Introduction

Several important societal and economic world problems can be addressed bythe smart use of technology. The past 40 years have witnessed therealization of computational systems and networks, rooted in our ability tocraft complex integrated circuits out of billions of electronic devices.Nowadays, the ability to master materials at the molecular level and theirinteraction with living matter opens up unforeseeable horizons. Networkingbiological sensors through body-area, ad hoc and standardcommunication networks boosts the intrinsic power of local measurements, andallows us to reach new standards in health management. The Swiss Nano-Teraprogram addresses applications of nanotechnologies to health management, andit has been instrumental in fostering research and innovation in thisdomain.

The Nano-Tera program

Nano-Tera addresses system engineering research that leverages micro-, nano-,information, and communication technologies. The broad objectives of theprogram are both to improve quality of life and security of people acrossdifferent levels of education, wealth and age, and eventually to createinnovative products, technologies and manufacturing methods, thus resultingin job and revenue creation. Although the principal application domains arehealth and environment, energy and security issues are also investigated assupport areas. The intrinsic value of the underlying research is to bridgetraditional disciplines, including electrical engineering,micro/nano-mechanical systems engineering, biomedical sciences, andcomputer/communication sciences, with the objectives of (i) deepeningthe understanding of enabling technologies, (ii) reducing scientificconcepts to practice, and (iii) mastering the novel challenges of designinglarge-scale complex systems.

Abstract

Recent research in nanobioelectronic devices has opened up a new wave ofenthusiasm in revolutionizing electronic circuit design, marking thebeginning of a new era for biomimicry phenomena to advance into high-densitylogic and memory applications. This chapter describes the formation anddevelopment of a protein-based biomemory device composed of recombinantprotein variants, together with some experimental results on protein filmformation with various readout mechanisms for constructing future memorydevices. To elucidate the concept of the memory device, a redox protein inwhich cysteine residues were incorporated by recombinant technology wasimmobilized on a gold electrode surface. Application of the correctpotentials then causes carrier trapping or detrapping in protein films tooccur, as shown by the electrochemical measurements, thus performing thememory function. The chapter also summarizes recent research on nanoscalebiomemory devices, considering first the basic nature of thewrite-once-read-many (WORM) characteristics. The concept of WORM is thenextended to multi-bit storage of protein variants and towards development ofa nanoscale biomemory device. The fact that these developed devices,operating at very low voltages, can be patterned and addressed locally, andalso have good stability with excellent reversibility, makes them apromising platform for non-volatile memory devices.

We have seen in the different sections of this book that bioelectronics, bornin the early 1990s [1], has expanded over the years into several differentbranches. Bioelectronics now includes molecular components for electronicswith thin-film [2] and protein-based [3] transistors, bio-memories [4],nanogap devices [5] for single-molecule electronics [6], and single enzymesimmoblized on carbon nanotubes [7]. One of its major contributions to thestate-of-the-art of the modern technology is the branch of biosensors, wherebioelectronics has contributed to developing circuits for biomedicalapplications [8, 9], systems based on carbon nanotubes and proteins forapplications in personalized therapy [10, 11], contactless monitors formeasuring respiratory rate [12], and other very smart biomedical devices.Another fascinating branch is the development of biofuel cells based onenzymes [13], even implantable ones [14] that can exploit the body’smetabolism for their energy needs (Figure 44.1 illustrates a famousexperiment in which the energy recovered from the body of a lobster by usingan implanted biological fuel cell is used to power a watch). The moreadvanced developments in the field of electronics, such as epidermalelectronics [15] and memristors [16], have enabled the development ofbiomimetic systems such as electronic skin [17], electronic brains withconventional CMOS technology [18], with memelements [19] orwith organic polymers [20], and the design of synthetic genetic networks[21].

The new possibility of developing electronic skin as well as distributedneural systems brings us immediately to the area of bionics. Severalinnovative implantable devices have been proposed, some already on themarket and others coming soon: artificial cochlea [22], eyes [23, 24],muscles [25], bacteria [26], and even full arms [27] that enable amputees togo back to playing guitar again (Figure 44.2). Human/machineinterfaces have been pushed to the point of sending direct commands from thebrain to artificial arms [28].

Introduction

There is an opportunity for greatly increased synergy between electronics andbiology, fostered by the march of electronics technologies to the atomicscale, and by rapid advances in system, cell, and molecular biology. Theconvergence of biology and electronics has the potential for significantimpacts on many areas important to national economies and well-being,including healthcare and medicine, homeland security, forensics, andprotecting the environment and the food supply. Electrochemical biosensorsare label-free detection, which eliminates the external labels or indicatorsand greatly shortens the assay time. They are widely used for the detectionof protein binding events, hybridized DNA, neuron tissue, bacteria, andenzyme reactions.

Miniaturized sensor arrays are capable of parallel analysis of multipleparameters. Because of the distinct advantages of microsystem platforms,there has been a trend to integrate sensor arrays onto the surface ofsilicon chips and perform measurement using on-chip CMOS electronics[1–3]. At the same time, there is a great opportunity to expandlab-on-a-chip solutions that replace bulky benchtop sample analysis toolswith simple, low-power, portable systems. The fabrication compatibilitybetween many bio/chemical sensor interfaces and CMOS technology makesa CMOS circuit an outstanding candidate for a silicon-based lab-on-chipsolution [4].

The future of bioelectronics has to follow from present electronics andpresent health needs. The present state of electronics is mainly based onpersonal computing (smartphones in our pockets, tablets and laptops in ourhandbags, navigators in our cars, etc.), while the new needs in health arebased on personalization of treatments and therapies. This leads to the newconcept of personal devices for health. Both the academic and the industrialworld have already started targeting this new frontier, and the literaturereflects that. New personal devices to be used directly by patients or onthe patient’s body have been proposed recently: for example, sensorsthat provide artificial excitation to a portion of the patient’s bodyand acquire information about blood pulses [1], devices that integrateseveral sensors for measuring patient weight, temperature, blood pressure,and ECG waveforms [2], systems that also include personal storage devices[3], information management systems [4], and systems with a computer onboard for receiving, storing, processing, and transmitting information[5].

It seems that the future will present us with wearable and/orimplantable devices as commodities in medical technology. Good examples ofthat are several devices already present in the market, such asbrain–machine interfaces [6], wearable monitors for vital signs [7]and/or physical activity [8], and personal glucometers, bothhand-held [9] and implanted [10], which may now also be connected to aniPhone [11].

Muscles are the mechanical actuators of the body controlled by neurons. Weuse these actuators to perform many actions during the activities of ourdaily life. Moreover, we have benefited throughout history from the musclepower of larger animals, for farming, transportation, and industry. However,the muscle power of insects has not yet been exploited reliably orreproducibly, although insects possess a much higher ratio of muscle forceto body mass than most large domesticated mammals. The novel field ofinsect–machine interfaces (IMI) combines microtechnology andneuroengineering to benefit from the muscle power of insects in a“biobotic” manner. To facilitate this, Early MetamorphosisInsertion Technology (EMIT) provides a novel neurotechnological pathway forintegrating microelectronic sensing and actuation platforms into insectsduring metamorphosis. Metamorphic development not only provides an elegantand effective method of mechanically affixing artificial systems in or on aninsect, but also produces a reliable bioelectrical interface without anyobservable short-term adverse effect on insect flight behavior. As anapplication of biobotic control of insect locomotion, the first stepstowards flight and gait navigation in moths and cockroaches are presented inthis chapter.

Insect–machine interfaces (IMI)

Developments in micromachining technology have shifted the notion ofimplantable neuromotor prosthetics from science fiction to reality [1]. Thehighly miniaturized complementary metal oxide semiconductor (CMOS)electronics on these micromachined probes have made possible a number ofcomplicated neurophysiological studies by coupling state-of-the-art signalprocessing technologies to initiate and record advanced brain function [2,3]. This technology provides techniques and tools that allow us tounderstand and generate robust electronically controlled muscle movement.Restoring impaired motor function has been possible in vertebrates such asrabbits, cats, and monkeys, and will eventually be useful for humans, bycontrolling their motor function using either external operator commands orthe output of the subject’s own brain [4, 5]. These systems are at asuitable scale (~5 mm3) to fit on an insect to buildinsect–machine interfaces (IMI). For a reliable IMI, hybridbioelectronic structures with insects need to be formed through which CMOSdevices and micro-electromechanical systems (MEMS) structures are coupledwith the insect’s natural sensors and actuators.

Introduction

Lowering the costs of healthcare and increasing its accessibility is acritical need of today’s society. Miniaturized electronic sensors area possible way to both improve healthcare and lower the cost of medicaldiagnostics. Their small size and portability can lead to integration intopersonalized diagnostics tools and emergency care. In addition, faster,smaller and more efficient sensors can greatly impact chemical andbiological safety.

The rapid progress demonstrated in the computer industry and in genomics isstirring interest for growth and applications in healthcare and safety. Therelentless progress and developments in microfabrication predicted byMoore’s law, which forecast that the number of transistors on anintegrated circuit would double every two years, has until now beencontinually producing faster, cheaper, and smaller consumer electronics. Ananalogous exponential growth in DNA sequencing is even faster thanMoore’s law. Ten years ago, it would have taken many months tosequence a human genome. Today, the same task can be completed within oneday. This impressive progress is possible owing to innovative applicationsof microfabrication technologies. If this can be applied to healthcare, itcould stimulate a similar evolution, with applications such as early stagedetection of biological infection outbreaks and chemical hazards, whichcould mitigate epidemics tremendously.

The conventional brain–machine interface (BMI) concept is based on anelectrical circuit that includes electrodes for sensing and/orstimulation. In most cases, electrodes are in contact with biologicaltissue, while the electrical circuit can be positioned on the backside ofelectrodes or connected through a wireless link [1–3]. In both cases,a tremendous amount of work is done to design a high-sensitivity circuit todetect a few millivolts related to electrical signal propagation in thebrain [4, 5].

With recent advances in microfabrication and processing, more advancedsystems can be considered to build a BMI [6–8]. Following these majoradvances, the highly integrated lab-on-a-chip (LoC) emerged, which led tothe design of compact LoC in the size range of a few millimeters [9, 10].LoC has become attractive as an advanced brain–machine interface anda promising approach for future new brain discoveries.

Conventional brain–machine interfaces: deep brain electrodestimulation

There are two major operations that are handled by BMI, which are stimulationand sensing. Conventional BMIs are deep brain electrodes (DBE) or patchelectrodes [11, 12] used to detect the electrical activity of the brain. Inthe stimulation mode, DBE applies voltages or currents to tissue to generateaction potentials (AP). In the sensingmode electrodes are used to detect thepropagation of AP and brain electrical activity.

As stated in the previous chapter, Wolfgang Göpel wrote,“Bioelectronics is aimed at the direct coupling of biomolecularfunction units of high molecular weight and extremely complicated molecularstructure with electronic or optical transducer devices” [1]. Thestatement emphasizes two key points: the “direct coupling” andthe “high molecular weight”. This leads us now to developbioelectronic circuitries by moving from building blocks, or molecularcomponents, that involve high-molecular-weight biological molecules(typically proteins) by providing electrical contact at the nanoscale, inorder to address direct coupling. The first problem to solve is thereforethat of a nanoscale electrical contact.

During the last 15 years, several fabrication methods have been proposed toobtain a nanogap [2], based on the original work of Morpurgo etal. [3]. Among the possible solutions, a very effectivestrategy is to create an extremely tiny disconnection along a conductingwire in order to accommodate a biological molecule in between (Figure 2.1).The idea is to erode the electrical wire laterally in order to reduce itssize until one obtains a nanoscale conductor that becomes disconnected at acertain stage of the erosion. Morpurgo et al. [3]demonstrated that the wire’s conductivity becomes quantized in themoments immediately before the electrical connection breaks because thewavelength of the Schrödinger function associated with electronsbecomes comparable to the lateral size of the wire. We can therefore controlthe breaking of the connection by monitoring this quantum current. Now, wecan obtain a nanoscale interruption in the wire by stopping the erosionimmediately after the appearance of quantum states. If electrochemicaletching provides the erosion, then it is easy to control the process bymeans of a feedback system driven by the wire conductivity. Experimentalresults show that gaps can be obtained in the interrupted wire with sizesdown to 20 nm [3]. Considering now the typical size ofmetalloproteins, close to 5 nm [4], or of antibodies, up to15 nm [5], we can see that gaps of 20 nm are too large forquantum tunneling from the Fermi level in the metal to the LUMO (lowestunoccupied molecular orbital) in the protein [6].

Most probably, the term “lab-on-a-chip” came into the publicdomain with a nice publication that appeared in ScientificAmerican in 2007. That paper focused on recent developments intiny and portable chips for rapid testing in blood samples for pathogens orbiological weapons [1]. The article emphasized microfluidics as a keyfeature of the chip in order to make the lab-on-a-chip practical. The use ofair pressure or electricity is presented as the way to move and preciselymanipulate microscopic droplets through tiny chemical-reaction chambers [1].This sentence shows us the intimate connection between lab-on-a-chip andbioelectronics: we need electronics for precisely manipulating microscopicdroplets that contain pathogens or biological weapons. More than that, wealso need on board a quantitative technique for quantifying the pathogens orthe toxic agents. Therefore, biosensors are immediately involved. Figure35.1 schematically shows this deep interconnection addressed by modernsystems: a platform on a silicon chip that hosts a complex network ofmicrofluidic chambers and channels operating differently, and intimatelyintegrated with a complex microelectronic system. The whole system presentsloading ports for injection of samples and reagents. The loaded materialsare then mixed and pushed to the first reaction chamber by compressed air(as in point 1 of Figure 35.1) or by electrical or magnetic fields. Thereaction chamber performs thermal cycles to assure PCR (polymerase chainreaction) amplification (point 2 in Figure 35.1). In principle, a similarreaction chamber in the chip may perform other chemical reactions requiredby the assay (e.g. combination with another molecule to extract the targetmolecule from a complex). Then the reagent products are further moved intoanother reaction chamber to let a second reaction occur (point 3). Thesecond reaction may be required by the detection method. For example, areaction with a label (e.g. gold nanoparticles or fluorescent dyes) may beprovided in the case of labelled detection. Finally, the marked productsarrive in the analysis chamber, and the products are detected (point 4). Inthe example of Figure 35.1, the detection is provided by a series of diodesthat detect the pathogens as well as by electrophoretic tests.

This chapter explores electrical stimulation of excitable biologicalentities. It provides a brief history of electrical stimulation, stimulationparameters, theory of electrode interface impedance, and types ofstimulation. Focus is on the technology of charge balancing, power losses,voltage compliance, and associated hardware complexities of electricalstimulators. Stimulus artifacts and inductive power delivery are alsodiscussed, and are often used with stimulators for applications in neuralprostheses and therapeutics [1, 2].

Introduction

Electrical stimulation is an important and popular method in which injectedcharges are mainly responsible for excitation or inhibition of neural ormotor structures [3–5]. It can be utilized for treatment of diseasesand restoration of dysfunctional organs, such as for the brain [6, 7],retina [8, 9], cochlea [10], or peripheral nerve [11]. The electricalstimulation process is accomplished by using conductive electrodes ofspecific size and shape, which are placed at desired biological sites ofinterest. Coulombic charge is injected through such electrodes by means ofconstant current or constant voltage pulses. Charge injection accuracy,power loss minimization, output voltage compliance, and miniaturization areimportant factors that can enhance practical performance in electronicstimulators [12]. In the following subsections we provide a brief historyand introduce technical parameters associated with electricalstimulation.

Introduction

The notion of creating artificial vision using visual prostheses has beenwell represented though science fiction literature and films. When we thinkof retinal prostheses, we immediately think of fictional characters like TheTerminator scanning across a bar to assess patrons for appropriately fittingclothing, or Star Trek’s Geordi La Forge with his VISOR, a visualinstrument and sensory organ replacement placed across his eyes and attachedinto his temples to provide him with vision. Such devices are no longerfarfetched. In the past 20 years, significant research has been undertakenacross the globe in the race for a “Bionic Eye”. Advances inBionic Eye research have come from improvements in the design andfabrication of multielectrode arrays (MEAs) for medical applications. MEAsare already commonplace in medicine with use in applications such as thecochlear device, cardiac pacemakers, and deep brain stimulators whereinterfacing with neuronal cell populations is required.

The use of MEAs for vision prostheses is currently of significant interest.For the most part, retinal prostheses have dominated the research landscapeowing to the ease of access and direct contact to the retinal ganglion nervecells. However, MEAs are also in use for direct stimulation into the opticnerve [1]. Retinal prostheses bypass the damaged photoreceptor cells withinthe retina and instead replace the degenerate retina with electricalstimulation to the nerve cells. Using electrical stimulation, stimulatedretinal ganglion cells have been shown to elicit a percept in the form of aphosphene in blind patients [2–6]. Accordingly, the two diseasescommonly linked to the justification for Bionic Eye research are age-relatedmacular degeneration (AMD) and retinitis pigmentosa (RP), diseases whichlead to progressive loss of photoreceptor cells and diseases where thepatient has had previous vision and thus exhibits prior visual-brainpathways. At present, there has been no reliable cure for any of the retinaldiseases that target the photoreceptor cells, and thus the development ofprosthetic devices is a viable clinical treatment option [7–9].