Electronic systems for health managementsi2.epfl.ch/~demichel/publications/archive/2015/Handbook...42 Electronic systems for health management Giovanni De Micheli 42.1 Introduction

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Electronic systems for healthmanagementGiovanni De Micheli

42.1 Introduction

Several important societal and economic world problemscan be addressed by the smart use of technology. The past40 years have witnessed the realization of computationalsystems and networks, rooted in our ability to craft complexintegrated circuits out of billions of electronic devices.Nowadays, the ability to master materials at the molecularlevel and their interaction with living matter opens upunforeseeable horizons. Networking biological sensorsthrough body-area, ad hoc and standard communicationnetworks boosts the intrinsic power of local measurements,and allows us to reach new standards in health manage-ment. The Swiss Nano-Tera program addresses applica-tions of nanotechnologies to health management, and ithas been instrumental in fostering research and innovationin this domain.

42.2 The Nano-Tera program

Nano-Tera addresses system engineering research thatleverages micro-, nano-, information, and communica-tion technologies. The broad objectives of the programare both to improve quality of life and security of peopleacross different levels of education, wealth and age, andeventually to create innovative products, technologiesand manufacturing methods, thus resulting in job andrevenue creation. Although the principal applicationdomains are health and environment, energy and securityissues are also investigated as support areas. The intrinsicvalue of the underlying research is to bridge traditional

disciplines, including electrical engineering, micro/nano-mechanical systems engineering, biomedical sciences,and computer/communication sciences, with the objec-tives of (i) deepening the understanding of enablingtechnologies, (ii) reducing scientific concepts to practice,and (iii) mastering the novel challenges of designinglarge-scale complex systems.

The Nano-Tera program was launched by the Swissgovernment in 2008. After a first 5-year phase devoted tothe search of enabling technologies, a second phase startedin 2013 with a focus on applying new technologies tosystems. The governmental funding rate is approximatively15M USD/year. This funding is matched by an equalamount provided by the partner institutions and by thirdparties (e.g. industry). Nano-Tera has been established as asimple partnership, which enables universities and researchcenters to provide a neutral platform for collaboration anddevelopment.

Nano-Tera distributes money for funding projectson a competitive basis, and the Swiss National ScienceFoundation provides it with proposal reviews for qualitycontrol. Nano-Tera funded 19 large projects during thefirst phase, and 18 new large projects are starting underphase two in 2013. A similar number of small projects andeducation/dissemination events are also supported. Morethan 80% of the total funds are dedicated to the large proj-ects, dubbed Research, Technology and Development (RTD)projects, which, by construction, involve multi-discipline,multi-institutional teams of researchers addressing cuttingedge topics within the program scope. Typically, these

Handbook of Bioelectronics, Sandro Carrara and Krzysztof Iniewski. Published by Cambridge University Press.© Cambridge University Press 2015.

projects require a strong investment which is not readilyavailable from other funding sources. A total of about 700researchers participate in the RTD projects and about 120doctoral theses are supported by the program at the timeof writing (Q1 2013). This chapter provides a glimpse ofthe current RTD projects addressing health management.A detailed description and statistics of these and otherprojects are available online [1], as well as citations tospecific scientific work.

42.3 Health management technologies

Future health management systems will require an increas-ingly large presence of automation, information extraction,and elaboration, as well as control of themedical procedures.In essence, we can envision three major areas that requireinnovation: (i) real-time sensing and data acquisition ofbio-chemical compound concentrations; (ii) informationnetworking through a specialized physical layer; (iii) dataelaboration, retrieval, and classification.

Sensing is a discipline that traditionally has beendeveloped by communities related to fundamental scien-ces (e.g., physics, chemistry, and biology). Despite thelarge number of sensors available, their effective use islimited by size, power consumption, and lack of effectiveintegration with electronic and information systems. Inother words, sensing is still based on discrete compo-nents, in much the way that a transistor radio wasassembled 50 years ago. The integration of sensing withelectronics, and thus the merging of sensing and elec-tronic design, is key to achieving miniaturized, low-power, low-noise data acquisition chains with detectionlimits in regions of interest for clinical studies. To date,only glucose monitoring has reached some form of matur-ity, and FDA-approved devices are available for diabeticpatient monitoring.

The challenges of biomedical electronic systems arerelated to both data acquisition and communication.Indeed, sensors in the body need to communicate to exter-nal devices. Power delivery means can obviate the need forimplanted batteries, which always present some risk factor.Sensors on the body communicate through body-area net-works (BAN), a new technology with several challenges,including energy efficiency, bandwidth, and security.Biocompatibilty and the selection of materials and relatedtechnologies are also important topics of research.

Information systems for biomedical applications havebeen developed, but they are typically used offline. Theneed for fast responses and their secure interaction withelectronics on the body and/or in the body is still an area ofresearch. Nevertheless, the combination of networked data-bases with online data acquisition chains opens the door tobetter therapy as well as to promoting the autonomy of thepatient and convalescent.

42.4 Sensing and diagnosis

42.4.1 Biosensing

Biosensors are used in the medical practice for online andoffline diagnosis. Few systems for online monitoring areavailable on the market. Monitoring metabolism is a com-plex and expensive process, mainly because of the unavail-ability of accurate, fast, and affordable sensing devices thatcan detect and quantify multiple compounds in parallel andseveral times a day. To date, most medical systems availableon the market for human telemetry use wearable devices(accelerometers, heartbeat monitoring system, etc.) butthey do not measure molecular metabolites. The only avail-able real-time, implantable/wearable systems for metaboliccontrol are limited to glucose monitoring in diabeticpatients. For other pathologies, molecules are monitoredin daily hospital practice by means of blood sampling andoffline analysis. This requires large and expensive labora-tory equipment. Offline bio-measurements are achieved bya wide array of techniques. Still, there is a strong potentialfor improvement, by exploring various sensing mech-anisms, using advanced electronic devices and materials,and tightly coupling electronic sensing to data acquisitionchains.

The i-IronIC project (Figure 42.1) addresses an innova-tive, highly integrated, fully implantable and real-timemon-itoring system for human metabolism. The monitoredmetabolic molecules are lactate, cholesterol, ATP, gluta-mate, glucose, and others. The system to be realized con-sists of: (i) an implantable integrated sensor array and dataacquisition electronic unit; (ii) a wearable station for remotepowering and signal processing; (iii) a remote station for

Figure 42.1 The i-IronIC implantable sensor. Courtesy of S. Carrara.

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data collection and storage. The main scientific challenge isrelated to fabricating the implant to be housed in a bio-compatible cylinder of about 2 mm in diameter and 15 mmin length, to be placed in the interstitial tissue. The currentprototype includes: a sensor array, a CMOS mixed signalchip, and a tridimensional integrated coil for receivinginductive power and transmitting data via backscattering.The sensor array is realized with an innovative technology,in which carbon nanotube (CNT)-nanostructured elec-trodes enable us to measure metabolites with increasedsensitivity and lower detection limits as compared withthe state of the art. The integrated electronic and sensorarray requires 0.5 mW to operate: the electronic power isharvested by the coil. An electronic patch on the bodyproduces the inductive field to power the implant, receivesthe backscattered data, and transmits it to a base stationusing the bluetooth standard.

The NanowireSensor project seeks to develop a modu-lar sensor platform for the electronic detection of analytes insolution. The platform uses silicon nanowire (SiNW) field-effect transistors as a sensor array and combines them withstate-of-the-art microfabricated interface electronics as wellas with microfluidic channels for liquid handling. Suchsensors have the potential to be mass manufactured atreasonable costs, allowing their integration as the activesensor part in electronic point-of-care diagnostic devices.The platform can be used for offline analysis of substancesat very low concentrations. While promising biosensingexperiments based on SiNW field-effect transistors havebeen reported, real-life applications still require improvedcontrol, together with a detailed understanding of the basicsensing mechanisms. For instance, it is crucial to optimizethe geometry of the wire, a still rather unexplored aspect upto now, as well as its surface functionalization or its selec-tivity to the targeted analytes.

The IrSens project aims at building a platform basedon optical spectroscopy in the near and mid-infraredrange, by exploiting optical absorption properties of theanalytes. The sensors probe the vibrational frequencies ofthe targeted molecules of gases and liquids. The sensingplatform for gases under development is based on multi-path absorption cells with various semiconductor lightsource and detector types. In particular the platform candetect Helicobacter pylori, a bacterium responsible forgastric ulcers, by means of isotopic ratio measurementsin exhaled CO2. The integrated sensing platform forliquids is based on wave-guiding and surface measure-ment technologies, and the same sources and detectors asfor the gas sensing. The sources are coupled to a silicon-based optical module where the liquid analyte flowsthrough a built-in microfluidic channel (Figure 42.2).This is intended to be used for the detection of drugsand doping agents in human fluids, such as cocaine inhuman saliva.

42.4.2 Advanced diagnosis tools

Advanced diagnosis relates to the design of new methodsfor probing the human body as well as making diagnosistools portable and available at points of care. The miniatur-ization of diagnosis equipment often requires the use ofnew technologies, and opens the way to radically newprocedures.

The Nexray project targets the development of novelsmall X-ray sources and detectors whose outputs will becombined to new image processing systems. The miniatur-ized X-ray sources are based on multi-walled carbon nano-tube (MWCNT) cold-electron emitters. Unlike classicalthermionic emission, field electron emission of the CNTis voltage-controlled, and thus enables high modulationfrequencies up to GHz level. The X-ray direct detectorsare based on crystalline germanium absorption layersgrown directly on a CMOS sensor chip, yielding high-resolution and high-sensitivity X-ray detectors. Single pho-ton detection enables a significant improvement of contrast.Moreover, the direct integration of germanium absorptionlayers into CMOS sensors results in on-pixel signal pre-processing capabilities, which can be exploited for variousapplications (Figure 42.3).

The outcome of this project relates to two radical newapproaches to X-ray imaging. First, X-ray time-of-flight(XTOF) measurements can be used to probe the depthinside objects. This calls for an intensity-modulated X-raysignal in the MHz range which is not possible with conven-tional X-ray sources but can be achieved with CNT-basedcold emitters. Second, we can achieve tomographic imagingby exploiting the fact that both the X-ray source and theX-ray detector are pixelated. Indeed, the X-ray source isbuilt as a matrix of micro X-ray sources that can be

Figure 42.2 Printed circuit board to interface with fabricatedCMOS chip and to connect it with the silicon nanowire chip.Courtesy of C. Schöneberger.

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addressed and controlled individually. The combination ofpixelated X-ray sources and detectors opens up completelynew imaging capabilities.

The PATLiSCi project aims at investigating diagnosis oftissues based on micromechanical sensing (Figure 42.4).Scanning force microscopy and related techniques enablehigh-resolution imaging e.g. of membrane proteins, offer-ing unprecedented insights into their structure and theirfunctioning. Interestingly, it has been shown recently thatthe stiffness of cancer cells affects the way they spread in thebody. Equally important are the adhesion forces of cancercells to other cells. The measurement of nanomechanicalproperties of cells as well as cell–cell interactions as a func-tion of milieu parameters is thus of particular interest incancer research. The nanomechanical properties of micro-cantilevers allow us to use them as highly sensitive probesfor the detection of molecular species adsorbed to them.The additional mass and/or the surface stress exerted by the

adsorbents changes the mechanical properties, such astheir bending or their resonance frequency, and can bereadily detected. This method is often described as amechanical nose, since many of these cantilevers in paral-lel, each responsible for the detection of a specific targetsubstance, detect an ensemble of substances. The nano-mechanical nose mirrors the design of the human olfac-tory system, where mechano-transduction in olfactorycells is coupled to the biological neural network, i.e. thebrain. The old medical art of diagnosing disease by itsodor, limited by observer dependence, lack of quantitativeanalysis, and the limited sensitivity of the human nose,thus finds its correlation in nanomedicine, where nano-mechanical olfactory sensors enable quantitative andobjective analysis of carcinogenic diseases in point-of-care early diagnostics.

The NutriChip project aims at building an integratedlab-on-a-chip platform to investigate the effects of foodingestion by humans (Figure 42.5). The core of the systemis an integrated chip, the NutriChip, which, as a demon-strator of an artificial and miniaturized gastrointestinaltract, will be able to probe the health potential of dairyfood samples, using a minimal biomarker set identifiedthrough in vivo and in vitro studies. The project exploitsinnovative CMOS circuits at the nanoscale for high signal-to-noise ratio optical detection and proposes a specialmicrofluidic system closely integrating cell-based materialswithin the chip. The NutriChip will be tested for screeningand selection of dairy products with specific health-promoting properties.

42.5 Medical care support

42.5.1 Electronic textiles

Electronic textiles provide us with a very interesting func-tional material for realizing body-area networks. Moreover,

Figure 42.3 IrSens fluid detection: first fully integrated prototype for cocaine detection in saliva. Courtesy of J. Faist.

Figure 42.4 Test X-ray source. Courtesy of A. Domman.

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electronic textiles can merge both sensing and communi-cation in the same medium.

The TecInTex project aims at the development of textile-based advanced (electrical/optical) fibers incorporatingsensors, signal transmission, and other active nano-components (Figure 42.6). The research objectives are todevise both: (i) a family of new functional fibers, enablingin situ measurements of body functions like continuouselectrocardiograph (ECG) monitoring and biological speciesin body proximity; and (ii) approved fabrication processes

and working prototypes dedicated for healthcare, rehabil-itation, and prevention. A demonstrator of this technologyis embodied by electronic underwear for paraplegics, whotypically suffer from pressure ulcers twice a year on aver-age. With intelligent textiles, ulcers can be prevented, withan important reduction of pain and associated healthcarecosts. The research includes development of biosensingoptical fibers and the design of a prototype for testing thefibers. Biosensing fibers are obtained by modifying stand-ard optical fibers with a sensitive, porous layer specific torelevant biomarkers. Detection is based on optical trans-mission changes: for example pH sensing fibers weredeveloped by replacing the cladding of the fiber over alength of 2–6 cm with a porous sol-gel layer encapsulatingpH sensitive dyes. pH changes result in color changes ofthe layer, which are detected by measuring absorbancechanges at the wavelength of maximum absorbance. Anoptical source, a photodetector, and a trans-impedanceamplifier are needed to convert light into photocurrentand eventually into a voltage for further signal processing.This trans-impedance amplifier is integrated into thetextile, as close as possible to the photodetector, to reducethe noise influence.

42.5.2 Smart prostheses

Over one million hip and knee prostheses are implantedeach year in the European Union and the United States. Theexpected lifetime for these prostheses is between 10 and 20years, but premature failure is quite common (about 20%for people less than 50 years old). Prosthesis failures requirerevision surgeries that are generally complex and traumatic.None of these prostheses contains microchips, and few areanalyzed based on motion analysis devices.

Figure 42.5 NutriChip principle: schematic of the microfluidic PDMS chip forming the microfluidic gastro-intestinal tract. Courtesy of M. Gijs.

Figure 42.6 Microcantilevers of the PATLiSCi project. Courtesy ofH. Heinzelman.

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The SYmOS project seeks to design innovative tools tomeasure in vivo biomechanical parameters of joint pros-theses, orthopaedic implants, bones, and ligaments. Thesetools, partly implanted, partly external, will record and ana-lyze relevant information in order to improve medical treat-ments. An implant module includes sensors to measure theforces, temperature sensors to measure the interface fric-tions, magneto-resistance sensors to measure the 3D ori-entation of the knee joint, and accelerometers to measurestem micro-motion and impacts. An external module, fixedon the patient’s body segments, includes electronic compo-nents to power and to communicate with the implant, aswell as a set of sensors for measurements that can berealized externally. This equipment is designed to help thesurgeon with the alignment and positioning phase duringsurgery. After surgery, the prostheses will allow the surgeonto detect any early migration and potentially avoid failure byproviding information on excessive wear and micro-motion. During rehabilitation, it will provide useful data toevaluate in vivo joint functions. The tools provided can alsobe implanted during any joint surgery in order to give thephysician the information needed to diagnose future dis-ease such as ligament insufficiency or osteoarthritis, orprevent further accident. Although the scientific and tech-nical developments proposed in this project can be appliedto all orthopaedic implants, the technological platformwhich is being built as a demonstrator is limited to thecase of knee prosthesis (Figure 42.8). In addition, by reach-ing theminimum size achievable thanks to clever packagingtechniques and also by reducing, or even removing, thecumbersome battery, it paves the way for a new generationof autonomous implantable medical devices.

42.5.3 Drug delivery

Medical progress is increasingly improving the survivalrate and life quality of patients affected by serious

life-threatening conditions, such as HIV infection, dissemi-nated cancers, and/or vital organ failure. These achievementsrely significantly on new radical improvements in drug regi-mens and therapeutic protocols. Newly adopted treatmentsfor such diseases require the daily administration of highlyactive therapies in the long term. The huge variability rangein drug response poses strong limits and severe problems indrug treatment definition. The largest part of variability indrug response (roughly 80%) resides in the pharmacokineticphase, i.e. in dose–concentration relationships.

The ISyPeM project aims at providing advanced tech-nologies for assessing drug response by measuring drugconcentrations and relevant biomarkers. In particular, itaims at providing drug treatment optimization based onprocessing of statistical and personal data, and to enableseamless monitoring and delivery by an ultra-low-powerintegrated system. Thus it is the purpose of the projectto create new enabling technologies for drug monitoringand delivery control rooted in the combination of sensing,in situ data processing, short-range wireless communica-tion, and drug release control mechanisms. These newtechnologies, in combination with currently available med-ical devices (micro-pumps, micro-needles, etc.) can signifi-cantly improve medical care and reduce the related costs.Targeted application domains are HIV infection, cancerdiseases, and post-transplant therapies, which are currentlyaddressed by the research in pharmacokinetics carried outat the regional hospital CHUV in Lausanne.

42.6 Summary and conclusions

Advances in sensing technology, nanoelectronics, dataprocessing and communication enable the design of newhealth monitoring and management systems. Research inthese area is multifaceted, and can only be achievedthrough the collaborative effort of various groups withdiversified competences. The Nano-Tera.ch program has

Figure 42.7 Configuration of implanted and external antennas.Courtesy of P. Ryser.

Figure 42.8 Electro-optical textile fabric. Courtesy of G. Troester.

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spearheaded some important challenges in these domains.It is unique as a research funding program because it cre-ates a fabric of scientists and engineers whose combinedeffort can meet the various challenges.

Acknowledgements

This author acknowledges and thanks the Nano-Tera.chcommunity of researchers for their contributions to

engineering and technology. The author acknowledgesalso the sustained support of the Swiss Governmentto this program, and the valuable help of Dr. PatrickMajor in elaborating the information on Nano-Tera.chprojects.

Reference

[1] www.nano-tera.ch

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