It is widely recognized that the welfare of the most advanced economies is at risk, and that the only way to tackle this situation is by controlling the knowledge economies. To achieve this ambitious goal, we need to improve the performance of each dimension in the "knowledge triangle": education, research and innovation. Indeed, recent findings point to the importance of strategies of adding-value and marketing during R+D processes so as to bridge the gap between the laboratory and the market and so ensure the successful commercialization of new technology-based products.
Moreover, in a global economy in which conventional manufacturing is dominated by developing economies, the future of industry in the most advanced economies must rely on its ability to innovate in those high-tech activities that can offer a differential added-value, rather than on improving existing technologies and products. It seems quite clear, therefore, that the combination of health (medicine) and nanotechnology in a new biomedical device is very capable of meeting these requisites.
Nanotechnology provides breakthroughs that support endless sources of innovation and creativity at the intersection between medicine, biotechnology, engineering, the physical sciences and information technology, and the discipline is opening up new directions in R+D, knowledge management and technology transfer. A number of nanotech products are already in use and analysts expect markets to grow by hundreds of billions of euros during the present decade. After a long R+D incubation period, several industrial segments are already emerging as early adopters of nanotech-enabled products1 (Fuji-Keizai, 2007); in this context, surprisingly rapid market growth is expected and high mass market opportunities are envisaged for targeted research sub-segments. Findings suggest that the Bio&Health market will provide some of the greatest advances over the next few years and that, as a result, the applications of nanoscience and technology to medicine will benefit patients by providing new prevention assays, early diagnosis, nanoscale monitoring, and effective treatment via mimetic structures. Doubtless, there are considerable challenges in the design of nanostructures which can operate reliably over extended timescales in the body.
The scale-length reduction that has been achieved through nanosynthesis (bottom-up technology) and nanomachining (top-down technology) has the potential to interact with the biological world as never before. The bio-nanotechnologies operate at the interface between organized nanostructures and biomolecules, which are key control routes for achieving new breakthroughs in medicine; dentistry and therapeutics; in food of animal and vegetable origin; and in daily care products such as cosmetics. According to the GENNESYS White Paper (2009), this new field of research will provide significant breakthroughs in the near future in the realms of bioreactors, biocompatible materials and lab-on-chip technologies.
Convergence of Technologies in Nanomedicine
nanomedicine is defined as the application of nanotechnology to health. It exploits the improved and often novel physical, chemical, and biological properties of materials at the nanometric scale. Nanomedicine has a potential impact on the prevention, early and reliable diagnosis, and treatment of diseases. In the nanomedicine case, there is a wide range of technologies that can be applied to medical devices, materials, procedures, and treatment modalities. A closer look at nanomedicine introduces emerging nanomedical techniques such as nanosurgery, tissue engineering, nanoparticle-enabled diagnostics, and targeted drug delivery. Still in its infancy, much of the work in the discipline involves R+D and it is, therefore, crucial that health institutions, research institutes and manufacturers work together efficiently.
In particular, multidisciplinary research groups and technology transfer offices are playing a key role in the development of new nano-enabled implantable biomedical devices through an advanced understanding of the microstructure/property relationship for biocompatible materials and of their effect on the structure/performance of these devices. To proceed further, a general framework is required that can facilitate an understanding of the technical and medical requirements so that new tools and methods might be developed. Moreover, in medicine there is a pressing need to ensure close cooperation between University-Hospital-Industry-Administration while specific tools and procedures are developed for use by clinicians. Drawing on the experience of the authors, in this case study we seek to demonstrate the importance of cooperation and collaboration between these four stakeholders and the citizens involved in the innovation process leading to the development of new biomedical products ready for the market.
The interaction between medicine and technology allows the development of diagnostic devices to detect or monitor pathogens, ions, diseases, etc. Today, the integration of rapid advances in areas such as microelectronics, microfluidics, microsensors and biocompatible materials allows the development of implantable bio-devices such as the Lab-on-Chip and the Point-of-Care devices2,3. As a result, continuous monitoring systems are available to develop faster and cheaper clinical tasks - especially when compared with standard methods. It is in this context that we present an integrated front-end architecture for in-vivo detection.
The Biomedical Device for in-Vivo Analysis
The system introduced in this paper is designed to be implanted under the human skin. The powering and communication between this device and an external primary transmitter are based on an inductive link. The architecture presented is designed for two different approaches: defining a true/false alarm system based on either amperometric or impedance nano-biosensors. Among the diseases that might be monitored by in-vivo analysis, it is the aim of this paper to focus on diabetes given that its incidence and prevalence is increasing worldwide, reflecting lifestyle changes and aging populations. Specifically, this growing prevalence is closely linked to that of obesity, creating significant market opportunities as reported in the World Diabetes Market Analysis 2010-20254, and, especially, because the World Health Organization estimates that the number of diabetics will exceed 350 million by 2030.
For this in-vivo implantable biomedical device, we also examine an ambitious approach that covers the entire value chain (from basic research, through engineering and technology, to industry), the infrastructure required and the implications for society of these and similar current market challenges. In this instance, the entire value chain is hosted by the university system, which highlights the social turnover of public research investment. We also consider the extent to which recent technological innovations in the biomedical industry have been based on academic research, and the time lags between investment in such academic research projects and the industrial application of their findings - i.e., so as to estimate the social rate of return from academic research. Because the results of academic research are so widely disseminated and their effects so fundamental, subtle and widespread, it is often difficult to identify and measure the links between academic research and industrial innovation. Nevertheless, there is convincing evidence, particularly from industries such as drugs, instruments, and information processing, that the contribution of academic research to industrial innovation has been considerable5.
State-of-the-Art Innovative Biomedical Device
Many different problems need to be overcome in obtaining the ideal implantable device6. First and foremost, the device must be biocompatible to avoid unfavorable reactions within the body. Secondly, the medical device must provide long-term stability, selectivity, calibration, miniaturization and repetition, as well as power in a downscaled and portable device. In terms of the sensors, label-free electrical biosensors are ideal candidates because of their low cost, low power and ease of miniaturization. Recent developments in nanobiosensors provide suitable technological solutions in the field of glucose monitoring7, pregnancy and DNA testing8. Electrical measurement, when the target analyte is captured by the probe, can exploit either voltmetric, amperometric or impedance techniques. Ideally then the device should be able to detect not just one target agent or pathology, but rather different agents and it should be capable of working in a closed-loop feedback, as described by Wang9 in the case of glucose monitoring.
Several biomedical devices for in-vivo monitoring are currently being developed. Thus, highly stable, accurate intramuscular implantable biosensors for the simultaneous continuous monitoring of tissue lactate and glucose have recently been produced, including a complete electrochemical cell-on-a-chip. Moreover, with the parallel development of the on-chip potentiostat and signal processing, substantial progress has been made towards a wireless implantable glucose/lactate sensing biochip10. Elsewhere, implantable bio-micro-electromechanical systems (bio-MEMS) for the in situ monitoring of blood flow have been designed. Here, the aim was to develop a smart wireless sensing unit for non-invasive early stenosis detection in heart bypass grafts11. Interestingly, this study examines the use of surface coatings in relation to biocompatibility and the non-adhesion of blood platelets and constituents. In this case, nanotechnology presents itself as being a useful tool for improving the biocompatibility of silicon bio-MEMS structures when nanoscale metallic titanium layers are used, since it enhances biocompatibility.
The next step involves developing a configurable application-specific integrated circuit (ASIC) working with a multiplexed array of nanosensors designed to be reactive for a set of target agents (enzymes, viruses, molecules, chemical elements, molecules, etc.). Multiple sensors of the array can then be used for one specific target, while other arrays can be prepared for the other targets, while also seeking a redundant response. Thus, a panel of biomarkers needs to be developed. In this way, the reproducibility and accuracy can be improved for each target, and different targets can be assayed simultaneously. The configuration capacity of the ASIC should also be defined in terms of the type of measurement that is to be conducted, as in the studies undertaken by Hassibi and Lee12 and Beach et al.13: it could be amperometric, measuring current variations and detecting threshold values14, or it could be electrochemical impedance spectroscopic, for a fixed frequency, detecting both impedance variations crossing threshold values and anomalies.
The combination of both techniques of measurement could be used to obtain a more reliable method of detection. Power and communications are also key features in the design of implantable devices. The former is concerned with methods of transferring sufficient energy to the devices, whereas the latter involves the integration of instrumentation and communication electronics to control the sensors and to send the information provided by the sensors through human skin. However, if the detection of vital signs or the threshold detections are sufficient for monitoring purpose, it is not necessary to measure and send raw data with a high degree of accuracy from the user to an external data processing unit. Indeed, local processing within the same sensor would reduce power and communication requirements.
RF power harvesting through inductive coupling is an increasingly used alternative for transmitting energy to the implanted device, as opposed to using batteries or wires15,16. Furthermore, this alternative permits a bidirectional communication to be established between the implanted device and an external base or reader. A number of implantable telemetry circuits based on inductive coupling can be found in the literature17,18,19. By contrast, several studies have developed integratable electronics for in-vivo monitoring. Examples of this are provided in the studies by Gore et al.20, where femtoampere-sensitivity applications for conductometric biosensor are used, and by Haider et al.21, where a signal processing unit based on a current-to-frequency converter and a communication protocol is presented.
Architecture of the Implantable Device
At this juncture, the architecture presented represents an initial approach for the development of applications based on biosensors aimed at detecting the presence or absence of certain levels of proteins, antibodies, ions, oxygen, glucose, etc. These in-vivo detection circuits, or true/false applications20, work as an alarm. When the concentration level under analysis falls outside a range of accepted values, a threshold value activates the alarm. For instance, in the case of glucose monitoring, the detection of a threshold decrease in glucose levels would be mandatory for avoiding critical situations such as hypoglycaemia21,22. Such detection would be achieved when the amplitude of the measured signal falls below a specified threshold value.
Various approaches have been developed for the continuous monitoring of glucose23. These range from commercial solutions such as the blood glucose tester marketed by Cygnus Inc. to subcutaneous Minimed Medtronic and Abbott Inc. solutions that control the glucose level every 3-5 minutes. These devices, placed just under the skin, have a closed-loop control to deliver insulin and enjoy an autonomy of 3-5 days. Solutions that seek minimum biological impact so as to resist biofouling include an inhibitor (nitric oxide)24 in addition to coated needle-type electrochemical sensors25,26,27.
The generic implantable, front-end architecture is based on inductive coupling for the in-vivo monitoring of the presence or absence of pathogens, ions, oxygen concentration levels, etc.
Fig. 1. Conception of the implantable device.
The system in Fig.1 shows a platform with a true/false alarm for the monitoring of different targets. The data are transferred to a central database where all the inputs can be personalized for each patient. The data collected can be measured in different scenarios: when the patient is at rest, undertaking a certain type of physical activity, etc., depending on the particular medical interest, and hence an accurate prognosis and diagnosis can be obtained28. The system has a research application in the constant monitoring of patients as they carry out their daily activities in normal conditions (outdoors) and in this way secondary effects such as the psychological alterations caused by the stress of being in a hospital, with unknown people, etc. can be avoided. The proposed architecture (see Fig.2) is at this stage analyzed as a threshold detector for one sensor, working amperometrically, and includes on-chip biasing, the potentiostast to drive the biosensor, a conditioning module, and the modulation and data-processing block. The conditioning module is designed to adapt to the level of the signals measured. The detection of targets using the threshold methodology needs to guarantee sufficient signal level so as to ensure a sufficiently high signal-to-noise ratio (SNR).
This modulation and data processing block is designed to analyse and send to the external reader the levels it detects. Two different approaches are defined: a generic amperometric biosensor application and an impedance biosensor, for label-free systems, based on an integrated analogue lock-in amplifier, which will proceed with analogue processing on the sensor for detection and transmission. For future implementation, this module will be designed so that it can be re-configured.
To validate the first proposal (amperometric), a full custom IC has been designed including several modules of the architecture and a PCB-transponder antenna (30 mm x 15 mm), tuned to 13.56MHz, to provide the power and communication link. The design also incorporates an integrated analogue lock-in amplifier in case of impedance detection.
The proposal for the generic implantable architecture is presented in Fig. 2. It comprises a nanobiosensor, an antenna and the electronic modules.
Fig. 2. Proposed generic implantable front-end architecture.
nanobiosensor or nanosensor is generally defined as a nanometer size scale measurement system comprising a probe with a sensitive biological recognition element, or bioreceptor, a physicochemical detector component, and a transducer in between. Two types of nanosensors with potential medical applications are cantilever array sensors and nanotube/nanowire sensors and nanobiosensors, which can be used to test nanoliters or less of blood for a wide range of biomarkers. In our work, a nanobiosensor with three electrodes has been selected to explain and develop the system. Its topology can be readily adapted for any kind of sensor. The three electrodes making up the sensor are: a) the working electrode (W), which serves as a surface on with the electrochemical reaction takes place; b) the reference electrode (R), which measures the potential at the W electrode, and c) the auxiliary or counter electrode (A/C), which supplies the current required for the electrochemical reaction at the W electrode.
The system is designed as a wireless powered active RFID Tag29,30 where the inductively coupled link, generated by the implantable and the external antenna, is able to supply enough energy to power the entire system and to provide wireless bidirectional communication through the human skin. Thus it can transmit the information obtained by the nanobiosensor and receive data from the external reader who in turn can configure the implanted electronics and read the data acquired.
The Choice of the Nanobiosensor
The most promising solution for an effective nanobiosensor involves using the electrochemical impedance spectroscopy (EIS) technique. EIS represents a more effective method for probing the interfacial properties of the modified electrode by measuring the change in electron transfer resistance at the electrode surface due to the adsorption and desorption of chemical or biological molecules. Several studies have been published on this subject. The classical approach is the ELISA test31, based on the use of semiconducting polymers and the use of the EIS technique, while polystyrene (PS) is the typical insulating polymer used in biomedical research.
A widely reported application is the glucose biosensor32,33,34, which is based on the electron transfer that occurs during the enzymatic reduction of glucose. In recent years, several studies have been published in this field, including Patel et al.35 who present an electro-enzymatic glucose sensor. Other interesting studies are provided by Huang et al. (2009), who introduce a capacitively based MEMS affinity sensor for continuous glucose monitoring applications; Teymoori, Mir Majid et al., who describe a MEMS for glucose and other generic sensors with medical applications; and Rodrigues et al.36, who developed a new cell-based biochip dedicated to the real-time monitoring of transient effluxes of glucose and oxygen, using arrays of amperometric microsensors integrated in the inlet and the outlet of a PDMS cell chamber.
A complete design is provided by Rahman et al.37, who present the design, microfabrication, packaging, surface functionalization and in vitro testing of a complete electrochemical cell-on-a-chip (ECC) for the continuous amperometric monitoring of glucose, performing cyclic voltammetry, electrical impedance spectroscopy (EIS) and microscopic examination.
Various examples of the development of nanosensors for application in this field are reported by Usman Ali et al.38. Here ZnO Nanowires are used for a GCM application directly connected to the gate of a standard low-threshold MOSFET. Lee et al.39 design a flexible enzyme-free glucose micro-sensor with a nanoporous platinum working electrode on a bio-compatible PET film. Goud et al.40 introduce a nanobioelectronic system-on-package (SOP) with an integrated glucose sensor based on carbon-nanotube working electrodes. Jining Xie et al.41 suggest platinum nanoparticle-coated carbon nanotubes for amperometric glucose biosensing; and Ekanayake et al.42 describe the manufacture and characterization of a novel nano-porous polypyrrole (PPy) electrode and its application in amperometric biosensors, with enhanced characteristics for glucose sensing.
Nanobiotechnology and Nanomedicine
Scientific Policies and Global Investment
The availability of in-vivo biomedical devices, such as the one described above, is closely linked to advances in nanobiotechnology. Nanotechnology is expected to have a rapid impact on society43: creating future economic scenarios, stimulating productivity and competitiveness, converging technologies, and promoting new education and human development. Evidence of this rapid impact of nanotechnology can be seen in government investment figures for nanotechnology R+D activities, facilities and workforce training. The 2008 US National Nanotechnology Initiative budget request for nanotechnology R+D across the Federal Government was over US$1.44 billion (NNI, 2007). In Europe, the VIIth Framework Programme (FP) will contribute about €600 million per year to nanotechnology research until 2013, with an additional, similar amount being provided by individual countries. This gives Europe a larger yearly expenditure on nanotechnology than the United States or Japan44.
In the context of European policy, N&N is a key area for the European Commission: the VIIth FP (2007-2013) provides a specific program for the nanosciences, nanotechnologies, materials and new production technologies with a budget of €3,475 million (10.72% of the VIIth FP total budget). Moreover, several specific programs are involved in nanoscale research, and thus the total budget invested in nanoactivities will be increased by several thousands of €millions (Meur) coming from the following programmes: Health (6 100 Meur); Food, agriculture and biotechnology (1 935 Meur); ICT (9 050 Meur) and Energy (2 350 Meur)
Nano-Related Papers and Patents
Several overviews and comparative studies of the worldwide expansion of nanopublications and nanopatents are available45,46,47. Scientific papers and patents in the nanotechnology sector have grown exponentially over the last two decades. The relative growth in number of "nano-title-papers" in various bibliographic databases, i.e. the increase in the number of "nano-title-papers" as a proportion of all papers has been dramatic: if we take the Science Citation Index as being representative of all the sciences (albeit that chemistry is somewhat underrepresented), the proportion of "nano-title-papers" grew from 1985 to mid-2003 by about 1.2% at an average annual growth rate of about 34%, which means it has doubled every 2.35 years. Since the mid-1990s the speed has slowed somewhat to an annual growth rate of about 25% (doubling every 3.1 years)48.
In 2007 over 15,000 nanoscience and nanotechnology-related papers were published, and there is now intense activity as regards intellectual property (IP) - the ownership of innovations, inventions, ideas and creativity - in the nanoscale field. Nanotechnology is increasing the shift towards a knowledge-oriented economy and so intellectual property is in a position to increase wealth creation, growth and development across the world49. Several reports have sought to map nano-related patents50, and figures for nanotechnology-related IP are startling. In the European Patent Office a nanotechnology working group (NTWG) was created in 2003 and 90,000 patents were tagged to class Y01N. The proportion of nanotechnology patents more than doubled between the mid-1990s and the mid-2000s (USA 40%, Japan 19%, and Germany 10%). The Compendium of Patent Statistics 200751 provides internationally comparable data on patents.
Before 1980, 250 nanotechnology-related patents were granted annually to universities worldwide, but by 2003 this number had increased 16-fold to 3,993 patents, which have been filed for the fundamental building blocks, materials and tools required to develop this technology. The US patent office has received applications regarding the composition of matter, devices, apparatus, systems and control of nanomaterial and devices, and methods. Cross-industry patent claims are being made for single nanoscale innovations that may have diverse applications. Thus, applications have been identified in major patent classes such as electricity, human necessities, chemistry and metallurgy, performing operations and transporting, mechanical engineering, physics, fixed construction, fabrics and paper. In order to analyze the impact on the industrial sector, the OECD has categorised nanotechnology patents into six fields of application: Electronics, Optoelectronics, Medicine and biotechnology, Measurements and manufacturing, Environment and energy, and Nanomaterials.
As the research of Miyazakia52 revealed, universities account for a particularly large share of the research in nanotechnologies (representing 70.45% of nanotech-related research worldwide). In this they are complemented by public research institutes (who account for 22.22% of articles). Thus, it is estimated that universities now hold 70% of key nanotechnology patents. The private sector plays a more limited role (7.33% of articles globally), but it is a more prominent player in the US (12.41%). In Asia, Japan holds a strong share (12.30%) in the private sector, while South Korea (8.25%) and to a lesser extent India (3.52%) compete with Japan. In the future, nanotechnology development is likely to shift from large publicly funded organizations and universities to small start-up companies that seek to exploit the earlier publicly funded research efforts to generate the first commercial applications, in a similar way to what we have witnessed in the biotechnology industries.
Research Challenges for Nanobiotechnologies
Nanobiotechnology is a rapidly developing area of scientific and technological opportunity that provides advances in the food industry, energy, environment and medicine. In nanomedicine, there is a wide range of technologies that can be applied to medical devices, materials, procedures, and treatment modalities. A closer look at nanomedicine identifies such emerging nanomedical techniques as nanosurgery, tissue engineering, nanoparticle-enabled diagnostics, and targeted drug delivery.
According to an expert group of the European Medicines Evaluation Agency (EMEA), the majority of current commercial applications of nanotechnology to medicine are devoted to drug delivery. More novel applications of nanotechnology include tissue replacement, transport across biological barriers, remote control of nanoprobes, integrated implantable sensory nanoelectronic systems and multifunctional chemical structures for targeting of disease.
Thus, nanobiotechnology can provide not just the miniaturization of implantable biomedical devices (microfluidics, microelectronics, etc) but also reliable multifunctional arrays for disease detection. There is probably no better example of the technological convergence of the top-down (miniaturization) and bottom-up (design and creation of new functional structures) strategies, which seek the point of equilibrium where technological advances and market demands might meet.
Finally, it has been argued that current nanoscale research reveals no particular patterns and degrees of interdisciplinarity and that its apparent multidisciplinarity consists of different, largely mono-disciplinary fields which are quite unrelated to each other and which have little more in common than the prefix "nano" 48. At this point, the discussion regarding the discontinuous or incremental nature of nanotechnology might arise in the innovation and technology transfer process. Based on the empirical findings of the survey conducted by Nikulainen and Palmberg53, it seems that, at the moment, there is no need for nano-specific technology transfer related initiatives. This conclusion may nonetheless have to be revisited if nanotechnology becomes more radical and discontinuous. Today, chemists developing drugs, reactors and catalysts are working at the nanoscale, as they have for many years, even though they simply refer to their work as chemistry. Certainly, policymakers need to take into account relevant environmental, health and safety issues by setting standards and implementing regulations to facilitate the diffusion of nanotechnology.
Conclusions and Final Recommendations
In this paper, the design of a generic in-vivo implantable biomedical device capable of detecting threshold values for targeted concentrations (i.e. detection of glucose levels) has been presented. Given the speed with which diabetes can spread and the improvements that are possible in its diagnosis and control if needle-free systems are available, the medical device introduced in this paper is designed to reach a huge market over the next few years. Moreover, when the entire value chain is publicly funded, this means that the goals of technology transfer from university to industry and the social returns on the public investment have been fully realized. Thus, a successful model for research, innovation and technology transfer can be introduced to a particular scenario typified by the convergence of technologies and disciplines, as well as by the convergence of various stake-holders combining representatives from research centers, hospitals, market, policy centers and citizens as well.
The complete overview provided here of the value chain of research and technology transfer processes highlights the importance of a common framework in which multidisciplinary teams and organizations can work together directed by determined scientific leadership. In this specific case, the Department of Electronics at the University of Barcelona has had overall charge of the research and commercialization activities. The resulting biomedical device is nano-enabled in a dual sense: when miniaturizing the system (fluidics, electronic, energy autonomy) and when new functional structures are included (nanobiosensors developed by the IBEC). The CIBER-DEM joins the value chain when clinical research and commercialization are considered.
Still an emerging technology, the future ASIC will work with an array of nanobiosensors with different targets, and it will define the configuration of the measurement method. Each array will be used to detect a specific type of target, and the multiplexed system will be used to analyze each array focusing on a particular target. Then, top down approaches using nanoengineering and nanofabrication and bottom up approaches using supramolecular chemistry can produce novel diagnostics which will increasingly focus on delivering a personalized solution based on the analysis of array data in real time, and where appropriate, applying this decision to deliver an automated therapy (theranostics).
In conclusion, despite the somewhat limited availability of information discussing the safety of medical nanomaterials, the case history presented in this paper is a clear demonstration of how to strengthen the bonds between the science community, hospitals and industry. The process described offers an efficient method for performing experiments at large test and clinical facilities, within an innovative framework that takes advantage of new scientific tools and discoveries. Biomedical devices represent a strategic gamble for the future of Spain's scientific and technological policy areas as they seek accelerated economic growth within the knowledge-based society. In this way, the country's regions can strengthen the network links between their R&D agents - science and technology parks, institutes and research centres, hospitals, technology platforms and incubators - as they explore and confront the new scientific and market challenges presented by the nanotech life sciences.
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