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Über dieses Buch

The application of CMOS circuits and ASIC VLSI systems to problems in medicine and system biology has led to the emergence of Bio/CMOS Interfaces and Co-Design as an exciting and rapidly growing area of research. The mutual inter-relationships between VLSI-CMOS design and the biophysics of molecules interfacing with silicon and/or onto metals has led to the emergence of the interdisciplinary engineering approach to Bio/CMOS interfaces. This new approach, facilitated by 3D circuit design and nanotechnology, has resulted in new concepts and applications for VLSI systems in the bio-world.

This book offers an invaluable reference to the state-of-the-art in Bio/CMOS interfaces. It describes leading-edge research in the field of CMOS design and VLSI development for applications requiring integration of biological molecules onto the chip. It provides multidisciplinary content ranging from biochemistry to CMOS design in order to address Bio/CMOS interface co-design in bio-sensing applications.

Inhaltsverzeichnis

Frontmatter

Chapter 1. Introduction

Abstract
Electronic provides devices that are ubiquitous features of our lives. We watch television and listen to the radio, connect to the rest of the world using Wi-Fi systems, adjust our home heating systems remotely, and on and on. This control over our world extends to our cars: electronic regulation of air conditioning, stability, antilock brakes, anti-skating systems, and other microprocessors that constitute new electronics control units that enable complete control over total-vehicle operations, including the engine and transmission. The next step in car evolution will be cars that drive themselves (there are already cars on the market equipped with automatic blocking of obstacles). The same goes for airplanes: nobody wants to use it, but the technology already exists to fly airplanes without a pilot, including takeoff and landing. Electronics are part of our daily lives: we have a mobile phones in our pockets and laptops in handbags. Some of us also carry an iPod® or iPhone® (which is more than just a mobile phone!) in our pockets and an iPad® in a case. You don’t have to look far before coming across someone using e-book readers in airports or on airplanes. We have fully integrated electronics into our daily lives in a manner that is totally organic. We are so comfortable with it that we sometimes aren’t even cognizant of electronic devices and consider them an extension of our own bodies. They are what we might also call personal electronics.
Sandro Carrara

Chapter 2. Chemistry of Conductive Solutions

Abstract
When we interface our CMOS circuits with an environment suitable for life, we usually obtain an interface between a conducting or an insulating surface and a conductive solution. The reason is that an environment suitable for life requires two conditions: first, water in liquid phase is required to support complex molecules for free movement, and second, salts dissolved in that water are required to support the right 3D structure of the molecules. The 3D organization is necessary for the functionality of any organic or biological molecule. Mobility and functionality are two of the main features of living organisms and their components. These features are of key importance for the complexity and the high degree of organization of life. They assure the proper functioning of all organs in organisms. They serve to harvest, transport, transform, and use energy and matter for organisms’ benefit. They also facilitate communication and exchange between biological systems.
Sandro Carrara

Chapter 3. Biochemistry of Targets and Probes

Abstract
The interaction of biological molecules with the surface is one of the most relevant phenomena when it comes to interfaces between CMOS circuits and biological systems. We may have nonspecific or specific interactions depending on the nature of the interface. If our interface is developed for a specific sensing aim, then the only interacting molecules are expected to be the molecular targets. For example, if we develop an implantable system for measuring human glycemia (the measure of glucose in the blood), then glucose must be the only molecule to interact with our interface. Then we can define specific interactions, with all interactions occurring at the interface that are specifically related to the aim of the Bio/CMOS interface we are dealing with. In biosensing, the specifically related molecules are called target molecules, or simply targets. In the example of a CMOS circuit for measuring glycemia, glucose is the biosensing target. However, all biological systems typically contain many different components that would interact with our interface. For example, 1 μl of blood contains millions of cells and thousands of proteins and metabolites. We can define as nonspecific interactions all interactions occurring at the interface that are not specifically related to the aim of our Bio/CMOS interface. Sometimes, the molecules that have nonspecific interactions at the Bio/CMOS interface are also called nontarget molecules, or simply nontargets. The interaction of these nonspecific molecules generates nonspecific electrical signals, which are nonetheless registered by our CMOS circuit. We can also consider these signals a kind of interference.
Sandro Carrara

Chapter 4. Target/Probe Interactions

Abstract
All the molecules that we saw in the previous chapter are useful for defining, organizing, and improving the properties of our Bio/CMOS interfaces. The biological functions of complex macromolecules like DNA, RNA, and proteins provide the right molecular recognition at the interface. Molecular recognition is required to assure specificity in sensing. By definition, the molecular recognition is the ability of molecular systems to distinguish between molecules and then to “recognize” molecules accordingly. Molecular recognition is a general concept widely used in discussions of biological systems. It is related to specific interactions occurring between two or more molecules. Typically, hydrogen bonding, van der Waals forces, hydrophobic forces, or other kinds of electrostatic forces have molecular interactions. Molecular complementarity assures specific recognition thanks to the complementary sequence of the involved molecules. Molecular recognition has a key role in biology because it is the fundamental phenomenon occurring in systems such as, for example, receptors/ligands in cell membranes, antigens/antibodies in the immune system, and DNA-DNA and DNA-RNA pairings in cell nuclei. Molecular complementarity also assures the right pairing in target/probe recognition at the Bio/CMOS interface. The aim of this chapter is to discuss some examples of target/probe interaction that will be used in Chaps.​ 6, Chaps.​ 7, Chaps.​ 8, Chaps.​ 9, and Chaps.​ 10 to design different kinds of Bio/CMOS interfaces.
Sandro Carrara

Chapter 5. Surface Immobilization of Probes

Abstract
We saw in the previous chapter that the working functions of biological molecules are of key importance for target/probe interactions. The probe characteristics are important to assure specificity in target detection. Targets are either small metabolites or large proteins, and probes are typically proteins that manifest specific interactions with the targets. Targets may also be genes, and then probes should be single-stranded short chains of nucleic acids that provide specific hybridization with the DNA or RNA target. In all cases, we need to immobilize the probes onto the chip surface to create a stable Bio/CMOS interface. Furthermore, molecules providing specificity toward a specific target are not the only ones required on the surface. Sometimes, special alkanethiols or silanes are required to improve the quality at the nanoscale of a probe’s interface (Chap.​ 6). Thus, we need to study now the different mechanisms of molecular assembly onto a surface
Sandro Carrara

Chapter 6. Nanotechnology to Prevent Electron Transfer

Abstract
We saw in Chap.​ 5 different mechanisms of molecular assembly onto surfaces. These mechanisms also play a role in molecular assembly onto Bio/CMOS surfaces. In this chapter, we will show how to use DNA short oligonucleotides or antibodies (Chap.​ 3) to develop Bio/CMOS interfaces to sense DNA hybridization or to provide antigen detection. The chapter also shows how different kinds of adsorption mechanisms and different kinds of DNA monolayers produce different Bio/CMOS interfaces with completely different electrical behaviors. In particular, the chapter shows how to use special alkanethiols to improve the quality of these probe surfaces on the nanoscale. We will see that the nanoscale quality of the Bio/CMOS interface is so important that, in some cases, this means we can have the sensing or if we fail on that.
Sandro Carrara

Chapter 7. Bio/CMOS Interfaces for Label-Free Capacitance Sensing

Abstract
We saw in Chap.​ 4 how singe-stranded DNA oligonucleotides hybridize to form double-stranded DNA; we also saw that antibodies and antigens interact to form immune complexes. In both cases, we can immobilize one of the two molecules of the complex (the probe) in our Bio/CMOS interface and obtain a surface that can detect the other molecule (the target) in a specific manner. We saw in Chap.​ 6 the electrical behavior of hybridization at an interface. We discussed that hybridization affects the equivalent capacitance of the Bio/CMOS interface. Chapter 6 also demonstrated the use of special molecules to improve the Bio/CMOS interface on the nanoscale. It was demonstrated that the improvement provides a more reliable interface for biosensing. The aim of this chapter is to address the “CMOS side” of the interface, in other words, to discuss some CMOS architectures that have been implemented to obtain biochips for label-free sensing of biomolecules.
Sandro Carrara

Chapter 8. Nanotechnology to Enhance Electron Transfer

Abstract
We saw in Chap.​ 4 how different macromolecules interact with each other due to their specific functions in biology. Chapter 7 showed how to translate their interactions into an electrical signal for biosensing of DNA. In this chapter, we see how to translate the specific interactions into an electrical signal for biosensing with enzyme-based detection. We also saw in Chap.​ 6 how to use nanotechnology to decrease electrical signals coming from nonspecific interactions occurring at an interface. In this chapter, we will see how to use nanotechnology to increase the electrical signals coming from specific interactions at the Bio/CMOS interface between enzymes and their substrates.
Sandro Carrara

Chapter 9. Bio/CMOS Interfaces in Constant Bias

Abstract
In the case of metabolite detection, we saw in Chap.​ 8 how to design the “nano” and “bio” parts of our Bio/Nano/CMOS interface. In that chapter, we saw that we could observe several redox reactions involving hydrogen peroxide. We also saw that each redox occurred at a certain proper bias (Eqs. 8.3–8.5 in Chap.​ 8). These different reactions are very important because the hydrogen peroxide is generated in redox catalyzed by enzymes from the protein family of oxidases (Eq. 8.2 in Chap.​ 8). Thus, we can fix the bias potential across the interface at the proper values and monitor over time the presence of all the metabolites catalyzed by oxidases. The aim of this chapter is to show Bio/CMOS interfaces for constant bias detection of metabolites. The chapter focuses on the CMOS design of a system.
Sandro Carrara

Chapter 10. Bio/CMOS Interfaces in Voltage Scan

Abstract
We saw in the previous chapter how to deal with metabolite monitoring by applying a constant bias across the Bio/CMOS interface. This is definitely suitable for monitoring several endogenous metabolites that are catalyzed by oxidases while producing hydrogen peroxide. However, this does not cover all of our needs. Constant bias detection is exhaustive neither for exogenous nor for endogenous metabolites. In some cases, the scan of bias potential across an interface is required to identify the metabolite. This chapter focuses on the needs for voltage scan and on Bio/CMOS interfaces that operate in voltage scan mode.
Sandro Carrara

Backmatter

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