” Signals are transmitted between the cell and the ECM, allowing communication for cell adhesion, migration, growth, differentiation, programmed cell death, modulation of cytokine and growth factor activity, and activations of intracellular signaling. Any scaffold material must be able to interact with cells in three dimensions and facilitate communication. Scaffold pore size, pore orientation, fiber structure, and fiber diameter are known to regulate proliferation, cellular organization, and subsequent tissue morphogenesis.

Current research in tissue engineering is approaching a major breakthrough in the treatment of injury and disease due to the ability to routinely create ECM-analogous nanofibers.¹³⁶ For example, reports of nanostructure approaches to tissue engineering have markedly increased in the literature in the last 4 years (from 32 in 2004 to 219 in 2008, as identified by a literature search of ISI Web of Science www.isiwebofknowledge.com using the simple key words nanofib* and tissue). An ECM mimic must:

There are several approaches being explored for the manufacture of nanofibers for ECM including electrospinning,¹¹¹, ¹⁴⁰, ¹⁴¹, ¹⁴², ¹⁴³ phase separation,¹⁴⁴ self-assembly,¹⁴⁵, ¹⁴⁶, ¹⁴⁷ and template.¹⁴⁸ Each approach is different and results in a unique set of characteristics as a scaffolding system. Electrospinning is a process that can be used to fabricate scaffolds economically at large scales and can incorporate solid nanomaterials within electrospun fibers in a well-dispersed and spatially controlled manner.¹⁴⁹ Electrospun collagen nanofibers, for example, have been shown to produce skin substitutes with similar cellular organization, proliferation, and maturation to the current, clinically utilized model, and were shown to reduce wound contractions, which may lead to reduced morbidity in patient outcomes.¹⁴⁰ Phase separation has generated fiber diameters in the same range as the ECM and allows for the design of macroporous structures.¹⁴⁴ Self-assembling peptides have emerged as an attractive class of three-dimensional (3D) scaffolding materials, mainly as a result of the nanoscale fibrous and porous topographies that mimic the natural ECM features. Cell behavior can be controlled by cell-materials interactions if biofunctional sites are synthesized into the scaffolds.¹⁴⁷, ¹⁵⁰, ¹⁵¹, ¹⁵², ¹⁵³

Research issues and opportunities include:

Self-assembly and biomineralization are used in biological systems for the fabrication of many composite materials. Bone tissue is a particularly complex biological system, because it contains multiple levels of hierarchical organization. Bone has been hard to replicate, so alternative materials such as titanium alloys or composites with microfillers have been substituted.

The lifetime of orthopedic implants is limited primarily by implant loosening, a result of interfacial breakdown and stress.⁶² Implant materials—titanium, stainless steel, and cobalt alloys—are much stiffer than bone; a cement must buffer their respective mechanical properties. Polymethyl methacrylate (PMMA) is commonly used in orthopedic implant cements; without it, metal directly contacting bone leads to strong inflammatory response and creates highly localized stresses and micromotion of the implants. Disadvantages of PMMA include limited radiopacity, exothermic setting, and poor ossification with juxtaposed bone. The application of nanoparticles in PMMA cements, an approach that can address all of these issues, is still in its infancy. Current approaches to implant materials include creating porous surfaces⁶³, ¹⁵⁴ in attempts to improve fixation, but this does not necessarily solve stiffness mismatch. Additionally, osteoblast activity can be significantly enhanced using controlled nanotopographies¹⁵⁵; for instance, nanotubular titania surfaces have been shown to provide a favorable template for bone cell growth and differentiation.¹⁵⁶, ¹⁵⁷ There is a published broad review on the topic of nanomaterial interactions with proteins and cells.¹⁵⁸

In a somewhat simpler application, new dental restorative materials already in the marketplace are exploiting composites incorporating nanoparticles of silica (for improved mechanical properties and luster) and zirconia (for improved radiopacity) in a polymer matrix.¹⁵⁹

Research issues and opportunities include:

The next generation of drug delivery systems, in addition to having spatial and temporal control, is expected to be “smart” and to permit therapy that is responsive to the patient's specific needs. These advanced systems would protect drugs from environmental or biological degradation in the body, use closed-loop control to assist the patient with homeostasis, and provide autonomous drug administration. MEMS/NEMS methods can provide a sophisticated approach. With controlled delivery, appropriate and effective amounts of drug might be precisely calculated by the controller and released or manufactured at an appropriate time. Present MEMS-based microfluidic drug delivery devices¹⁶⁰, ¹⁶¹ include microneedle-based transdermal devices, osmosis-based devices, micropump-based devices, and microreservoir-based devices. Micropumps for transdermal insulin delivery, injection of glucose for diabetes, and administration of neurotransmitters to neurons have been reported.¹⁶²

The fabrication of nanoscale and microscale 3D programmable volume enclosures (voxels) to encapsulate nanoscale quantities of various materials is expected to greatly expand current capabilities. If cells/tissue are incorporated into the voxel as the drug manufacturing mechanism, the enclosure walls must have pores small enough to prevent immunoresponse, but large enough to permit the suffusion of metabolites.⁵⁷ Nanoscale approaches to power for such devices include stored energy (battery),¹⁶³ wireless transfer,¹⁶⁴, ¹⁶⁵ and local generation.¹⁶⁶, ¹⁶⁷, ¹⁶⁸, ¹⁶⁹

Research issues and opportunities include:

The nervous system has a poor healing capacity. Additionally, an aging population leads to more persons acquiring disabilities such as hearing loss, stroke, and Parkinson's disease. The demand for solutions is growing.¹⁷⁰ The meeting report,¹⁷¹ “Smart Prosthetics: Exploring Assistive Devices for the Body and Mind”, focused on several themes relevant to future prosthetics wherein it is expected that the nanoscale will be important. The potential of nanotechnology applications in neuroscience is becoming accepted and is the subject of several reviews.⁶⁸, ¹⁰, ¹⁷², ¹⁷³, ¹⁷⁴

Dating from 1972, about 100,000 patients worldwide have received cochlear implants. The current state of this technology is bulky and difficult for the surgeon to implant, and it does not allow a broad range of perceived frequencies.¹⁷⁵ The human auditory nerve contains ∼30,000 axons, which cochlear implants stimulate currently with 3–22 electrodes. MEMS, micromechanical devices are being developed to ameliorate these problems. Because the human ear itself already uses nanostructures,¹⁷⁶ continued miniaturization beyond the microscale is certain to provide additional improvements.

In contrast to the auditory nerve, the optic nerve has about a million fibers. Visual prosthesis must also deal with two-dimensional spatial data and the highly complex signal processing that occurs in the retina before transmission to the brain. A fully implantable retinal prosthesis would ideally capture all of the functions performed by the mammalian retina in one autonomous device. It is postulated that the needed computations can be performed at an energy-efficient and physical scale comparable to biology by incorporating principles derived from neural circuits into nanoelectronic circuits.¹⁷⁷, ¹⁷⁸, ¹⁷⁹

For the control of artificial limbs the next generation of prosthetics will use regions of undamaged nervous tissue to provide command/sensory signals.¹⁸⁰ However, problems range from improper neuronal adhesion to inadequate signal stability. Implanted electrodes do not remain statically placed as a result of different flexibilities in implants materials versus tissue, or the growth of fibrous tissue around the implant. So new materials solutions are needed.¹⁸¹, ¹⁸² Single-wall carbon nanotubes have received promising attention because of their unique physical and chemical features.¹⁸³, ¹⁸⁴ Nanostructured porous silica is found to be more biocompatible than a smooth surface, producing less glial activation and allowing more neurons to remain close to the device.¹⁸⁵ Light-activated semiconducting nanoparticles have been shown to wirelessly stimulate neurons in the rat brain.¹⁸⁶

Research issues and opportunities include:

Biological systems engineering 

A goal of systems biology is to fundamentally transform the practice of medicine.¹⁸⁸, ¹⁸⁹, ¹⁹⁰, ¹⁹¹, ¹⁹² Systems biology is the study of an organism, viewed as an integrated and interacting network of genes, proteins, and biochemical reactions. The study of systems biology has been aided by cyber-enabled information storage/processing, advances in nanotechnology, advances in modeling and simulation, and the infusion of science and scientists from other disciplines (e.g. computer scientists, mathematicians, physicists, and engineers).

Facilitated in part by the rapid progress in nanoscale science and engineering, and the growing sophistication of computers and cyberinfrastructure, systems biology is a field coming of age. The potential impact on medicine and health is enormous. Nanoscience can accelerate this field in a number of ways. First, it provides the ability to examine the properties of individual nanostructures rather than the average properties measured by techniques that require ensembles for adequate signal to noise. Work at the nanoscale allows the study of single-molecule properties previously very hard to measure, such as protein folding/unfolding,¹⁹³, ¹⁹⁴ molecular motors,¹⁹³ and DNA/RNA sequencing.¹⁹⁵, ¹⁹⁶, ¹⁹⁷, ¹⁹⁸ Second, as microfluidics and sensing technologies become further miniaturized, there will be growing capability to provide arrays that can potentially detect and identify many constituents in a biological sample in time frames of minutes rather than hours or days. Two microfluidic foundries are now available for the academic community.¹⁹⁹, ²⁰⁰ Third, somewhat incidental but still important, the advent of nanoelectronics is continuing the increase in computational power that will be essential to model a system as complex as a cell.

The complexity of biological systems will continue to require the sampling of multiple cells. However, as with single-molecule studies, the capability to probe individual cell behavior is essential to rapid progress. Microfluidics offers analytical devices with length scales that are comparable to (a) the intrinsic dimensions of prokaryotic and eukaryotic cells and organelles, and (b) the length scale of diffusion of oxygen and carbon dioxide in tissues.¹⁰⁷, ²⁰¹ The growing availability and sophistication of microfluidic chips will accelerate single-cell studies.²⁰², ²⁰³, ²⁰⁴ As examples of new capabilities, nano-enabled probes have been shown to physically penetrate the cell membrane with minimal disruption,²⁰⁵ improve the resolution of optical probes with 3D resolution at the nanoscale,²⁰⁶ acquire spectroscopic⁷² and fluorescent signatures,⁷¹, ²⁰⁷ actuate membrane receptor–mediated signal transduction,²⁰⁸ probe cell mechanical behaviors,⁹⁷, ²⁰⁹, ²¹⁰ characterize calcium release,²¹¹ grow and probe neurons,²¹², ²¹³ and probe single-cell motility and metabolic calorimetry.²¹⁴

In addition to the controlled study of single cells previously mentioned, microfluidics is being used to study processes such as blood clotting.²¹⁵ Scaling (thousands of identical microfluidic structures) is of increasing importance in biology as the field moves toward quantitative data, because it allows multiple parallel experiments under identical conditions.²⁰²

Research issues and opportunities include:

Innovations in medical instrumentation and devices 

Work at the nanoscale requires the continued miniaturization of measurement devices, both for spatial localization and for augmented sensitivity to the small signals associated with a nanostructure. Adaptations of these new devices for medical applications are forthcoming. As examples, the force microscope is capable of measuring differences between cancer and normal cells⁹⁷ and bone viability.²¹⁶, ²¹⁷ Carbon nanotubes function better than glass pipettes for cellular delivery.²¹⁸ The incorporation of microdevices/nanodevices into catheters and other instruments is growing,²¹⁹ including incorporation of silver nanoparticles to impart antimicrobial activity.²²⁰ Nanostructures are enabling electronic circuitry on flexible substrates, including high-performance circuit elements (e.g., silicon or carbon nanotube devices).²²¹, ²²² One can envision the incorporation of signal processing and sensing capabilities into mechanically flexible implants and even surgical gloves that might detect important parameters.⁷⁴ Nanopore-based devices show considerable promise for low-cost, rapid DNA sequencing.²²³

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Present federal programs 

Several US federal agencies fund pertinent health research. The foremost is the NIH. In addition, NASA is interested in medical practice in space; the DOD has an interest in warfighter health issues and battlefield medicine; the NSF provides the foundations of medicine in systems biology; the Environmental Protection Administration is concerned with impact on living systems in the environment; and the US Department of Agriculture is concerned with the impact on agriculture. The total federal investment in the NNI is given in Table 1. Table 3 provides an estimate of the investment more directly relevant to medicine and health.

Table 3. Approximate federal investment in nanoscale science/engineering relevant to medicine and health

DOD, US Department of Defense; NCI, National Cancer Institute; NHLBI, National Heart Lung and Blood Institute; NIH, National Institutes of Health; NSF, National Science Foundation.

National Institutes of Health 

There is an individual investigator-initiated research investment in nano-enabled medicine of about $140 million annually distributed throughout the NIH; an additional $50 million is invested in centers. The NIH investment in nano-enabled medicine is monitored by a Trans-NIH Task Force.

The NIH has a Nanomedicine Implementation Group with membership from the various institutes.⁶ Under its Roadmap for Medical Research—New Pathways to Discovery, NIH has established a national network of eight Nanomedicine Development Centers (NDCs, Table 4), which serve as the intellectual and technological centerpiece of the nanomedicine initiative. These collaborative centers are staffed by multidisciplinary research teams comprising biologists, physicians, mathematicians, engineers, and computer scientists. In the initial phase of the program (FY2005–FY2010), research has been primarily directed toward gathering extensive information about the chemical and physical properties of nanoscale biological structures. A second phase for the program has been approved during which the acquired fundamental knowledge and developed tools will be applied to understanding and treating disease. The NDCs reach out to clinical investigators with ongoing opportunities for potential medical applications that build on the science emerging from the NDCs.

Table 4. Federal multidisciplinary center programs relevant to medicine and health

Program	PI name	Institution name	Center title
NIH
CCNE	Rudolph Juliano	University of North Carolina	Carolina Ctr. of Cancer Nanotechnology Excellence
CCNE	Sanjiv Gambhir	Stanford University	Ctr. for Cancer Nanotechnology Excellence Focused on Therapy Response
CCNE	Robert Langer	Mass. Inst. of Technol.	Ctr. of Cancer Nanotechnology Excellence
CCNE	Sadik Esener	University of California San Diego	Ctr. of Nanotechnology for Treatment, Understanding, & Monitoring of Cancer
CCNE	Shuming Nie	Georgia Inst. of Technol.	Nanotechnology Ctr. for Personalized and Predictive Oncology
CCNE	Chad Mirkin	Northwestern University	Nanomaterials for Cancer Diagnostics and Therapeutics
CCNE	James Heath	California Inst. of Technol.	Nanosystems Biology Cancer Ctr. (NSBCC)
CCNE	Samuel Wickline	Washington University	The Siteman Ctr. of Cancer Nanotechnology Excellence
CNPP	Douglas Hanahan	University of California San Francisco	Detecting Cancer Early with Targeted Nano-probes for Vascular Signatures
CNPP	James Baker	University of Michigan	DNA-Linked Dendrimer NP Systems for Cancer Diagnosis & Treatment
CNPP	Kattesh Katti	University of Missouri	Hybrid Nanoparticles in Imaging and Therapy of Prostate Cancer
CNPP	Scott Manalis	Mass. Inst. of Technol.	Integrated System for Cancer Biomarker Detection
CNPP	Panos Fatouros	Virginia Commonwealth University	Metallofullerene Nanoplatform for Imaging & Treating Infiltrative Tumor
CNPP	Paras Prasad	SUNY, Buffalo	Multifunctional Nanoparticles in Diagnosis & Therapy of Pancreatic Cancer
CNPP	Miqin Zhang	University of Washington	Nanotechnology Platform for Pediatric Brain Cancer Imaging and Therapy
CNPP	Jan Schnitzer	Sidney Kimmel Cancer Ctr.	Nanotechnology Platform for Targeting Solid Tumors
CNPP	Mansoor Amiji	Northeastern University	Nanotherapeutic Strategy for Multidrug Resistant Tumors
CNPP	Chun Li	University of Texas Anderson Cancer Ctr.	Near-infrared Fluorescence NP for Targeted Optical Imaging
CNPP	Ravindra Pandey	Roswell Cancer Inst.	Cancer Nanotechnology Platforms for Photodynamic Therapy & Imaging
CNPP	Tayyaba Hasan	Mass. General Hospital	Photodestruction of Ovarian Cancer: EfbB3 Targeted Aptamer-NP
PEN	Karen Wooley	Washington University	Integrated Nanosystems for Diagnosis and Therapy
PEN	Gang Bao	Georgia Inst. of Technol.	Nanotechnology: Detection & Analysis of Plaque Formation
PEN	Jeffrey Smith	Burnham Inst.	Nanotherapy for Vulnerable Plaque
PEN	Ralph Weissleder	Mass. General Hospital	Translational Program of Excellence in Nanotechnology
NDC	Wah Chiu	Baylor College of Medicine	Ctr. for Protein Folding Machinery
NDC	Chih-Ming Ho	University of California Los Angeles	Ctr. of Cell Control
NDC	Wendell Lim	University of California San Francisco	Engineering Cellular Control: Synthetic Signaling and Motility Systems
NDC	Gang Bao	Georgia Inst. of Technol.	Nanomedicine Ctr. for Nucleoprotein Machines
NDC	Michael Sheetz	Columbia University	Nanotechnology Ctr. for Mechanics in Regenerative Medicine
NDC	Eric Jakobsson	University of Illinois, Urbana Champaign	National Ctr. for Design of Biomimetic Nanoconductors
NDC	Ehud Isacoff	University of California Berkeley	Optical Control of Biological Function
NDC	Peixuan Guo	University of Cincinnati	Phi29 DNA-Packaging Motor for Nanomedicine
NSF
NSEC	Dawn Bonnell	University of Pennsylvania	Ctr. for Molecular Function at the Nanoscale
NSEC	Vicki Colvin	Rice University	Ctr. for Biological and Environmental Nanotechnology
NSEC	Richard Siegel	Rennselaer Polytechnic Institute	Ctr. for Directed Assembly of Nanostructures
STC	Harold Craighead	Cornell University	The Nanobiotechnology Ctr.
MRSEC	Mehmet Sarikaya	University of Washington	Genetically Engineered Materials Science and Engineering Ctr.
DOD
MURI	Jimmie Xu	Brown University	Direct Nanoscale Conversion of Biomolecular Signals
MURI	G. Oberdorster	University of Rochester	Physicochemical Characterization & Toxicology for Air/Space
MURI	Naomi Halas	Rice University	Nanoscale Optical Imaging with Integrated Spectroscopies
MURI	H. Abarbanel	University of California San Diego	Chem. Discrimination & Localization Using Bio-Based Olfactory Processing
MURI	Chad Mirkin	Northwestern University	Bioinspired Supramolecular Enzymatic Systems

CCNE, Centers for Cancer Nanotechnology Excellence; CNPP, Cancer Nanotechnology Platform Partnerships; DOD, US Department of Defense; MRSEC, Materials Research Science and Engineering Center; MURI, Multidisciplinary University Research Initiatives; NDC, Nanomedicine Development Centers; NIH, National Institutes of Health; NSEC, Nanoscience and Engineering Center; NSF, National Science Foundation; PEN, Program of Excellence in Nanotechnology; STC, Science and Technology Center.

Unlike any other NIH Institute or Center, the NIBIB's mission is focused on emerging technology development. The Institute has a mandate to enable and promote fundamental discoveries, and to support the design, development, translation, and assessment of technological capabilities in biomedical imaging and bioengineering. The NIBIB has programs in microsystems/nanosystems²²⁴ and nanotechnology.²²⁵ In addition, NIBIB sponsors centers that are pertinent to nanotechnology. The pertinent Biotechnology Resource Centers include the Biomicroelectromechanical Systems (BioMEMS; Massachusetts General Hospital), Biophysical Imaging Opto-Electronics (Cornell University), National ESCA and Surface Analysis Center (University of Washington), Tissue Engineering (Tufts University), and Computer Integrated System for Microscopy and Manipulation (University of North Carolina). The pertinent Point-of-Care Technologies Research Network includes centers on Emerging Neurotechnologies (University of Cincinnati), Rapid Multipathogen Detection (University of California at Davis), Diagnostics for Global Health (PATH, Seattle), and Sexually Transmitted Diseases (Johns Hopkins University). These centers coordinate development, clinical evaluation, and reduction to practice of new point-of-care devices. The NIBIB sponsors an Interfaces Initiative for Interdisciplinary Graduate Research Training (T32) program with $3–4 million annually devoted to nanotechnology, and works with the NSF and Howard Hughes Medical Institute to address interdisciplinary training.

Initiated in 2004, the NCI Alliance for Nanotechnology in Cancer encompasses four major program components: Centers for Cancer Nanotechnology Excellence (Table 4), the Nanotechnology Characterization Laboratory (in collaboration with the FDA and the National Institute of Standards and Technology, NIST), the Cancer Nanotechnology Platform Partnerships (Table 4), and a multidisciplinary research training and team development program. The funding level for the Alliance is projected at $144 million over 5 years.²²⁶ The partnerships are designed to develop technologies for new products in six key partnership areas: molecular imaging and early detection, in vivo imaging, reporters of efficacy (e.g., real-time assessments of treatment), multifunctional therapeutics, prevention and control, and research enablers (opening new pathways for research). The NCI and the NSF are collaborating in training programs for US science and engineering doctoral students through the Integrative Graduate Education and Research Traineeship Program—Rutgers (nanopharmaceutical), Northeastern (brain machine), University of New Mexico (micro-nano-bio interfaces), and the University of Washington (nanotechnology workforce).

Starting in 2004, the National Heart Lung and Blood Institute (NHLBI) of the NIH has made four 5-year awards to initiate a unique, diverse, and nationwide Program of Excellence in Nanotechnology²²⁷ (Table 4). This program brings together bioengineers, materials scientists, biologists, and physicians who work in interdisciplinary teams to spur the development of novel technologies to diagnose and treat heart, lung, and blood diseases.

The National Institute of Environmental Health Sciences (NIEHS) administers the National Toxicology Program (NTP), which has research activities focusing on four classes of nanostructured materials²²⁸:

The National Institute of General Medical Sciences has research on, and development of, new and improved instruments, methods, and technologies for nanoscience, and for the analysis of single-protein and nucleic acid molecules and their complexes both in vivo and in vitro.

The National Center for Research Resources (NCRR) consortium is to transform how clinical and translational research is conducted, ultimately permitting researchers to provide new treatments more efficiently and quickly to patients.²²⁹ CTSAs support clinical and translational research by providing access to clinical and translational research resources developed by the CTSAs, government-sponsored research communities, government agencies, or private sector. The NCRR consortium could become a powerful tool in the translation on nanoscience/nanoengineering discoveries.

The NIH is exploring a NanoHealth Enterprise that would comprise an integrated, interdisciplinary program that draws upon the expertise and interests of the NIH institutes and centers, in partnership with private industry, to address critical research needs for the safe development of nanoscale materials and devices. This initiative outlines an integrated, interdisciplinary program that draws upon the expertise and interests of the NIH institutes and centers, and addresses critical research needs for the safe development of nanoscale materials and devices. The initiative proposes five components: Materials Science Research, Basic Biology Research, Pathobiology Research, Informatics, and Training.

The NIH is one of several agencies having a “nano”-specific topic in its SBIR/STTR announcement. Few small businesses possess the highly specialized resources needed for nanoengineering, so applications are encouraged from teams of investigators from commercial, academic, and other sectors of the research community. The NIH Pipeline to Partnerships is a virtual space for NIH SBIR/STTR awardees to showcase technology and product development for an audience of potential strategic partners and investors.

National Science Foundation 

Although much of the extensive (∼$350 million) NSF investment in “nano” has the potential to impact medicine and health, the most directly involved programs are located in the Biological Sciences Directorate and in the Chemical, Biological, Environmental, and Transport Systems (CBET) Division of the Engineering Directorate. Biological Sciences has the role to promote and advance scientific progress in biology. The CBET Division supports research in bioengineering (among other topics). These two programs provide much of the underlying science and engineering base for medicine and health applications, which is critical to rapid advancement.

The CBET Division has programs in “Integration of Life Sciences with Engineering”, as well as “Nanoscale Science and Engineering”. The current high-emphasis research and education areas include post-genomic engineering, tissue engineering, biophotonics, and nanobiosystems. The CBET Division has approximately $25 million invested in nanobio projects.

The Molecular and Cellular Biosciences (MCB) Division effort under the Biological Sciences Directorate at NSF emphasizes systems biology; it has approximately $25 million invested in nanobio projects. The research includes databases and informatics, instrument development, biomolecular systems, cellular systems, and genes and genome systems. The latter three encourage multidisciplinary approaches, including research carried out at the interfaces of biology, physics, chemistry, mathematics and computer science, and engineering.

The National Nanotechnology Infrastructure Network is an integrated partnership of 13 user facilities, supported by NSF, providing unparalleled opportunities for nanoscience and nanotechnology research.²³⁰ The network provides extensive support in nanoscale fabrication, synthesis, characterization, modeling, design, computation, and hands-on training in an open, hands-on environment, available to all qualified users.

US Food and Drug Administration 

The regulation of nano-enabled products may involve more than one traditional FDA category, for example a "drug" delivery "device". In these cases the assignment of regulatory lead is the responsibility of the Office of Combination Products. To facilitate the regulation of nanotechnology products, the Agency has formed a NanoTechnology Interest Group composed of representatives from all its Centers. The NanoTechnology Interest Group meets quarterly to ensure there is effective communication between the Centers. An FDA task force report on nanotechnology is available.²¹ The FDA is a co-sponsor of the Nanotechnology Characterization Laboratory, along with the NCI and NIST, and the nanostructure evaluation in the NTP with the NIEHS. There is an FDA intramural research program, but it does not presently have any “nano”-focused projects.

The FDA and Alliance for NanoHealth co-convened a workshop on nanomedical regulatory science in Houston in March 2008 to identify the top scientific hurdles in bringing nanoengineered products to patients, specifically in the preclinical, clinical, and manufacturing phases of product development.²³¹ Six priority areas were identified:

Department of Defense 

The DOD does not have any appreciable program in nanomedicine per se. The Defense Advanced Research Projects Agency (DARPA) Defense Science Office has thrusts on tactical and restorative biomedical technologies that may exploit nanotechnologies. There are some limited efforts from the various service research offices examining how to exploit nanotechnology with medical implications; five such Multidisciplinary University Research Initiatives are listed in Table 4, and the Office of Naval Research has a recent initiative on Autonomous Devices for Advanced Personnel Treatment. The US Army funds the Institute of Soldier Nanotechnologies (MIT University Affiliated Research Center) that addresses some medical applications. The Army Telemedicine and Advanced Technology Research Center (TATRC) oversees a diverse portfolio, largely congressional adds to the DOD budget, ranging from new nanomaterial-based contrast agents for cardiac and brain imaging to new drug delivery systems for the treatment of cancer. In each case TATRC assists the program in identifying military needs, defining metrics, and comparing the new technology to existing methods.

Department of Energy 

The Department of Energy (DOE) Nano Centers are user facilities for interdisciplinary research at the nanoscale. Each of the five Centers is co-located with other large scientific facilities to take advantage of complementary capabilities, such as the Spallation Neutron Source at Oak Ridge, Tennessee, the synchrotron light sources at Argonne (Argonne, Illinois), Brookhaven (Upton, New York), and Lawrence Berkeley (Berkeley, California) National Laboratories, as well as semiconductor, microelectronics, and combustion research facilities at Sandia (Albuquerque New Mexico) and Los Alamos (Los Alamos, New Mexico) National Laboratories. The Centers contain clean rooms, laboratories for nanofabrication, one-of-a-kind signature instruments, and other instruments (such as nanopatterning tools and research-grade probe microscopes) not generally available except at major scientific user facilities.

European Union 

The Framework 7 included an ERA-NET (European Research Area–network) on nanomedicine project (NMP-2008-4.0-13) with the expectation of improved coordination and reduced overlapping and fragmentation; achieving critical mass and ensuring better use of limited resources; sharing good practices in implementing research programs; and promoting transnational collaborations and generating new knowledge. In Fiscal Year 2008 approximately €8 million were allocated for the first-call ERA-NET plus (of which nanomedicine is a part).

As another example, the project “Healthy Aims: Developing New Medical Implants and Diagnostic Equipment” is a €23 million, 4-year project to develop intelligent medical implants and diagnostic systems. Though not confined to nano-enabled technology, products under development will almost certainly benefit from nanoscale capabilities. The funded projects include retinal implant, functional electrical stimulation of systems for restoration of upper limb movement as well as bladder and bowel control, cochlear implant, glaucoma sensor, intracranial pressure sensor, and a sphincter sensor for monitoring bladder pressure.²³²

The European Technology Platform: Nanomedicine–Nanotechnology for Health identifies the following as strategic research priorities⁷:

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Recommendations 

Research opportunities and challenges have been identified in each of the subcategories in the third section, “Nanoscale Science and Engineering Research Needed to Enable More Effective Technology”; they are many. It should be noted that more generic questions were addressed in this workshop and that the research funding levels and prioritization among these opportunities and challenges was beyond its scope. From the discussions at the “Re-Engineering Basic and Clinical Research to Catalyze Translational Nanoscience” workshop at the University of Southern California, augmented by literature search and subsequent evaluation by other experts, the following overarching recommendations are made:

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References 

1. National Science and Technology Council, Committee on Technology (CT) . The National Nanotechnology Initiative: research and development leading to a revolution in technology and industry, Supplement to the President's FY2009 Budget. Available from: http://www.nano.gov/NNI_09Budget.pdf
   • View In Article
2. The National Nanotechnology Initiative: FY2009 Budget and Highlights. Available from: http://www.nano.gov/NNI_FY09_budget_summary.pdf
   • View In Article
3. In: Nanoscience and Nanotechnology: Shaping Biomedical Research, Symposium Report, Bethesda, Maryland, June 25-26. 2000;
   • View In Article
4. National Science and Technology Council, Subcommitte on Nanoscale Science, Engineering, and Technology . In: Nanobiotechnology: Report of the National Nanotechnology Initiative Workshop, 9–11 October. 2003;Available from: http://www.nano.gov/nni_nanobiotechnology_rpt.pdf
   • View In Article
5. Moghimi SM, Hunter AC, Murray JC. Nanomedicine: current status and future prospects. FASEB J. 2005;19:311–330
   • View In Article
   • CrossRef
6. Division of Program Coordination, Planning and Strategic Initiatives, National Institute of Health . NIH roadmap for medical research. Available from: http://nihroadmap.nih.gov/nanomedicine
   • View In Article
7. European Technology Platform—Nanomedicine: Nanotechnology for Health. Available from: http://cordis.europa.eu/nanotechnology/nanomedicine.htm
   • View In Article
8. In: Giersig M, Khomutov GB editor. Nanomaterials for application in medicine and biology. New York: Springer; 2008;
   • View In Article
9. European Society for Nanomedicine (ESNAM) . [homepage on the Internet]. Available from: http://www.esnam.org
   • View In Article
10. European Foundation for Clinical Nanomedicine . [homepage on the Internet]. Available from: http://www.clinam.org
    • View In Article
11. Jain KK. The handbook of nanomedicine. New York: Humana Press; 2008;
    • View In Article
12. Nanomednet. [homepage on the Internet]. Available from: http://www.nano.org.uk/nanomednet/
    • View In Article
13. Royal Society of Chemistry . Lab on a chip. Available from: http://www.rsc.org/Publishing/Journals/lc/index.asp
    • View In Article
14. NanoDDS’09 [homepage on the Internet]. Nanomedicine and drug delivery symposium—Indianapolis. Available from: http://www.nanodds.org
    • View In Article
15. American Academy of Nanomedicine . [homepage on the Internet]. Available from: http://www.aananomed.org
    • View In Article
16. Society for Biomaterials . [homepage on the Internet]. Available from: http://www.biomaterials.org
    • View In Article
17. AVS–Science and Technology of Materials, Interfaces, and Processing. [homepage on the Internet]. Available from: http://www.avs.org
    • View In Article
18. European Science Foundation . ESF research conferences. Fostering collaboration across disciplines and generations. Available from: http://www.esf.org/activities/esf-conferences/
    • View In Article
19. Nanotechnology for the healthcare challenges of the 21st century. In: Sixth International Conference on Biomedical Applications of Nanotechnology, 4–6 March. 2009;Berlin. Available from: http://nm09.nanoevents.de/
    • View In Article
20. Bawa R, Johnson S. The ethical dimensions of nanomedicine. Med Clin North Am. 2007;91:881–887
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (101 KB)
    • CrossRef
21. Nanotechnology: A Report of the U.S. Food and Drug Administration Nanotechnology Task Force, 23 July 2007. Available from: http://www.fda.gov/ScienceResearch/SpecialTopics/Nanotechnology/NanotechnologyTaskForceReport2007/default.htm
    • View In Article
22. National Science and Technology Council, Subcommittee on Nanoscale Science, Engineering, and Technology . Strategy for nanotechnology-related environmental, health, and safety research. Available from: http://www.nano.gov/NNI_EHS_Research_Strategy.pdf
    • View In Article
23. Castranova V, Hoover MD, Maynard A. NIOSH Nanotechnology Safety and Health Research Program. Nanomaterials: a risk to health at work?. In:  Mark D editors. Report of the First International Symposium on Occupational Health Implications of Nanomaterials, Buxton, Derbyshire, UK, 12–14 October. UK: The Social and Economic Challenges of Nanotechnology, Economic & Social Research Council; 2004;Available from: http://www.hsl.gov.uk/capabilities/nanosymrep_final.pdf
    • View In Article
24. International Council on Nanotechnology (ICON) . Towards predicting nano-biointeractions: an international assessment of nanotechnology environment, health and safety research needs. ICON. 2008;(No. 4):Available from: http://cohesion.rice.edu/CentersAndInst/ICON/emplibrary/ICON_RNA_Report_Full2.pdf
    • View In Article
25. Rickerby DG. Nanotechnological medical devices and nanopharmaceuticals: the European regulatory framework and research needs. J Nanosci Nanotechnol. 2007;7:4618–4625
    • View In Article
26. Goya GF, Grazu V, Ibarra MR. Magnetic nanoparticles for cancer therapy. Curr Nanosci. 2008;4:1–16
    • View In Article
27. Alexis F, Rhee JW, Richie JP, Radovic-Moreno AF, Langer R, Farokhzad OC. New Frontiers in Nanotechnology for Cancer Treatment. Urol Oncol. 2008;26:74–85
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (2054 KB)
    • CrossRef
28. Woodrow Wilson Center Project on Emerging Nanotechnologies . Inventories. Available from: http://www.nanotechproject.org/inventories/
    • View In Article
29. Wagner V, Dullaart A, Bock AK, Zweck A. The emerging nanomedicine landscape. Nat Biotechnol. 2006;24:1211–1217
    • View In Article
    • MEDLINE
    • CrossRef
30. Bawarski WE, Chidlowsky E, Bharali DJ, Mousa SA. Emerging nanopharmaceuticals. Nanomedicine. 2008;4:273–282
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (380 KB)
    • CrossRef
31. Wei CM, Liu NH, Xu PY, Heller M, Tomalia DA, Haynie DI, et al. From bench to bedside: successful translational nanomedicine. Nanomedicine. 2007;3:322–331
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (162 KB)
    • CrossRef
32. http://nihroadmap.nih.gov/clinicalresearch/overview-translational.asp
    • View In Article
33. President's Council of Advisors on Science and Technology . The National Nanotechnology Initiative: second assessment and recommendations of the National Nanotechnology Advisory Panel, April 2008. Available from: http://www.nano.gov/PCAST_NNAP_NNI_Assessment_2008.pdf
    • View In Article
34. Caruthers SD, Wickline SA, Lanza GM. Nanotechnological applications in medicine. Curr Opin Biotechnol. 2007;18:26–30
    • View In Article
    • MEDLINE
    • CrossRef
35. Gao JH, Xu B. Applications of nanomaterials inside cells. Nano Today. 2009;4:37–51
    • View In Article
36. Sahoo SK, Parveen S, Panda JJ. The present and future of nanotechnology in human health care. Nanomedicine. 2007;3:20–31
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (198 KB)
    • CrossRef
37. American Cancer Society. Cancer facts and figures 2007. 2007;
    • View In Article
38. Kim KY. Nanotechnology platforms and physiological challenges for cancer therapeutics. Nanomedicine. 2007;3:103–110
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (315 KB)
    • CrossRef
39. Koo YEL, Reddy GR, Bhojani M, Schneider R, Philbert MA, Rehemtulla A, et al. Brain cancer diagnosis and therapy with nanoplatforms. Adv Drug Deliv Rev. 2006;58:1556–1577
    • View In Article
    • MEDLINE
    • CrossRef
40. Chin CD, Linder V, Sia SK. Lab-on-a-chip devices for global health: past studies and future opportunities. Lab on a Chip. 2007;7:41–57
    • View In Article
    • MEDLINE
    • CrossRef
41. Christodoulides N, Floriano PN, Miller CS, Ebersole JL, Mohanty S, Dharshan P, et al. Lab-on-a-chip methods for point-of-care measurements of salivary biomarkers of periodontitis. Ann NY Acad Sci. 2007;1098:411–428
    • View In Article
42. Hild WA, Breunig M, Goepferich A. Quantum dots—nano-sized probes for the exploration of cellular and intracellular targeting. Eur J Pharm Biopharm. 2008;68:153–168
    • View In Article
    • CrossRef
43. Fuller JE, Zugates GT, Ferreira LS, Ow HS, Nguyen NN, Wiesner UB, et al. Intracellular delivery of core-shell fluorescent silica nanoparticles. Biomaterials. 2008;29:1526–1532
    • View In Article
    • CrossRef
44. El-Sayed I, Huang X, Macheret F, Humstoe JO, Kramer R, El-Sayed M. Effect of plasmonic gold nanoparticles on benign and malignant cellular autofluorescence: a Novel probe for fluorescence based detection of cancer. Technol Cancer Res Treat. 2007;6:403–412
    • View In Article
45. Sharrna P, Brown S, Walter G, Santra S, Moudgil B. Nanoparticles for bioimaging. Adv Colloid Interface Sci. 2006;123:471–485
    • View In Article
    • CrossRef
46. He J, VanBrocklin HF, Franc BL, Seo Y, Jones EF. Nanoprobes for medical diagnostics: current status of nanotechnology in molecular imaging. Curr Nanosci. 2008;4:17–29
    • View In Article
47. Burns A, Ow H, Weisner U. Fluorescent core-shell silica nanoparticles: towards "lab on a particle" architectures for nanobiotechnology. Chem Soc Rev. 2006;35:1028–1042
    • View In Article
    • MEDLINE
    • CrossRef
48. Tomalia DA, Reyna LA, Svenson S. Dendrimers as multi-purpose nanodevices for oncology drug delivery and diagnostic imaging. Biochem Soc Trans. 2007;35:61–67
    • View In Article
    • MEDLINE
    • CrossRef
49. Briones E, Colino CI, Lanao JM. Delivery systems to increase the selectivity of antibiotics in phagocytic cells. J Control Release. 2008;125:210–227
    • View In Article
    • CrossRef
50. Hwang SH, Rait A, Pirollo KF, Zhou O, Yenugonda VM, Chinigo GM, et al. Tumor-targeting nanodelivery enhances the anticancer activity of a novel quinazolinone analogue. Mol Cancer Ther. 2008;7:559–568
    • View In Article
    • CrossRef
51. Sutton D, Nasongkla N, Blanco E, Gao JM. Functionalized micellar systems for cancer targeted drug delivery. Pharm Res. 2007;24:1029–1046
    • View In Article
    • MEDLINE
    • CrossRef
52. Conti M, Tazzari V, Baccini C, Pertici G, Serino LP, De Giorgi U. Anticancer drug delivery with nanoparticles. In Vivo. 2006;20:697–701
    • View In Article
    • MEDLINE
53. Maier-Hauff K, Rothe R, Scholz R, Gneveckow U, Wust P, Thiesen B, et al. Intracranial thermotherapy using magnetic nanoparticles combined with external beam radiotherapy: results of a feasibility study on patients with glioblastoma multiforme. J Neurooncol. 2007;81:53–60
    • View In Article
    • MEDLINE
    • CrossRef
54. American Diabetes Association . Economic costs of diabetes in the U.S. in 2007. Diabetes Care. 2008;31:596–615
    • View In Article
    • CrossRef
55. Lee TMH. Over-the-counter biosensors: past, present and future. Sensors. 2008;8:5535–5559
    • View In Article
56. Cavalcanti A, Shirinzadeh B, Kretly LC. Medical nanorobotics for diabetes control. Nanomedicine. 2008;4:127–138
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (1053 KB)
    • CrossRef
57. Desai TA, West T, Cohen M, Boiarski T, Rampersaud A. Nanoporous microsystems for islet cell replacement. Adv Drug Deliv Rev. 2004;56:1661–1673
    • View In Article
    • MEDLINE
    • CrossRef
58. Berkowitz M, O'Leary PK, Kruse DL, Harvey C. Spinal cord injury: an analysis of medical and social costs. New York: Demos Medical Publishing; 1998;
    • View In Article
59. Harvey C, Wilson SE, Greene CG, Berkowitz M, Stripling TE. New estimates of the direct costs of traumatic spinal-cord injuries—results of a nationwide survey. Paraplegia. 1992;30:834–850
    • View In Article
    • MEDLINE
    • CrossRef
60. Silva GA. Neuroscience nanotechnology: progress, opportunities and challenges. Nat Rev Neurosci. 2006;7:65–74
    • View In Article
    • MEDLINE
61. Tysseling-Mattiace VM, Sahni V, Niece KL, Birch D, Czeisler C, Fehlings MG, et al. Self-assembling nanofibers inhibit glial scar formation and promote axon elongation after spinal cord injury. J Neurosci. 2008;28:3814–3823
    • View In Article
    • CrossRef
62. Liu-Snyder P, Webster TJ. Developing a new generation of bone cements with nanotechnology. Curr Nanosci. 2008;4:111–118
    • View In Article
63. Khang D, Lu J, Yao C, Haberstroh KM, Webster TJ. The role of nanometer and sub-micron surface features on vascular and bone cell adhesion on titanium. Biomaterials. 2008;29:970–983
    • View In Article
    • CrossRef
64. Chan CK, Kumar TSS, Liao S, Murugan R, Ngiam M, Ramakrishman S. Biomimetic nanocomposites for bone graft application. Nanomedicine. 2006;1:177–188
    • View In Article
65. White AA, Best SM, Kinloch IA. Hydroxyapatite-carbon nanotube composites for biomedical applications: a review. Int J Appl Ceram Technol. 2007;4:1–13
    • View In Article
66. New natural plastic extends life of bone implant. Science Daily, 1 November 2007. Available from: http://www.sciencedaily.com/releases/2007/10/071030132322.htm
    • View In Article
67. Qian XM, Peng XH, Ansari DO, Yin-Goen Q, Chen GZ, Shin DM, et al. In vivo tumor targeting and spectroscopic detection with surface-enhanced Raman nanoparticle tags. Nat Biotechnol. 2008;26:83–90
    • View In Article
    • CrossRef
68. Leary SP, Liu CY, Apuzzo MLJ. Toward the emergence of nanoneurosurgery: Part II. Nanomedicine: diagnostics and imaging at the nanoscale level. Neurosurgery. 2006;58:805–822
    • View In Article
    • CrossRef
69. Huang XH, El-Sayed IH, Qian W, El-Sayed MA. Cancer cells assemble and align gold nanorods conjugated to antibodies to produce highly enhanced, sharp, and polarized surface Raman spectra: a potential cancer diagnostic marker. Nano Lett. 2007;7:1591–1597
    • View In Article
    • CrossRef
70. Zhang P, Guo Y. Surface-enhanced Raman scattering inside metal nanoshells. J Am Chem Soc. 2009;131:3808–3809
    • View In Article
    • CrossRef
71. Stewart ME, Anderton CR, Thompson LB, Maria J, Gray SK, Rogers JA, et al. Nanostructured plasmonic sensors. Chem Rev. 2008;108:494–521
    • View In Article
    • CrossRef
72. Tang HW, Yang XB, Kirkham J, Smith DA. Probing intrinsic and extrinsic components in single osteosarcoma cells by near-infrared surface-enhanced Raman scattering. Anal Chem. 2007;79:3646–3653
    • View In Article
    • MEDLINE
    • CrossRef
73. McAlpine MC, Ahmad H, Wang DW, Health JR. Highly ordered nanowire arrays on plastic substrates for ultrasensitive flexible chemical sensors. Nat Mater. 2007;6:379–384
    • View In Article
    • MEDLINE
    • CrossRef
74. Kim DH, Ahn JH, Choi WM, Kim HS, Kim TH, Song JZ, et al. Stretchable and foldable silicon integrated circuits. Science. 2008;320:507–511
    • View In Article
    • CrossRef
75. Alcohol Monitoring Systems, Inc. . [homepage on the Internet]. Available from: http://www.alcoholmonitoring.com/
    • View In Article
76. Echo Therapeutics . [homepage on the Internet]. Available from: http://www.echotx.com/
    • View In Article
77. Flexible Medical Systems . [homepage on the Internet]. Available from: http://www.flexmedsys.com/index.htm
    • View In Article
78. Ren S, Yoon HR, Kim SY. Trends in three-dimensional biochips. Biochip J. 2008;2:155–159
    • View In Article
79. Abraham AM, Kannangai R, Sridharan G. Nanotechnology: a new frontier in virus detection in clinical practice. Ind J Med Microbiol. 2008;26:297–301
    • View In Article
80. Bake KD, Walt DR. Multiplexed spectroscopic detections. Annu Rev Anal Chem. 2008;1:515–547
    • View In Article
81. Collard D, Takeuchi S, Fujita H. MEMS technology for nanobio research. Drug Discov Today. 2008;13:989–996
    • View In Article
    • CrossRef
82. Wimberger-Friedl R, Nellissen T, Weekamp W, van Delft J, Ansems W, Prins M, et al. Packaging of silicon sensors for microfluidic bio-analytical applications. J Micromechanics Microeng. 2009;19:015015
    • View In Article
83. Zengerle R, Koltay P, Ducree J. Microfluidics: an enabling technology for the life sciences. In: Proceedings of the 2004 International Symposium on Micro-Nanomechatronics and Human Science, 2004 and The Fourth Symposium Micro-Nanomechatronics for Information-Based Society. 2004;p. 1–6
    • View In Article
84. Sathuluri RR, Yamamura S, Tamiya E. Microsystems technology and biosensing. Adv Biochem Eng Biotechnol. 2008;109:285–350
    • View In Article
85. Samel B, Nock V, Russom A, Griss P, Stemme G. A disposable lab-on-a-chip platform with embedded fluid actuators for active nanoliter liquid handling. Biomed Microdevices. 2007;9:61–67
    • View In Article
    • MEDLINE
    • CrossRef
86. Kakuta M, Takahashi H, Kazuno S, Murayama K, Ueno T, Tokeshi M. Development of the microchip-based repeatable immunoassay system for clinical diagnosis. Measurement Sci Technol. 2006;17:3189–3194
    • View In Article
87. Virdi GS, Chutani RK, Rao PK, Kumar S. Fabrication of low cost integrated micro-capillary electrophoresis analytical chip for chemical analysis. Sensors Actuators. 2008;B128:422–426
    • View In Article
88. Hunt HC, Wilkinson JS. Optofluidic integration for microanalysis. Microfluid Nanofluid. 2008;4:53–79
    • View In Article
89. Moran-Mirabal JM, Torres AJ, Samiee KT, Baird BA, Craighead HG. Cell investigation of nanostructures: zero-mode waveguides for plasma membrane studies with single molecule resolution. Nanotechnology. 2007;18:195101
    • View In Article
    • CrossRef
90. Weibel DB, DiLuzio WR, Whitesides GM. Microfabrication meets microbiology. Nat Rev Microbiol. 2007;5:209–218
    • View In Article
    • CrossRef
91. Stern E, Klemic JF, Routenberg DA, Wyrembak PN, Turner-Evans DB, Hamilton AD, et al. Label-free immunodetection with CMOS-compatible semiconducting nanowires. Nature. 2007;445:519–522
    • View In Article
    • CrossRef
92. Kalorama Information . Analytical chip technology: U.S. markets for lab on a chip, DNA/gene, protein and other microarrays. 3rd ed. Market Research Report; 2007;ID KLI 1393085
    • View In Article
93. Christodoulides N, Floriano PN, Acosta SA, Ballard KLM, Weigum SE, Mohanty S, et al. Toward the development of a lab-on-a-chip dual-function leukocyte and C-reactive protein analysis method for the assessment of inflammation and cardiac risk. Clin Chem. 2005;51:2391–2395
    • View In Article
    • MEDLINE
    • CrossRef
94. Reigger L, Grumann M, Steigert J, Lutz S, Steinert CP, Mueller C, et al. Single-step centrifugal hematocrit determination on a 10-$ processing device. Biomed Microdevices. 2007;9:795–799
    • View In Article
    • CrossRef
95. Snider RM, Ciobanu M, Rue AE, Cliffel DE. A multiwalled carbon nanotube/dihydropyran composite film electrode for insulin detection in a microphysiometer chamber. Anal Chim Acta. 2008;609:44–52
    • View In Article
    • CrossRef
96. Price CP, Kricka LJ. Improving healthcare accessibility through point-of-care technologies. Clin Chem. 2007;53:1665–1675
    • View In Article
    • CrossRef
97. Cross SE, Jin YS, Rao J, Gimzewski JK. Nanomechanical analysis of cells from cancer patients. Nat Nanotechnol. 2007;2:780–783
    • View In Article
    • CrossRef
98. Institute for Alternative Futures . The Biomonitoring Futures Project: Final Report and Recommendations, Institute for Alternative Futures. Available from: http://www.altfutures.com/BFP2006;
    • View In Article
99. Martinez AW, Phillips ST, Carrilho E, Thomas SW, Sindi H, Whitesides GM. Simple telemedicine for developing regions: camera phones and paper-based microfluidic devices for real-time, off-site diagnosis. Anal Chem. 2008;80:3699–3707
    • View In Article
    • CrossRef
100. Haeberle S, Zengerle R. Microfluidic platforms for lab-on-a-chip applications. Lab on a Chip. 2007;7:1094–1110
     • View In Article
101. Kang LF, Chung BG, Langer R, Khademhosseini A. Microfluidics for drug discovery and development from target selection to product lifecycle management. Drug Discov Today. 2008;13:1–13
     • View In Article
     • CrossRef
102. Gross S, Piwnica-Worms D. Molecular imaging strategies for drug discovery and development. Curr Opin Chem Biol. 2006;10:334–342
     • View In Article
     • MEDLINE
     • CrossRef
103. Ferrari M. Beyond drug delivery. Nat Nanotechnol. 2008;3:131–132
     • View In Article
     • CrossRef
104. Hanley C, Layne J, Punnoose A, Reddy KM, Coombs I, Coombs A, et al. Preferential killing of cancer cells and activated human T cells using ZnO nanoparticles. Nanotechnology. 2008;19:1–10
     • View In Article
105. Maguire AM, Simonelli F, Pierce EA, Pugh EN, Mingozzi F, Bennicelli J, et al. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med. 2008;358:2240–2248
     • View In Article
     • CrossRef
106. Byrappa K, Ohara S, Adschiri T. Nanoparticles synthesis using supercritical fluid technology—towards biomedical applications. Adv Drug Deliv Rev. 2008;60:299–327
     • View In Article
     • CrossRef
107. Hartman KB, Wilson LJ, Rosenblum MG. Detecting and treating cancer with nanotechnology. Mol Diagn Ther. 2008;12:1–14
     • View In Article
108. Heath JR, Davis ME. Nanotechnology and cancer. Ann Rev Med. 2008;59:251–265
     • View In Article
109. Leary SP, Liu CY, Apuzzo MLI. Toward the emergence of nanoneurosurgery: Part III—nanomedicine: targeted nanotherapy, nanosurgery, and progress toward the realization of nanoneurosurgery. Neurosurgery. 2006;58:1009–1026
     • View In Article
     • CrossRef
110. Linkov I, Satterstrom FK, Corey LM. Nanotoxicology and nanomedicine: making hard decisions. Nanomedicine. 2008;4:167–171
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (227 KB)
     • CrossRef
111. Ashammakhi N, Wimpenny I, Nikkola L, Yang Y. Electrospinning: methods and development of biodegradable nanofibres for drug release. J Biomed Nanotechnol. 2009;5:1–19
     • View In Article
     • CrossRef
112. Gu F, Zhang L, Teply BA, Mann N, Wang A, Radovic-Moreno AF, et al. Precise engineering of targeted nanoparticles by using self-assembled biointegrated block copolymers. Proc Natl Acad Sci U S A. 2008;105:2586–2591
     • View In Article
     • CrossRef
113. Winter PM, Cai K, Caruthers SD, Wickline SA, Lanza GM. Emerging nanomedicine opportunities with perfluorocarbon nanoparticles. Exp Rev Med Devices. 2007;4:137–145
     • View In Article
114. Lesniak WG, Kariapper MST, Nair BM, Tan W, Hutson A, Balogh LP, et al. Synthesis and characterization of PAMAM dendrimer-based multifunctional nanodevices for targeting alpha(v)beta(3) integrins. Bioconjug Chem. 2007;18:1148–1154
     • View In Article
     • CrossRef
115. Lowery AR, Gobin AM, Day ES, Halas NJ, West JL. Immunonanoshells for targeted photothermal ablation of tumor cells. Int J Nanomed. 2006;1:149–154
     • View In Article
116. Fu K, Sun J, Bickford LR, Lin AWH, Halas NJ, Yu TK, et al. Measurement of immunotargeted plasmonic nanoparticles' cellular binding: a key factor in optimizing diagnostic efficacy. Nanotechnology. 2008;19:045103
     • View In Article
     • CrossRef
117. Rapoport N, Gao ZG, Kennedy A. Multifunctional nanoparticles for combining ultrasonic tumor imaging and targeted chemotherapy. J Natl Cancer Inst. 2007;99:1095–1106
     • View In Article
     • CrossRef
118. Piao Y, Kim J, Bin Na H, Kim D, Baek JS, Ko MK, et al. Wrap-bake-peel process for nanostructural transformations from β-FeOOH nanorods to biocompatible iron oxide nanocapsules. Nat Mater. 2008;7:242–247
     • View In Article
     • CrossRef
119. Myc A, Majoros IJ, Thomas TP, Baker JR. Dendrimer-based targeted delivery of an apoptotic sensor in cancer cells. Biomacromolecules. 2007;8:13–18
     • View In Article
     • MEDLINE
     • CrossRef
120. Birch DG, Liang FQ. Age-related macular degeneration: as target for nanotechnology derived medicines. Int J Nanomed. 2007;2:65–77
     • View In Article
121. Chumakova OV, Liopo AV, Andreev VG, Cicenaite I, Evers BM, Chakrabarty S, et al. Composition of PLGA and PEI/DNA nanoparticles improves ultrasound-mediated gene delivery in solid tumors in vivo. Cancer Lett. 2008;261:215–225
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (2419 KB)
     • CrossRef
122. Gill S, Lobenberg R, Ku T, Azarmi S, Roa W, Prenner EJ. Nanoparticles: characteristics, mechanisms of action, and toxicity in pulmonary drug delivery—a review. J Biomed Nanotechnol. 2007;3:107–119
     • View In Article
     • CrossRef
123. Torchilin VP. Multifunctional nanocarriers. Adv Drug Deliv Rev. 2006;58:1532–1555
     • View In Article
     • MEDLINE
     • CrossRef
124. Jin S, Ye KM. Nanoparticle-mediated drug delivery and gene therapy. Biotechnol Prog. 2007;23:32–41
     • View In Article
     • MEDLINE
     • CrossRef
125. Cho YW, Park SA, Han TH, Son DH, Park JS, Oh SJ, et al. In vivo tumor targeting and radionuclide imaging with self-assembled nanoparticles: mechanisms, key factors, and their implications. Biomaterials. 2007;28:1236–1247
     • View In Article
     • MEDLINE
     • CrossRef
126. Balogh L, Nigavekar SS, Nair BM, Lesniak W, Zhang C, Sung LY, et al. Significant effect of size on the in-vivo biodistribution of gold composite nanodevices in mouse tumor models. Nanomedicine. 2007;3:281–296
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (926 KB)
     • CrossRef
127. Roovers RC, van Dongen GAMS, Henegouwen PMPVE. Nanobodies in therapeutic applications. Curr Opin Mol Ther. 2007;9:327–335
     • View In Article
128. Bae YH. Cancer targeting paradigm: does it need to be shifted?. Nanomedicine. 2007;3:344
     • View In Article
     • Full Text
     • Full-Text PDF (63 KB)
     • CrossRef
129. Leroueil PR, Berry SA, Duthie K, Han G, Rotello VM, McNerny DQ, et al. Wide varieties of cationic nanoparticles induce defects in supported lipid bilayers. Nano Lett. 2008;8:420–424
     • View In Article
     • CrossRef
130. Huff TB, Tong L, Zhao Y, Hansen MN, Cheng JX, Wei A. Hyperthermic effects of gold nanorods on tumor cells. Nanomedicine. 2007;2:125–132
     • View In Article
131. Kalele SA, Tiwari NR, Gosavi SW, Kulkarni SK. Plasmon-assisted photonics at the nanoscale. J Nanophotonics. 2007;1:012501
     • View In Article
132. Gannon CJ, Cherukuri P, Yakobson BI, Cognet L, Kanzius JS, Kittrell C, et al. Carbon nanotube-enhanced thermal destruction of cancer cells in a noninvasive radiofrequency field. Cancer. 2007;110:2654–2665
     • View In Article
     • CrossRef
133. Christie JS, Kompella UB. Ophthalmic light sensitive nanocarrier systems. Drug Discov Today. 2008;13:124–134
     • View In Article
     • CrossRef
134. Gao D, Agayan RR, Xu H, Philbert MA, Kopelman R. Nanoparticles for two-photon photodynamic therapy in living cells. Nano Lett. 2006;6:2383–2386
     • View In Article
     • MEDLINE
     • CrossRef
135. Chen HT, Kaminski MD, Liu XQ, Mertz CJ, Xie YM, Torno MD, et al. A novel human detoxification system based on nanoscale bioengineering and magnetic separation techniques. Med Hypoth. 2007;68:1071–1079
     • View In Article
136. Barnes CP, Sell SA, Boland ED, Simpson DG, Bowlin GL. Nanofiber technology: designing the next generation of tissue engineering scaffolds. Adv Drug Deliv Rev. 2007;59:1413–1433
     • View In Article
     • CrossRef
137. Badylak SF, Freytes DO, Gilbert TW. Extracellular matrix as a biological scaffold material: structure and function. Acta Biomater. 2009;5:1–13
     • View In Article
     • CrossRef
138. Venugopal J, Low S, Choon AT, Ramakrishna S. Interaction of cells and nanofiber scaffolds in tissue engineering. J Biomed Mater Res. 2008;84B:34–48
     • View In Article
139. Venugopal J, Prabhakaran MP, Low S, Choon AT, Zhang YZ, Deepika G, et al. Nanotechnology for nanomedicine and delivery of drugs. Curr Pharm Design. 2008;14:2184–2200
     • View In Article
140. Hunley MT, Long TE. Electrospinning functional nanoscale fibers: a perspective for the future. Polym Int. 2008;57:385–389
     • View In Article
141. Powell HM, Supp DM, Boyce ST. Influence of electrospun collagen on wound contraction of engineered skin substitutes. Biomaterials. 2008;29:834–843
     • View In Article
     • CrossRef
142. Martins A, Araujo JV, Reis RL, Neves NM. Electrospun nanostructured scaffolds for tissue engineering applications. Nanomedicine. 2007;2:929–942
     • View In Article
143. Liao S, Li BJ, Ma ZW, Wei H, Chan C, Ramakrishna S. Biomimetic electrospun nanofibers for tissue regeneration. Biomed Mater. 2006;1:R45–R53
     • View In Article
     • CrossRef
144. Ma ZW, Kotaki M, Inai R, Ramakrishna S. Potential of nanofiber matrix as tissue-engineering scaffolds. Tissue Eng. 2005;11:101–109
     • View In Article
     • MEDLINE
     • CrossRef
145. Tsonchev S, Niece KL, Schatz GC, Ratner MA, Stupp SI. Phase diagram for assembly of biologically-active peptide amphiphiles. J Phys Chem. 2009;B112:441–447
     • View In Article
146. Hartgerink JD, Beniash E, Stupp SI. Self-assembly and mineralization of peptide-amphiphile nanofibers. Science. 2001;294:1684–1688
     • View In Article
     • MEDLINE
     • CrossRef
147. Chau Y, Luo Y, Cheung ACY, Nagai Y, Zhang SG, Kobler JB, et al. Incorporation of a matrix metalloproteinase-sensitive substrate into self-assembling peptides—a model for biofunctional scaffolds. Biomaterials. 2008;29:1713–1719
     • View In Article
     • CrossRef
148. Tao SL, Desai TA. Aligned arrays of biodegradable poly(epsilon-caprolactone) nanowires and nanofibers by template synthesis. Nano Lett. 2007;7:1463–1468
     • View In Article
     • MEDLINE
     • CrossRef
149. Erisken C, Kalyon DM, Wang HJ. A hybrid twin screw extrusion/electrospinning method to process nanoparticle-incorporated electrospun nanofibres. Nanotechnology. 2008;19:165302
     • View In Article
     • CrossRef
150. Hosseinkhani MD, Hosseinkhani M, Khademhoseini A. Tissue regeneration through self-assembled peptide amphiphile nanofibers. Yakhteh Med J. 2006;8:204–209
     • View In Article
151. Capito RM, Azevedo HS, Velichko YS, Mata A, Stupp SI. Self-assembly of large and small molecules into hierarchically ordered sacs and membranes. Science. 2008;319:1812–1816
     • View In Article
     • CrossRef
152. Wang XM, Horii A, Zhang SG. Designer functionalized self-assembling peptide nanofiber scaffolds for growth, migration, and tubulogenesis of human umbilical vein endothelial cells. Soft Matter. 2008;4:2388–2395
     • View In Article
153. Audette GF, Hazes B. Development of protein nanotubes from a multi-purpose biological structure. J Nanosci Nanotechnol. 2007;7:2222–2229
     • View In Article
     • CrossRef
154. Sargeant TD, Guler MO, Oppenheimer SM, Mata A, Satcher RL, Dunand DC, et al. Hybrid bone implants: self-assembly of peptide amphiphile nanofibers with porous titanium. Biomaterials. 2008;29:161–171
     • View In Article
     • CrossRef
155. Khang D, Park GE, Webster TJ. Enhanced chondrocyte densities on carbon nanotube composites: the combined role of nanosurface roughness and electric stimulation. J Biomed Mater Res A. 2008;86A:253–260
     • View In Article
     • CrossRef
156. Popat KC, Leoni L, Grimes CA, Desai TA. Influence of engineered titania nanotubular surfaces on bone cells. Biomaterials. 2007;28:3188–3197
     • View In Article
     • MEDLINE
     • CrossRef
157. Venugopal J, Vadgama P, Kumar TSS, Ramakrishna S. Biocomposite nanofibres and osteoblasts for bone tissue engineering. Nanotechnology. 2007;18:055101
     • View In Article
     • CrossRef
158. Ballard JD, Dulgar-Tulloch AJ, Siegel RW. Nanophase materials. In:  Akay M editors. Wiley encyclopedia of biomedical engineering. Vol 4:Malden, Massachusetts: Wiley-InterScience; 2006;p. 2489–2507
     • View In Article
159. 3M . Filtek Supreme Plus Universal Restorative. Available from: http://solutions.3m.com/wps/portal/3M/en_US/3M-ESPE/dental-professionals/products/category/direct-restorative/filtek-supreme-plus/
     • View In Article
160. Randall CL, Leong TG, Bassik N. Gracias DH: 3D lithographically fabricated nanoliter containers for drug delivery. Adv Drug Deliv Rev. 2007;59:1547–1561
     • View In Article
     • CrossRef
161. Chen B, Wei J, Tay FEH, Wong YT, Iliescu C. Silicon microneedle array with biodegradable tips for transdermal drug delivery. Microsyst Technol Micro- Nanosyst-Inform Storage Process Syst. 2008;14:1015–1019
     • View In Article
162. Nisar A, Aftulpurkar N, Mahaisavariya B, Tuantranont A. MEMS-based micropumps in drug delivery and biomedical applications. Sensors Actuators. 2008;B130:917–942
     • View In Article
163. Heller A. Potentially implantable miniature batteries. Anal Bioanal Chem. 2006;385:469–473
     • View In Article
     • MEDLINE
     • CrossRef
164. Li PF, Bashirullah R. A wireless power interface for rechargeable battery operated medical implants. IEEE Trans Circ Syst II—Express Briefs. 2007;54:912–916
     • View In Article
165. Riistama J, Vaisanen J, Heinisuo S, Harjunpaa H, Arra S, Kokko K, et al. Wireless and inductively powered implant for measuring electrocardiogram. Med Biol Eng Comput. 2007;45:1163–1174
     • View In Article
     • CrossRef
166. Wang XD, Song JH, Liu J, Wang ZL. Direct-current nanogenerator driven by ultrasonic waves. Science. 2007;316:102–105
     • View In Article
     • CrossRef
167. Qin Y, Wang XD, Wang ZL. Microfibre-nanowire hybrid structure for energy scavenging. Nature. 2008;451:809–813
     • View In Article
     • CrossRef
168. Laocharoensuk R, Burdick J, Wang J. Carbon-nanotube-induced acceleration of catalytic nanomotors. ACS Nano. 2008;2:1069–1075
     • View In Article
     • CrossRef
169. Wang ZL. The new field of nanopiezotronics. Mater Today. 2007;10:20–28
     • View In Article
170. Grill WM. NAKFI smart prosthetics: exploring assistive devices for the body and mind. Expert Rev Med Devices. 2007;4:107–108
     • View In Article
     • MEDLINE
     • CrossRef
171. National Academies Keck Futures Initiative . Smart prosthetics: exploring assistive devices for the body and mind: Task Group summaries. Washington, DC: The National Academies Press; 2007;
     • View In Article
172. Lebedev MA, Nicolelis MAL. Brain-machine interfaces: past, present, future. Trends Neurosci. 2006;29:536–546
     • View In Article
     • MEDLINE
     • CrossRef
173. Elder JB, Liu CY, Apuzzo MLJ. Neurosurgery in the realm of 10^–9, Part 2: Applications of nanotechnology to neurosurgery—present and future. Neurosurgery. 2008;62:269–284
     • View In Article
     • CrossRef
174. Silva GA. Nanotechnology approaches for drug and small molecule delivery across the blood brain barrier. Surg Neurol. 2007;67:113–116
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (117 KB)
     • CrossRef
175. Wise KD, Bhatti PT, Wang JB, Friedrich CR. High-density cochlear implants with position sensing and control. Hearing Res. 2008;242:22–30
     • View In Article
     • CrossRef
176. Duke T. The power of hearing. Physics World. 2002;15:29–33
     • View In Article
177. Zaghloul KA, Baohen K. A silicon retina that reproduces signals in the optic nerve. J Neural Eng. 2006;3:257–267
     • View In Article
     • MEDLINE
     • CrossRef
178. Cohen ED. Prosthetic interfaces with the visual system: biological issues. J Neural Eng. 2007;4:R14–R31
     • View In Article
     • MEDLINE
     • CrossRef
179. Pappas TC, Wickramanyake WMS, Jan E, Motamedi M, Brodwick M, Kotov NA. Nanoscale engineering of a cellular interface with semiconductor nanoparticle films for photoelectric stimulation of neurons. Nano Lett. 2007;7:513–519
     • View In Article
     • MEDLINE
     • CrossRef
180. Kuiken TA, Marasco PD, Lock BA, Harden RN, Dewald JPA. Redirection of cutaneous sensation from the hand to the chest skin of human amputees with targeted reinnervation. Proc Natl Acad Sci U S A. 2007;104:20061–20066
     • View In Article
     • CrossRef
181. Sharp AA, Panchawagh HV, Ortega A, Artale R, Richardson-Burns S, Finch DS, et al. Toward a self-deploying shape memory polymer neuronal electrode. J Neural Eng. 2006;3:L23–L30
     • View In Article
     • MEDLINE
182. Cabanlit M, Maitland D, Wilson T, Simon S, Wun T, Gershwin ME, et al. Polyurethane shape-memory polymers demonstrate functional biocompatibility in vitro. Macromol Biosci. 2007;7:48–55
     • View In Article
     • MEDLINE
     • CrossRef
183. Mazzatenta A, Giugliano M, Campidelli S, Gambazzi L, Businaro L, Markram H, et al. Interfacing neurons with carbon nanotubes: electrical signal transfer and synaptic stimulation in cultured brain circuits. J Neurosci. 2007;27:6931–6936
     • View In Article
     • CrossRef
184. Ouyang M, Huang JL, Lieber CM. Fundamental electronic properties and applications of single-walled carbon nanotubes. Accounts Chem Res. 2002;35:1018–1025
     • View In Article
185. Moxon KA, Hallman S, Aslani A, Kalkhoran NM, Lelkes PI. Bioactive properties of nanostructured porous silicon for enhancing electrode to neuron interfaces. J Biomater Sci Polym. 2007;18:1263–1281
     • View In Article
186. Zhao Y, Larimer P, Pressler RT, Strowbridge BW, Burda C. Wireless activation of neurons in brain slices using nanostructured semiconductor photoelectrodes. Angew Chem Int Edn. 2009;48:2407–2410
     • View In Article
187. Schanze T, Hesse L, Lau C, Greve N, Haberer W, Kammer S, et al. An optically powered single-channel stimulation implant as test system for chronic biocompatibility and biostability of miniaturized retinal vision prostheses. IEEE Trans Biomed Eng. 2007;54:983–992
     • View In Article
     • MEDLINE
     • CrossRef
188. Mogilner A, Wollman R, Marshall WF. Quantitative modeling in cell biology: what is it good for?. Dev Cell. 2006;11:279–287
     • View In Article
     • MEDLINE
     • CrossRef
189. Bruggeman FJ, Weserhoff HV. Approaches to biosimulation of cellular processes. J Biol Phys. 2006;32:273–288
     • View In Article
190. Assmus HE, Herwig R, Cho KH, Wolkenhauer O. Dynamics of biological systems: role of systems biology in medical research. Expert Rev Mol Diagn. 2006;6:891–902
     • View In Article
     • CrossRef
191. Zlatanova J, van Holde K. Single molecule biology: what is it and how does it work?. Mol Cell. 2006;24:317–329
     • View In Article
192. California Institute of Technology : Institute for Systems Biology . Introduction to ISB and systems biology. Systems biology – the 21st century science. Available from: http://www.systemsbiology.org/Intro_to_ISB_and_Systems_Biology/Systems_Biology_–_the_21st_Century_Science
     • View In Article
193. van den Heuvel MGL, Dekker C. Motor proteins at work for nanotechnology. Science. 2007;317:333–336
     • View In Article
     • CrossRef
194. Strychalski EA, Stavis SM, Craighead HG. Non-planar nanofluidic devices for single molecule analysis fabricated using nanoglassblowing. Nanotechnology. 2008;19:315301
     • View In Article
     • CrossRef
195. Rhee M, Burns MA. Nanopore sequencing technology: research trends and applications. Trends Biotechnol. 2006;24:580–586
     • View In Article
     • MEDLINE
     • CrossRef
196. Rhee M, Burns MA. Nanopore sequencing technology: nanopore preparations. Trends Biotechnol. 2007;25:174–181
     • View In Article
     • MEDLINE
     • CrossRef
197. Mannion JT, Craighead HG. Nanofluidic structures for single biomolecule fluorescent detection. Biopolymers. 2007;85:131–143
     • View In Article
     • MEDLINE
     • CrossRef
198. Clark J, Wu HC, Jayasinghe L, Patel A, Reid S, Bayley H. Continuous base identification for single-molecule nanopore DNA sequencing. Nat Nanotechnol. 2009;4:265–270
     • View In Article
     • CrossRef
199. Stanford Microfluidics Foundry . [homepage on the Internet]. Available from: http://thebigone.stanford.edu/foundry
     • View In Article
200. The Kavli Nanoscience Institute / Beckman Institute, Microfluidic Foundry . [homepage on the Internet]. Available from: http://kni.caltech.edu/foundry
     • View In Article
201. Wikswo JP, Prokop A, Baudenbacher F, Cliffel D, Csukas B, Velkovsky M. Engineering challenges of BioNEMS: the integration of microfluidics, micro- and nanodevices, models and external control for systems biology. IEEE Proc Nanobiotechnol. 2006;153:81–101
     • View In Article
202. Weibel DB, Whitesides GM. Applications of microfluidics in chemical biology. Curr Opin Chem Biol. 2006;10:584–591
     • View In Article
     • MEDLINE
     • CrossRef
203. Zhang XL, Yin HB, Cooper JM, Haswell SJ. A microfluidic-based system for analysis of single cells based on Ca²⁺ flux. Electrophoresis. 2006;27:5093–5100
     • View In Article
     • MEDLINE
     • CrossRef
204. Marcus JS, Anderson WF, Quake SR. Microfluidic single-cell mRNA isolation and analysis. Anal Chem. 2006;78:3084–3089
     • View In Article
     • MEDLINE
     • CrossRef
205. Schrlau MG, Falls EM, Ziober BL, Bau HH. Carbon nanopipettes for cell probes and intracellular injection. Nanotechnology. 2008;19:015101
     • View In Article
     • CrossRef
206. Schmidt R, Wurm CA, Jakobs S, Engelhardt J, Egner A, Hell SW. Spherical nanosized focal spot unravels the interior of cells. Nat Methods. 2008;5:539–544
     • View In Article
     • CrossRef
207. Zhong WW. Nanomaterials in fluorescence-based biosensing. Anal Bioanal Chem. 2009;394:47–59
     • View In Article
     • CrossRef
208. Mannix RJ, Kumar S, Cassiola F, Montoya-Zavala M, Feinstein E, Prentiss M, et al. Nanomagnetic actuation of receptor-mediated signal transduction. Nat Nanotechnol. 2008;3:36–40
     • View In Article
     • CrossRef
209. Reed J, Frank M, Troke JJ, Schmit J, Han S, Teitell MA, et al. High throughput cell nanomechanics with mechanical imaging interferometry. Nanotechnology. 2008;19:235101
     • View In Article
     • CrossRef
210. Addae-Mensah KA, Wikswo JP. Measurement techniques for cellular biomechanics in vitro. Exp Biol Med. 2008;233:792–809
     • View In Article
211. Schrlau MG, Brailoiu E, Patel S, Gogotsi Y, Dun NJ, Bau HH. Carbon nanopipettes characterize calcium release pathways in breast cancer cells. Nanotechnology. 2008;19:325102
     • View In Article
     • CrossRef
212. Bystrenova E, Jelitai M, Tonazzini I, Lazar AN, Huth M, Stoliar P, et al. Neural networks grown on organic semiconductors. Adv Function Mater. 2008;18:1751–1756
     • View In Article
213. Patolsky F, Timko BP, Yu GH, Fang Y, Greytak AB, Zheng GF, et al. Detection, stimulation and inhibition of neuronal signals with high-density nanowire transistor arrays. Science. 2006;313:1100–1104
     • View In Article
     • CrossRef
214. California Institute of Technology, Roukes Group. Current research projects. Available from: http://nano.caltech.edu/research_index.htm
     • View In Article
215. Neeves KB, Diamond SL. A membrane-based microfluidic device for controlling the flux of platelet agonists into flowing blood. Lab on a Chip. 2008;8:701–709
     • View In Article
     • CrossRef
216. Hansma PK, Turner PJ, Fantner GE. Bone diagnostic instrument. Rev Sci Instrum. 2006;77:075105
     • View In Article
     • CrossRef
217. Hansma P, Turner P, Drake B, Yurtsev E, Proctor A, Matthews P, et al. The bone diagnostic instrument II: indentation distance increase. Rev Sci Instrum. 2008;79:064303
     • View In Article
     • CrossRef
218. Freedman JR, Mattia D, Korneva G, Gogotsi Y, Friedman G, Fontecchio AK. Magnetically assembled carbon nanotube tipped pipettes. Appl Phys Lett. 2007;90:103108
     • View In Article
219. Haga Y, Matsunaga T, Makishi W, Totsu K, Mineta T, Esashi M. Minimally invasive diagnostics and treatment using micro-nano machining. Minim Invasive Ther Allied Technol. 2006;15:218–225
     • View In Article
     • MEDLINE
     • CrossRef
220. Roe D, Karandikar B, Bonn-Savage N, Gibbins B, Roullet JB. Antimicrobial surface functionalization of plastic catheters by silver nanoparticles. J Antimicrob Chemother. 2008;61:869–876
     • View In Article
     • CrossRef
221. Cao Q, Kim HS, Pimparkar N, Kulkarni JP, Wang CJ, Shim M, et al. Medium-scale carbon nanotube thin-film integrated circuits on flexible plastic substrates. Nature. 2008;454:495–500
     • View In Article
     • CrossRef
222. Kim DH, Rogers JA. Stretchable electronics: materials strategies and devices. Adv Mater. 2008;20:4887–4892
     • View In Article
223. Branton D, Deamer DW, Marziali A, Bayley H, Benner SA, Butler T, et al. The potential and challenges of nanopore sequencing. Nat Biotechnol. 2008;26:1146–1153
     • View In Article
     • CrossRef
224. National Institute of Biomedical Imaging and Bioengineering . Micro- and nano-systems; platform technologies program area. Available from: http://www.nibib.nih.gov/Research/ProgramAreas/MicroNanoPlatforms
     • View In Article
225. National Institute of Biomedical Imaging and Bioengineering . Nanotechnology program areas. Available from: ProgramAreas/Nanotech">http://www.nibib.nih.gov/Research/ProgramAreas/Nanotech"
     • View In Article
226. National Cancer Institute . NCI Alliance for Nanotechnology in Cancer. [homepage on the Internet]. Available from: http://nano.cancer.gov
     • View In Article
227. National Heart Lung and Blood Institute . Program of Excellence in Nanotechnology. [homepage on the Internet]. Available from: http://www.nhlbi-pen.net/default.php
     • View In Article
228. US Department of Health and Human Services, National Toxicology Program . NTP nanotechnology safety initiative. Available from: http://ntp.niehs.nih.gov/?objectid=7E6B19D0-BDB5-82F8-FAE73011304F542A
     • View In Article
229. US Department of Health and Human Services, National Center for Research Resources, National Institute of Health . [homepage on the Internet]. Available from: http://www.ncrr.nih.gov/
     • View In Article
230. National Nanotechnology Infrastructure Network . [homepage on the Internet]. Available from: http://www.nnin.org/nnin_overview.html
     • View In Article
231. Sanhai WR, Sakamoto JH, Canady R, Ferrari M. Seven challenges for nanomedicine. Nat Nanotechnol. 2008;3:242–244
     • View In Article
     • CrossRef
232. Hodgins D, Bertsch A, Post N, Frischholz M, Volckaerts B, Spensley J, et al. Healthy aims: developing new medical implants and diagnostic equipment. IEEE Pervasive Computing. 2008;7:14–21
     • View In Article