Applying chip manufacturing technologies to life science applications
09/01/2006
Semiconductor chip manufacturing technology in general, and MEMS manufacturing technology in particular, have applications in emerging life sciences fields. For example, IC fab lithography allows for massive parallelism in reagent analyses, and silicon is an excellent substrate material that allows for microelectronic circuit integration on-chip for many applications. However, life sciences includes applications such as academic and clinical research, drug discovery, in-vitro diagnostics, medical devices, and instrumentation, and different chip manufacturing technologies must be applied differently for each segment.
Clémence Labat, Géraldine Andrieux, Barbara Pieters, Jean-Christophe Eloy, Yole Développement, Lyon, France
For years, highly skilled researchers and clinicians have conducted life sciences analyses. However, with the sheer complexity of conceptual levels such as cells, DNA, RNA, and proteins, there is a need for more automated and parallelized ways of doing biological analysis, leading to higher throughput and enhanced efficiency. MEMS and semiconductor technologies, first used in telecommunication and automotive applications, are considered useful in managing the high-level of complexity needed in analyses.
We define biochips as microsystems with tailored surface properties for life sciences applications (see figure), which typically offer high parallelization of analysis. The first biochip based on semiconductor technologies has successfully reached the market and is now becoming a gold standard in drug discovery both in academic and industrial research labs. Produced by Affymetrix using a lithography process for the synthesis of nucleic acid probes on glass wafer substrates, it now enables expression analysis of the whole human genome with more than 54,000 probe sets on a single micro-array in hours.
 BioMEMS devices based on microfluidics are at the intersection of MEMS and biochips components. |
Agilent is another semiconductor company challenging Affymetrix on the micro-array market with a noncontact inkjet printing process that deposits oligonucleotide probes onto specially prepared glass slides.
Beyond basic research, chip technologies also offer other advantages for diagnostic applications such as reduced cost through miniaturized sample volume and reagents use, a controlled environment, faster analysis, lower energy consumption, and higher accuracy. Semiconductor production technologies and industrialization processes are also especially attractive in a high-volume/high-price-pressure market like diagnostics. Molecular diagnostics is expected to become a huge biochip market with many diverse applications for human and veterinary diagnostics as well as nonmedical diagnostics for agro-food and environment control.
Microelectronics manufacturing techniques have already proven their value in new medical devices. A product already on the market is the Respimat Soft Mist Inhaler (Boehringer Ingelheim microParts) for asthma or chronic obstructive pulmonary disease treatment. Medical BioMEMS are getting more and more use in such applications as pressure sensors for patient monitoring, silicon microphones integrated into hearing aids, and accelerometers for pacemakers.
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Semiconductor technologies thus provide a number of capabilities that can be applied to life sciences domains, particularly for molecular and cellular analysis (see table).
Required materials
The potential for microsystems technologies to add value in life sciences applications relies on the materials used and the associated processes, especially photolithography and etching. A wide range of different materials are available due to the establishment of standard microsystems technologies, including silicon, glass, polymers, metals, and hybrids of all of these. Each material and associated process creates unique structures with characteristics of interest to different life sciences applications.
Glass is currently the material of choice for biochips due to its optical transparency and favorable properties for cellular analysis and detection with micro-arrays. Glass can be biocompatible and chemically inert with remarkable resistance in harsh environments, allowing it to perform analysis such as micro-HPLC or electrophoresis. Caliper’s LabChip is a great example of the use of glass substrates for biological analysis, featuring separation channels 10µm deep and 50µm wide. Companies like Micronit Microfluidics BV, The Netherlands, work with glass to develop microfluidic systems suitable for molecular analysis.
Polymers are also being used and are challenging glass in many applications. In fact, more and more companies are selecting polymers as the biochip substrate for diagnostic test development, including Amic, Gyros, Epigem, and Greiner Bio-one.
Monocrystalline silicon is a relatively more expensive material, but it was the first substrate material used and is still the material of choice for micronozzle and sensor manufacturing. Silicon wafers are also used for the development of lab-on-chip devices combining multiple functions to achieve a complete analysis solution, including fluid management, amplification, hybridization or affinity binding, and detection. Silicon provides many useful physical effects for sensing, has a low heat capacity but a good thermal conductivity, and can be made porous to increase the surface-area and reaction efficiency. Silicon manufacturing processes also allow for the integration of electrodes to the chip, as well as “intelligence on board” with microelectronics circuitry.
A good example of silicon material integration for a life science application is the In-Check lab-on-chip platform developed by STMicroelectronics, Italy. Silicon’s thermal characteristics allow for relatively much faster heating/cooling such that polymerase chain reaction amplification can be accelerated. First applications targeted are in the field of molecular diagnostic through partnerships with diagnostic companies, such as Veredus Laboratories, Singapore, for the avian flu and other influenza virus strains detection, and Mobidiag, Finland, for the detection of microbes and antibiotic resistance.
An emerging trend is the combination of different substrate materials (i.e., silicon/polymer or glass/polymer) in the same system. Such “hybrid” components are now mainly used for the design of drug delivery systems (such as Boehringer Ingelheim microParts’ Respimat), autonomous diagnostic systems, or cell chips. The main issues with hybrid substrates are the assembly and bonding of the different materials while maintaining biocompatibility, and the need for some ability to perform sterilization at high temperatures.
Conclusion
Microelectronics companies can play a role in the life sciences field when their design and manufacturing expertise can provide at least part of a key solution to market expectations. However, life sciences as a general market includes many different industries like drug discovery, in-vitro diagnostics, medical devices, and instrumentation, each with their own unique challenges. The market is fundamentally segmented in term of applications and technologies.
A key success factor in entering this field is to first get a good understanding of market expectations, associated value chains, market timelines, and entry barriers. Some semiconductor players have already faced difficulties in entering life science markets. Materials and processes are not the most important elements to succeed in this field. To create value while targeting life science market segments, partnerships and collaborations are essential, and not just because access to a strong distribution network is crucial. New entrants benefit from existing life science players’ expertise regarding applications requirements, clinical trials, and regulatory issues.
Acknowledgments
This paper is derived from LifeScience IC report 2006 by Yole Développement. Respimat is a registered trademark and Soft Mist is a trademark of Boehringer Ingelheim microParts. Caliper and LabChip are registered trademarks of Caliper Life Sciences. In-Check is a trademark of STMicroelectronics. Biosite is a registered trademark of Biosite Inc. NanoMate is a registered trademark of Advion BioSciences Inc. Gyros, Gyrolab, and Bioaffy are trademarks of Gyros AB.
For more information, contact Clémence Labat, senior market analyst at Yole Développement, 45 rue Sainte Geneviève, Lyon, 69006, France; ph 33/472-830-194, fax 33/472-830-183, email [email protected].