Development

In-situ synthesis was first applied by Fodor and his colleagues to produce a DNA microarray. Affymetrix Inc developed photolithography (Fodor et al, 1991) in-situ synthesis method, which uses photo-chemical protection to synthesize oligonucleotide probes on the substrate directly. The advantage of this method is high accuracy while the drawback is time-consuming and expensive in manufacturing optical masking agents. Singh-Easson’s research group from University of Wisconsin used the computer designed virtual mask also known as photolithography using dynamic micro-mirror devices to prepare DNA microarrays.

An optical digital micro-mirror device, including 480000 small aluminum mirror arrays, was used to precisely control the direction of light reflection in the mirror by the computer, beaming the ultra-violet radiation directly to the glass substrate for selective removal of the protection of the base in a particular region of the substrate. Virtual mask technology is cost-effective and less time-consuming (Singh-Gasson et al, 1999). Nimblegen Company has taken advantage of this technology in production of the high density commercial DNA microarrays (Teng and Xiao, 2009).

LU Zuhong’s group (Xiao et al, 2002) from Southeast University in China has established another in-situ synthesis of oligonucleotide microarrays on glass surfaces by using soft lithography (called molecular stamp). This method is based on the standard phosphoramidite chemistry protocol. The coupling was achieved by the glass slide being printed with a set of polydimethylsiloxane (PDMS) microstamps, on which spread nucleoside monomer and tetrazole mixed solution. The elastic characteristic of PDMS allowed it to make conformal contact with the glass slide in the printing coupling. In this way, oligonucleotide microarrays can be fabricated with a feature size of 100 μm and 30 μm. In China, the government initiated the projects for research and development of biochip technology by the end of 1990s.

The first DNA microarray in China was made under the financial support from the Human Genome Project of the Chinese Academy of Sciences, using a large number of human cDNA clones identified by EST sequencing conducted by Chinese National Human Genome Center at Shanghai. It was successfully used in the first case of transcriptome comparison of hepatocellular carcinoma with those of the corresponding noncancerous tissue. This work was published in the PNAS in 2001 (Xu et al, 2001) which represent the breakthrough of DNA microarray application in China. By the end of the Ninth Five-Year Plan, research groups in Beijing, Shanghai and Nanjing began to accelerate the biochip technology study owing to the strategic support from the National High-Tech Developing Programs (also known as “863” Program). Hua Guan Biochip Company in Shanghai was thus set up and engaged mainly in research and development of diagnostic biochip (Teng and Xiao, 2009).

In addition, a number of domestic private enterprises have involved in the research and development of biochips, such as “Yi-sheng Tang” in Guangzhou, “Bio-Star” in Shanghai and “JianNan Biotechnology” in Zhejiang. In 2000, the government has invested nearly 500 million RMB in succession to set up two national engineering research centers for development of biochip technology and products in Beijing and Shanghai.

Under the support of “863” and other national grants during the Tenth Five-Year Plan and the Eleventh Five- Year Plan, a series of biochip technologies and products have been developed and commercialized. For example, the National Engineering Center for Biochip at Beijing has developed DNA microarray scanners, microarrayer, hybridization oven and sample handling equipments, forming a complete set of instruments for fabricating and application of DNA microarrays (Teng and Xiao, 2009).

Meanwhile, commercial products including gene expression microarrays, mRNA microarrays, CGH microarrays, DNA methylation microarrays have been developed through their own platform, which represents the establishment of a complete industry chain for fabrication and application of DNA microarrays with independent intellectual property rights. Microarrays start to be applied in food safety examination and clinical diagnosis.

The National Engineering Center for Biochip at Shanghai, on the other hand, established a DNA microarray platform based on the printing technology and developed independently more than 20 kinds of gene expression microarrays and pathway microarrays, including the genome-wide expression microarrays of rats, mice and microorganisms. At the same time, the globally widely used systems, such as Affymetrix, Agilent, Illumina and Nimgblegen, were also introduced into China to provide comprehensive solutions of microarray application (Teng and Xiao, 2009).

A standard operation protocol (SOP) and the criteria for quality controls were established which in turn promote the development of DNA microarray in China. Until now, more than 100 research papers have been published in PNAS (Zheng et al, 2005; Huang et l, 2006), Genomics (Hua et al, 2008; Zhang et al, 2007), BBRC (Zhao et al, 2007; Li et al, 2006), JBC (Ma et al, 2006), FEBS Letter (Huang et al, 2006; Xu et al, 2005), and other international journals related to DNA microarray application supported by “973”, “863”, “NSFC” and Shanghai Science and Technology Commission (Teng and Xiao, 2009).