1

1Bioelectronics – An Introduction

Itamar Willner and Eugenii Katz

The integration of biomolecules with electronic elements to yield functional devicesattracts substantial research efforts because of the basic fundamental scientific questionsand the potential practical applications of the systems. The research field gained thebuzzword ‘‘bioelectronics’’ aimed at highlighting that the world of electronics couldbe combined with biology and biotechnology [1–3]. Mother Nature has in course ofevolution processed the most effective catalysts (enzymes), and biomolecules of optimalrecognition and binding capabilities that lead to highly selective and specific biopolymercomplexes (antigen–antibody, hormone-receptor, or duplex DNA complexes). Similarly,biology provides the fastest and most complex computing and imaging systems whereoptical information is processed and stored in the form of three-dimensional memorableimages (vision process). The tremendous biochemical and biotechnological progressin tailoring new biomaterials by genetic engineering or bioengineering providesunique and novel means to synthesize new enzymes and protein receptors, andto engineer monoclonal antibodies or aptamers for nonbiological substrates (suchas explosives or pesticides) and DNA-based enzymes. All these materials provide abroad platform of functional units for their integration with electronic elements. Thelatter electronic elements may involve, for example, electrodes, field-effect transistordevices, piezoelectric crystal, magnetoresistance recording media, scanning tunnelingmicroscopy (STM) tips and others. The bioelectronic devices, Figure 1.1, may operate indual directions: In one configuration, the biological event alters the interfacial propertiesof the electronic element, thus enabling the readout of the bioreaction by monitoringthe performance of the electronic unit such as the readout of the potential, impedance,charge transport, or surface resistance of electrodes or field-effect transistors, or byfollowing the resonance frequencies of piezoelectric crystals. The second configurationof bioelectronic systems uses the electronic units to activate the biomaterials towarddesired functions.

The major activities in the field of bioelectronics relate to the development ofbiosensors that transduce biorecognition or biocatalytic processes in the form ofelectronic signals [4–6]. Other research efforts are directed at utilizing the biocatalyticelectron transfer functions of enzymes to assemble biofuel cells that convert organicfuel substrates into electrical energy [7, 8]. Exciting opportunities exist in the electrical

Bioelectronics. Edited by Itamar Willner and Eugenii KatzCopyright 2005 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 3-527-30690-0

2 1 Bioelectronics – An Introduction

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1 Bioelectronics – An Introduction 3

interfacing of neuronal networks with semiconductor microstructures. The excitation ofion conductance in neurons may be followed by electron conductance of semiconductordevices, thus opening the way to generating future neuron-semiconductor hybridsystems for dynamic memory and active learning [9]. The recent progress in nano-technology and specifically in nanobiotechnology adds new dimensions to the areaof bioelectronics. Metal and semiconductor nanoparticles, nanorods, nanowires, andcarbon nanotubes represent nano-objects with novel electronic properties. Recentstudies revealed that the integration of these objects with biomolecules yields newfunctional systems that may yield miniaturized biosensors, mechanical devices andelectronic circuitry [10–12].

A fundamental requirement of any bioelectronic system is the existence of electroniccoupling and communication between the biomolecules and the electronic supports.Special methods to immobilize biomolecules on solid supports while preservingtheir bioactive structures were developed. Ingenious methods to structurally alignand orient biomaterials on surfaces in order to optimize electronic communicationwere reported [13]. Although impressive advances in the functional tailoring ofbiomolecule electronic units–hybrid systems were accomplished, challenging issuesawait scientific solutions. The miniaturization of the bioelectronic systems is arequisite for future implantable devices, and these types of applications will certainlyintroduce the need for biocompatibility of the systems. The miniaturization of thesystems will also require the patterned, dense organization of biomolecules onelectronic supports. Such organized systems may lead to high throughput parallelbiosensing and to devices of operational complexity. The development of methodsto address and trigger specific biomolecules in the predesigned arrays is, however,essential. This book attempts to highlight different theoretical and experimentaltopics that place bioelectronics as a modern interdisciplinary research field inscience.

The understanding of charge transport phenomena through biological matricesattracted in the past decades, and continues to evolve, intensive theoretical andexperimental work. The seminal contributions of the Marcus theory [14], thesuperexchange charge transfer theory [15], and the definition of superior tunnelingpaths in proteins [16] had a tremendous impact on the understanding of biologicalprocesses such as the electron transfer in the photosynthetic reaction center, orthe charge transport in redox-proteins that are the key reactions for numerouselectrochemical and photoelectrochemical biosensing systems. A continuous feedback between elegant experimental work employing structurally engineered proteinsand theoretical analysis of the results led to the formulation of a comprehensiveparadigm for electron transport in proteins [17]. This topic is addressed in detail inChapter 2. The charge transport through DNA has recently been a serious scientificdebate [18, 19], and contradicting results claiming conductive [20], superconductive [21],semiconductive [22] or insulating [23] properties of DNA were reported. Theoriesdescribing charge transport through DNA (electrons or holes) that included hoppingmechanisms, tunneling paths, or ion-assisted electron transfer were developed [24, 25].Charge transport through DNA is anticipated to play a key role in the electrical detectionof DNA and in the analysis of base mismatches in nucleic acids, in the use of DNA

4 1 Bioelectronics – An Introduction

nanowires as circuitry in devices, and as a means to readout sequence specific DNAstructures (DNA computers).

The electrical contacting between biomolecules and electrodes is an essential featurefor most bioelectronic systems. Numerous redox enzymes exchange electrons with otherbiological components such as other redox-proteins, cofactors or molecular substrates.The exchange of electrons between the redox-centers of proteins and electrodes couldactivate the biocatalytic functions of these proteins, and may provide an importantmechanism for numerous amperometric biosensors. Nonetheless, most of the proteinslack direct electron transfer communication with electrodes, and the lack of electricalcommunication between the biomaterials and the electronic elements presents oneof the fundamental difficulties of bioelectronic systems. Although the barriers forcharge transport between redox-proteins are easily explained by the Marcus theoryand the spatial insulation of the redox-centers of enzymes by the protein matrices,they hinder the construction of electrically communicated biomolecular-electronichybrid systems. Ingenious methods for the electrical contacting of biomolecularassemblies associated with electronic units were developed in recent years [13]. Thestructural engineering of proteins with electron relays [26], the immobilization of redoxenzymes in conductive polymers or redox-active polymers [5], the steric alignmentof proteins on electron relays associated with electrodes [27], or the incorporationof redox-active intercalators in DNA [28] represent a few means to electronicallycommunicate the biomolecules with the electronic elements. These aspects areaddressed in several sections of the book (Chapters 3 and 4) and are exemplifiedhere with the electrical communication of redox enzymes with electrodes for thegeneration of amperometric biosensors and biofuel cells, and with the intercalationof a redox-label into double-stranded DNA for the electrical probing of DNA.The integration of glucose oxidase, which lacks direct electrical communicationwith electrodes, into a redox-active hydrogel film consisting of tethered Os(II)-polypyridine complex (1) units, and linked to the electrode, facilitates the electricalcontact between the enzyme and the conductive support, Figure 1.2(A). The flexibleredox-units linked to the polymer electrically wire the redox-center of the enzymewith the electrode by mediated electron transfer. Glucose sensing electrodes basedon this charge transport concept are already on the market, and the design ofmicrosized electrically wired enzyme electrodes for invasive continuous monitoringof glucose are close to commercial realization [29]. A different application of electricallycontacted enzyme electrodes rests in the design of biofuel cells [7, 8], Figure 1.2(B).Fuel cell systems represent a well-established technology, where electrical power isgenerated by two complementary oxidation and reduction processes occurring at acatalytic anode and cathode, respectively. While the generation of electrical powerby electrically contacted redox enzymes, in a biofuel cell configuration has probablylittle value in global energy production, the systems might have important merit asimplantable devices that generate electrical power from body fluids. For example,a glucose-based biofuel cell utilizing electrically contacted enzyme electrodes coulduse blood as a fuel for the electrical powering of pace makers, insulin pumps orprosthetic elements.

1 Bioelectronics – An Introduction 5

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6 1 Bioelectronics – An Introduction

The electrical contacting between molecular species and electrodes may be stimulatedby specific biorecognition events. For example, the intercalation of doxorubicin (2) intothe double-stranded DNA formed between a primer nucleic acid associated with anelectrode and the complementary analyte DNA enables the electrochemical reductionof the intercalator and the subsequent catalytic reduction of O2 to H2O2, Figure 1.3. Thelatter product induces in the presence of luminol and horseradish peroxidase (HRP)the formation of chemiluminescence as a readout signal for the DNA duplex formationon the electrode [28]. The analysis of DNA by different electrochemical methods isdiscussed in Chapter 5.

Scanning probe microscopy techniques have introduced exciting opportunities insurface science and specifically in the characterization of biomolecules on surfaces.Scanning tunneling microscopy allows one to probe tunneling currents throughproteins, thereby imaging the structure of individual protein molecules. Atomicforce microscopy (AFM) not only permits the imaging of single biomolecules onsurfaces but also permits the specific affinity interactions between complementary

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1 Bioelectronics – An Introduction 7

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antigen–antibody pairs, or double-stranded DNA complexes to be followed [30, 31].Scanning probe microscopes also add new dimensions as tools for patterning surfaceswith biomolecules. The use of dip pen–lithography for the generation of biomolecularpatterns [32], Figure 1.4(A) or the application of enzyme-functionalized AFM tips asa biocatalytic patterning tool [33], Figure 1.4(B), are just two examples demonstratingthe potential of these nano-tools to fabricate dense biomolecular arrays. Realizing thatbioelectronics involves the intimate coupling of biomolecules to electronic supports, theuse of scanning probe microscopy to characterize the structure-function relationshipsof single biomolecules, and to actuate single biomolecules are inevitable for the futuredevelopment of the field. Some aspects of scanning probe microscopy for bioelectronicapplications and the manipulation of single biomolecules are addressed in Chapters 6and 10.

Self-organization of biomolecules leads to unique 2D- and 3D-nanostructures thatinclude structurally defined pores or channels. These materials may act as templatesfor the assembly of other materials, and the generation of systems of hierarchicalstructural complexity. Figure 1.5 shows a scanning force microscopy image of S-layerprotein from Bacillus sphaericus on a silicon surface exhibiting square lattice symmetrywith a lattice constant of 13.1 nm. Alternatively, the pore or channel structures maybe utilized as ‘‘microreactors’’ of predefined dimensions for the synthesis of metallicor semiconductor nano-objects. This topic is addressed in Chapter 13, where theapplications of S-layer proteins in bioelectronic systems are discussed.

8 1 Bioelectronics – An Introduction

Fig. 1.5 AFM image of an S-layer protein from Bacillus sphaericus on a silicon surface.The image size corresponds to 150 × 113 nm.(Adapted from http://nanotechweb.org/articles/news/2/3/15/1, with permission).

Nanoparticles exhibit unique electronic, optical, catalytic and photoelectrochemicalproperties [34–36]. The dimensions of nanoparticles are comparable to those ofbiomolecules such as enzymes, antigens/antibodies or DNA. Not surprisingly, theconjugation of biomolecules with metal and semiconductor nanoparticles yields hybridsystems of new electronic and optoelectronic properties. Indeed, tremendous progresswas accomplished in the realization of biomolecule–nanoparticle hybrid systems forvarious bioelectronic applications [37]. The electrical contacting of redox enzymes withelectrodes by means of Au nanoparticles [38], the use of metal nanoparticle–nucleic acidconjugates for the catalytic deposition of metals and inducing electrical conductivitybetween electrodes [39], the electrochemical analysis of metal ions originating fromthe chemical dissolution of metallic [40] or semiconductor [41] nanoparticle labelsassociated with DNA, or the photoelectrochemical assay of enzyme reactions bymeans of semiconductor nanoparticles [42] represent a few examples that highlightthe potential of biomolecule–nanoparticle hybrid systems in biosensor design.Recent advances in the integration of biomolecules with semiconductors and theapplication of biomolecule–nanoparticle hybrids in bioelectronics are highlighted inChapters 7 and 8, respectively. Several other applications of biomolecule–nanoparticleor biomolecule–carbon nanotube systems are also discussed in other sections ofthe book.

1 Bioelectronics – An Introduction 9

Exciting opportunities exist in the applications of biomolecules as templates for thesynthesis of metallic or semiconductor nanowires [43]. Such nanowires provide greatpromise for future nanocircuitry and for the assembly of nanodevices. The possibilityof preparing DNA of desired shapes and base sequence, the availability of enzymesacting as biocatalytic tools for manipulating DNA, the binding of metal ions to thephosphate units of DNA chains, the specific intercalation of molecular componentsinto the DNA biopolymers, and the specific DNA–protein interactions, turn DNA intoan ideal matrix for its use as a template in the synthesis of nanowires consisting ofmetals or semiconductors. Indeed, tremendous progress has been accomplished byusing DNA as a template for the generation of nanowires and patterned nanowires [44].This subject is highlighted in Chapter 9, which demonstrates the use of patterned Au

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10 1 Bioelectronics – An Introduction

Neuron NeuronNeuronal net

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Fig. 1.7 (A) Neurons on top of a multielectrode array (adapted fromhttp://physicsweb.org/article/news/7/4/17#neuronsonelectrode withpermission). (B) A neuroelectronic hybrid system consisting of twoneurons; the first neuron is activated by a capacitive stimuli, the signaltransmission occurs through a neuronal network to a second neuron,where the information is recorded by a transistor.

nanowires on DNA as electrical contacts for the assembly of a nanotransistor. Theconstruction of the biomolecule-base nanotransistor [45], Figure 1.6(A), is based on theassembly of a carbon nanotube between gold contacts formed on a DNA templateusing biorecognition events as driving motives for the construction of the nanodevice.Recent advances in this area suggest that self-assembled protein tubules or filamentsmay similarly be employed as templates for the synthesis of nanowire system [46].

1 Bioelectronics – An Introduction 11

For example, Figure 1.6(B) depicts an impressive micrometer-long Ag wire exhibitinga width of ca 20 nm that was generated by the in situ reduction of silver ions in thetemplate composed of aromatic short-chain peptides (diphenylalanine β-amyloids), thatare considered as key proteins in the development of Alzheimer’s disease.

The interfacing of neurons with semiconductors provides a challenging approachto mimicking brain functions by bioelectronic information storage and processingmemory devices. Tremendous progress has been reported in the past decade in thedirected growth and organization of neurons connected by synapses on electrode arraysassociated with semiconductor supports to form neuroelectronic junctions and neuronalnetworks [47], Figure 1.7(A). The possibility of eliciting neuronal activity by capacitivestimuli induced by the semiconductor, and the imaging of neuronal functions by atransistor element, represent two fundamental write–read functions of bioelectroniccomputing devices. The further stimulation of one neural cell and the transfer of theneuronal activity through the synapse to a second cell that enables the readout of theinformation by the transistor unit, Figure 1.7(B), represents an information transferand processing device. Recent research demonstrates the organization and operationof such functional neuronal arrays as a viable approach to fabricate ‘‘brain computers’’.The neurobiology and physics involved in neuronal dynamics and thinking computationsystems are discussed in Chapter 12.

The combinatorial synthesis of nucleic acids paves the way for synthesizing mixturesof numerous DNAs with base sequence encoded information. The possibilities ofaddressing this mixture of DNA in solution, as well as on surfaces, by hybridization orby biocatalytic transformations, such as replication or scission, allow the manipulationof target(s) DNA in the mixtures. Furthermore, the possibility of amplifying minuteamounts of DNA enables us to fish out and identify the biomanipulated DNA.Not surprisingly, the rich information stored in DNA, and its retrieval capabilityhas established the paradigm of ‘‘DNA computers and DNA-based computations’’.The seminal suggestion of Adleman using DNA for parallel computation [48] wasfollowed by concepts of enhanced computation complexity. This topic and its practicalutility are critically reviewed in Chapter 14. Photonically triggered biomolecules offeradditional possibilities for optical information storage and processing. The futureapplications of light-triggered biomolecules for computing, reversible sensor design,targeted therapeutics, or light signal amplifiers are addressed in Chapter 11.

While organizing the book, we tried to combine well-established principles ofbioelectronics that are ripe for practical and commercial applications, with new scientificdisciplines that are at an embryonic phase of development, and their practical utilitystands for future evaluation. Although we made efforts to balance and present thedifferent facets of bioelectronics, we are sure that some topics are missing from thisessay, and we certainly apologize for any unbalanced presentation. The progress in thefield turned bioelectronics into an interdisciplinary area that combines research effortsof biologists, chemists, physicists, material scientists and electronic engineers. In viewof the impressive advances in the field and its promising perspectives, we anticipate abright future for bioelectronics. We would like to thank all contributors for their effortsto bring this book into reality, and we believe that it will provide a comprehensivebackground to researchers and scholars active in the field.

12 1 Bioelectronics – An Introduction

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