基因晶片之光罩設計與微影製程

Abstract

人體各部位器官功能的正常與否是由不同的基因序列表現是否正常來控制，若知道哪一個基因序列掌管哪一個器官功能，就可以對特定基因序列做檢驗，檢查那一個器官功能是否正常而達到疾病的預防與治療。基因晶片即是做基因序列檢驗的工具。 基因晶片是利用半導體技術中的光微影術加上光罩，在晶片上做出微細結構的方格陣列。再利用生物上的DNA合成儀，配合光微影術將鹼基依序放入方格陣列中，合成出寡核甘酸。基因晶片最大的功用是可檢驗出單一鹼基突變的基因，以便針對突變的基因，做修補或治療，如此一來將可避免傷害到正常基因。除此之外，基因晶片對於遺傳疾病與藥品檢驗也有很大的功用。 基因晶片的製作一項跨領域技術的合作，本論文的研究範圍涵蓋了基因資訊處理、光罩設計、微影製程、DNA合成、基因檢測等，而以半導體製程技術與生物DNA合成技術的結合為研究重點。由於在半導體製程上與DNA合成技術上一些化學藥品有相互衝突的情形，因此克服這個困難為我們研究的主要方向；也就是要找出基因晶片製程的最佳製程參數。 我們製作出一片測試用基因晶片，並用來和DNA目標檢體(Target)雜交，以測試光罩、光微影製程與DNA合成的整合效果。雜交後的螢光反應證實我們所研發的整合製程基本上是成功可行的。目前我們在基因晶片製作上，已掌握了一些關鍵參數與技術，將可供日後改進做參考。

The health of an individual heavily depends upon the expressions of the genes in the cells of the body. Each gene has its own nucleotide sequence and controls a particular function. Therefore, the traditional health examination may be performed by examining the nucleotide sequence of the genes. In this work, we study the fabrication of a gene chip, which is a tool capable of examining a vast of gene sequences of various kinds at a time. The method of oligonucleotide microarray fabrication developed in this experiment uses ultraviolet light passed through glass masks to direct the synthesis of oligonucleotides on a silicon wafer. Utilizing photolithography technique, we may synthesize oligonucleotides microarrays in selected patterns. After hybridization, the gene chip could discriminate single-base pair mismatches, which is one of the features of the oligonucleotides microarrays. The fabrication of gene chip is multidisciplinary, it involves the techniques on gene informatics, mask design, photolithography, DNA synthesis, and hybridization. Because we lack of references to solve the unwanted chemical interference with the photolithographic double-layer structure during the DNA synthesis process, our work is focused on the development a new protocol in fabricating our gene chip. We have fabricated a simplified gene chip for hybridization test. We will present the result of the fluorescence emitted from the labeled target oligonucleotide sequences after hybridization, which indicates the feasibility of our protocol. We believe a better protocol can be achieved in the near future.