Biochips beyond DNA: technologies and applications

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Abstract

Technological advances in miniaturization have found a niche in biology and signal the beginning of a new revolution. Most of the attention and advances have been made with DNA chips yet a lot of progress is being made in the use of other biomolecules and cells. A variety of reviews have covered only different aspects and technologies but leading to the shared terminology of “biochips.” This review provides a basic introduction and an in-depth survey of the different technologies and applications involving the use of non-DNA molecules such as proteins and cells. The review focuses on microarrays and microfluidics, but also describes some cellular systems (studies involving patterning and sensor chips) and nanotechnology. The principles of each technology including parameters involved in biochip design and operation are outlined. A discussion of the different biological and biomedical applications illustrates the significance of biochips in biotechnology.

Introduction

The completion of the sequence of the human genome commenced a new era in biology. For a long time, biology has been the poor cousin of the physical and chemical sciences due to the lack of quantitative rigor for characterizing biological phenomenon. This is mainly due to the inherent complexity of biological systems and the lack of tools to track these systems. Advances in technology and information sciences put humanity on the verge of conquering biological complexity.

An effective way to address biological complexity is to isolate the different components of the system and to understand how the different components interact. Historically, biology has been focused on studying one component at a time. The advent of Systems Biology has accelerated the shift to understanding multiple components at a time, which is more appropriate to characterize biological phenomenon. One area that will have immediate impact toward a better understanding of biology is through the use of chip technology to capture the different components in a miniaturized, well-defined, and quantifiable environment. The applications of chip technology in biology dawned during the genomics revolution. The power of DNA chips became imminent with its applications in profiling the expression of thousands of genes arrayed in a silicon chip. From then on the concept of chips have been extended to a variety of biomolecules such as proteins and including cells leading to the coining of the word “biochips.”

Although many reviews have been written on biochips (see Table 1), the aim of this particular review is to provide the users or potential users of non-DNA biochips with an understanding of a wide enough breadth to realize the different options that exist and, if pursued further, evaluate the effectiveness, appropriateness, and ultimately the value of biochips (from those that may or will be commercially available to those that will be designed to suit particular needs). This review also provides a perspective for those interested in the biotechnological aspect of biochips: many technical issues are not trivial but that research leads to knowledge, discovery, and/or even achievement. Furthermore, a list of abbreviations and a glossary are provided as appendices to cope with the complex terminologies that have floated in the field.

Section snippets

Microfabrication of chips

The development of a biochip involves several considerations: what type of experiments needs to be performed on the chip, what support is needed, how to apply the protein on the chip, and how to immobilize the protein without losing its functionality. The type of experiment will determine the chip format. In constructing a chip, an important consideration is what material works best or is compatible for a given type or range of required experiments. The chip in its final state goes through a

Principles of design and operation

This section on principles of design and operation provides the logic behind the tools, the rationale behind the choice of which materials and methods make sense in any one particular chip application as well as discusses the other aspects involved in operating a biochip, e.g., the detection system. This section is divided into a discussion on arrays and microfluidics. A separate section is dedicated to cell and tissue biochips because there are inherently different issues to be addressed as

Proteomics and drug discovery tools

The term proteomics can mean any of several different strategies aimed at unraveling the human proteome. The proteomics field can be categorized so as to provide a means of better understanding the complex field which leads to several approaches at solving the problem, each complementary to the others [[469], [470]]. Profiling and cataloging proteins in normal and diseased tissue constitute expression proteomics, an area where protein arrays have been applied. Another important part of current

Immunoassays

To reiterate the principle in carrying out assays in microarray format, as one goes down with the amount of binder on the chip, the detected signal is a function of the concentration of target or analyte molecules in solution and is independent of the solution or sample volume and the amount of binder in the microspot [[4], [326]]. This is because the fraction of analyte captured reflects the solution concentration [121]. There is a limit of course to the amount of binder as statistics starts

Biological and medical research

The use of biochips in basic biological and medical research has provided information that was heretofore inaccessible. Molecular profiles of cell types provided by tissue microarrays and the layered expression scanning technique [[464], [468]] are relevant in understanding biological processes. In addition, many other types of experiments performed on microchips from assays to mimicking cellular migration in tissues and neuronal behavior in vivo give new insight into processes relevant in

Conclusion

Recent advances in miniaturization, incorporation of complex components and adaptation of chips for non-DNA molecules signals a new era in biology. The shift towards studying biology as a complex interacting system (systems biology) requires the use of robust and reliable experimental systems that are amenable to analysis and quantitation of complex behavior. The use of biochips represents a platform to accelerate studies in systems biology and its applications in medicine and other fields are

Acknowledgements

We are grateful to Larry Gold, Olli-P. Kallioniemi, and Thomas Joos for providing reprints of their articles; Holger Becker, Konrad Büssow and Gerald Walter, Jed Harrison, Stephen Jacobson, Chad Mirkin and David Ginger, Christof Niemeyer, Menno Prins, Thomas Joos, Meike Kuschel, Gavin MacBeath, George M. Whitesides, Ravi Kane, and Shuichi Takayama, for granting permission and/or providing figures from their publications; Bernard Westerop who furnished us with all the figures we needed from

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