Although the term was first proposed in 1968, the birth of bioelectronics as we know it today is much more recent. In fact, the first meaning of the word bioelectronics was the intermolecular electron transfer found in biological systems [1], while its modern meaning is quite different, as discussed in this chapter.

Tony Turner, founder and Editor-in-Chief of the Elsevier journal Biosensors and Bioelectronics, wrote in 2005: “Bioelectronics is a recently coined term for a field of research that works to establish a synergy between electronics and biology” [2]. Over the years, his journal became the main forum in the field of bioelectronics. The journal originally appeared in 1985 with the simple name of Biosensors, and the title was expanded to include the term Bioelectronics in 1992 [2]. The expressed scope of the journal [3] explains that a key aspect of bioelectronics is the interface between biological materials and electronics.

To better understand the modern state of the field, we can also consider the meaning of “advanced bioelectronics” as mentioned in April 2013 by the National Institute of Standards and Technology (NIST – an agency of the US Department of Commerce) and represented by the example of electronic DNA sequencing, as supported by singlemolecule mass spectrometry to develop innovative electronic devices for healthcare [4]. The authors [4] refer to devices in which an electric field drives individual molecules of single-stranded DNA through a nanometer-scale pore (Figure 1.1). That approach is a step toward applications for rapid sequencing of DNA [5] and DNA transcription complexes [6], and could lead to further developments in protein sequencing [7] too. The application is clearly focused on devices for healthcare and, more generally, includes both diagnostic and therapeutic tools.

The concept of biomimetic systems was introduced in the early definition of bioelectronics. As we have already seen in the first chapter, the original definition of bioelectronics set by Wolfgang Göpel includes “structures [that] may consist… of chemically synthesized units such as molecules, supramolecules and biologically active (biomimetic) recognition centers” [1]. Over the years, the concept has been expanded in order to move from simple recognition systems to biomimetic membranes for voltage shifts in graphene-based transistors [2], systems for cell separation in the blood [3], electronic noses [4, 5], electronic tongues [6], smart info-chemical communication systems [7], electronic design [8], pancreatic beta-cells [9], and neurons [10].

Artificial brain architectures, with all the neurons fully interconnected in parallel, show issues in terms of scalability, especially because the number of interconnections scales exponentially with the number of neurons [11], while it would be desirable for it to scale like biologically plausible architectures [11]. This brings us to the concept of bio-inspired or biomimetic systems as possible solutions to solve problems emerging in extremely complex bioelectronics architectures. Over the years, several bio-inspired and neuromorphic architectures have been proposed in the literature for silicon neurons [10], synaptic and neural components made of NiTi [12, 13], sensors [14], orientation tuning devices [15], and pattern recognition systems [16]. In the direction of more complexity and functionality, the present state-of-the-art in the field proposes artificial systems for pancreas [9], skin [17, 18], cognitive architectures, and brains [19, 20].

We have seen in the different sections of this book that bioelectronics, born in the early 1990s [1], has expanded over the years into several different branches. Bioelectronics now includes molecular components for electronics with thin-film [2] and protein-based [3] transistors, bio-memories [4], nanogap devices [5] for single-molecule electronics [6], and single enzymes immoblized on carbon nanotubes [7]. One of its major contributions to the state-of-the-art of the modern technology is the branch of biosensors, where bioelectronics has contributed to developing circuits for biomedical applications [8, 9], systems based on carbon nanotubes and proteins for applications in personalized therapy [10, 11], contactless monitors for measuring respiratory rate [12], and other very smart biomedical devices. Another fascinating branch is the development of biofuel cells based on enzymes [13], even implantable ones [14] that can exploit the body’s metabolism for their energy needs (Figure 44.1 illustrates a famous experiment in which the energy recovered from the body of a lobster by using an implanted biological fuel cell is used to power a watch). The more advanced developments in the field of electronics, such as epidermal electronics [15] and memristors [16], have enabled the development of biomimetic systems such as electronic skin [17], electronic brains with conventional CMOS technology [18], with memelements [19] or with organic polymers [20], and the design of synthetic genetic networks [21].

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

The future of bioelectronics has to follow from present electronics and present health needs. The present state of electronics is mainly based on personal computing (smartphones in our pockets, tablets and laptops in our handbags, navigators in our cars, etc.), while the new needs in health are based on personalization of treatments and therapies. This leads to the new concept of personal devices for health. Both the academic and the industrial world have already started targeting this new frontier, and the literature reflects that. New personal devices to be used directly by patients or on the patient’s body have been proposed recently: for example, sensors that provide artificial excitation to a portion of the patient’s body and acquire information about blood pulses [1], devices that integrate several 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 on board for receiving, storing, processing, and transmitting information [5].

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

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

During the last 15 years, several fabrication methods have been proposed to obtain a nanogap [2], based on the original work of Morpurgo et al. [3]. Among the possible solutions, a very effective strategy is to create an extremely tiny disconnection along a conducting wire 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 its size until one obtains a nanoscale conductor that becomes disconnected at a certain stage of the erosion. Morpurgo et al. [3] demonstrated that the wire’s conductivity becomes quantized in the moments immediately before the electrical connection breaks because the wavelength of the Schrödinger function associated with electrons becomes comparable to the lateral size of the wire. We can therefore control the breaking of the connection by monitoring this quantum current. Now, we can obtain a nanoscale interruption in the wire by stopping the erosion immediately after the appearance of quantum states. If electrochemical etching provides the erosion, then it is easy to control the process by means of a feedback system driven by the wire conductivity. Experimental results show that gaps can be obtained in the interrupted wire with sizes down to 20 nm [3]. Considering now the typical size of metalloproteins, close to 5 nm [4], or of antibodies, up to 15 nm [5], we can see that gaps of 20 nm are too large for quantum tunneling from the Fermi level in the metal to the LUMO (lowest unoccupied molecular orbital) in the protein [6].

Most probably, the term “lab-on-a-chip” came into the public domain with a nice publication that appeared in Scientific American in 2007. That paper focused on recent developments in tiny and portable chips for rapid testing in blood samples for pathogens or biological weapons [1]. The article emphasized microfluidics as a key feature of the chip in order to make the lab-on-a-chip practical. The use of air pressure or electricity is presented as the way to move and precisely manipulate microscopic droplets through tiny chemical-reaction chambers [1]. This sentence shows us the intimate connection between lab-on-a-chip and bioelectronics: we need electronics for precisely manipulating microscopic droplets that contain pathogens or biological weapons. More than that, we also need on board a quantitative technique for quantifying the pathogens or the toxic agents. Therefore, biosensors are immediately involved. Figure 35.1 schematically shows this deep interconnection addressed by modern systems: a platform on a silicon chip that hosts a complex network of microfluidic chambers and channels operating differently, and intimately integrated with a complex microelectronic system. The whole system presents loading ports for injection of samples and reagents. The loaded materials are 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. The reaction chamber performs thermal cycles to assure PCR (polymerase chain reaction) amplification (point 2 in Figure 35.1). In principle, a similar reaction chamber in the chip may perform other chemical reactions required by the assay (e.g. combination with another molecule to extract the target molecule from a complex). Then the reagent products are further moved into another reaction chamber to let a second reaction occur (point 3). The second reaction may be required by the detection method. For example, a reaction with a label (e.g. gold nanoparticles or fluorescent dyes) may be provided in the case of labelled detection. Finally, the marked products arrive in the analysis chamber, and the products are detected (point 4). In the example of Figure 35.1, the detection is provided by a series of diodes that detect the pathogens as well as by electrophoretic tests.