全整合CMOS 生醫診斷系統單晶片平台

Abstract

對於全球未開發國家而言，醫師資源短缺仍是非常嚴重的問題。為了解決此問題，個人醫療診斷平台開發越益重要且其具有相當大的潛力。 由於半導體技術快速的成熟及發展，如何利用CMOS平台開發個人醫療體外診斷系統為未來主要研究發展方向。本論文除了對生醫系統單晶片診斷平台的設計做一完整介紹外，也將完整介紹所開發的三個系統單晶片並且實際應用於臨床血液檢體樣本。此三個系統單晶片分別為高靈敏度生物分子感測系統，微流體運輸系統，以及全整合式CMOS生醫系統單晶片。其依應用所需，整合適當之CMOS微感測器與流體致動器，並設計相對應的感測讀取及驅動電路。以下為所研發之生醫系統單晶片的摘要介紹： 1. 高靈敏度Bottom gate biodiagnosis system-on-chip (BG-bioSSoC)臨床血清樣本檢測系統單晶片 利用台積電0.35 μm製程技術，實現具高靈敏度之臨床血清樣本檢測單晶片，可針對急性心肌梗塞，檢測心臟衰竭指標蛋白。對於個人醫療診斷而言，如何避免臨床血液樣本中背景蛋白干擾，正確檢測血液中指標蛋白濃度為現今研究主要面對課題。在此系統單晶片設計上整合了CMOS矽奈米線元件以及其底部閘極結構設計，搭配低雜訊高CMRR的特性介面電路，針對臨床血清樣本實現一矽奈米線心肌梗塞特異蛋白檢測SoC晶片系統。此感測元件設計利用底部閘級結構，外加一電場於矽奈米線生物分子感測器，可增加外加電場對於生物分子蛋白的靜電吸引力。經由實驗結果證實，心肌梗塞蛋白感測訊號在50%稀釋的血清樣本中，相較未外加電場的感測訊號，可提升至26倍。 此結果顯示，BG-bioSSoC在臨床血清樣本中仍具有感測高靈敏度，十分適合為個人醫療體外診斷應用。 2. 臨床血清樣本流體驅動幫浦系統單晶片 利用台積電0.35 μm製程技術以及後製程步驟，結合微流道設計將流體驅動幫浦結構以及其驅動電路實現並整合於CMOS晶片上，完成一個CMOS流體驅動幫浦系統單晶片。由於大多數臨床生物樣本都以液態存在，因此流體驅動為個人醫療體外診斷平台開發的重點項目。此單晶片系統設計根據交流電滲泳原理技術，在平行排列電極上輸入具有九十度相位差訊號，可驅動臨床稀釋血清樣本。此晶片具備微型化，可大量製造，低功率等優點，並且極容易與CMOS 高靈敏生物分子感測器整合。根據實驗結果，利用所設計相對應的驅動電路，在1.5伏的電壓下，此流體晶片可成功驅動稀釋的臨床血清樣本。而此晶片耗能僅需1.74 毫瓦，其特性十分適合為個人醫療體外診斷應用。 3. 生醫體外診斷平台應用之CMOS系統整合感測晶片 此整合感測晶片利用台積電 0.35 μm製程技術結合了微流體驅動以及矽奈米線生物分子感測元件，成功驅動稀釋全血樣本溶液，並且在全血溶液中實際感測心肌梗塞蛋白分子。此整合感測晶片結合以上介紹之系統單晶片，分別為高靈敏度BG-bioSSoC生物分子感測晶片以及微流體致動幫浦系統單晶片，搭配相對驅動以及感測電路，結合微流道系統來實現生醫體外診斷平台之感測生醫晶片系統，可應用於全血樣本檢測。根據實驗數據，此單晶片系統可驅動全血樣本運送至矽奈米線感測區域，流速可達10 μm/s。此外利用矽奈米線感測元件在全血樣本中量測心肌梗塞蛋白，最小可成功感測濃度為3.2pM。此整合晶片成功實現了生醫體外診斷平台，十分適合發展為個人化醫療產品。

To date, doctor shortage is still a critical problem across the global world. To solve this issue, point-of-care testing (POCT) platform has more significant potential for performing diagnosis owing to its merits in clinical healthcare application. Among various POCT devices, in vitro diagnosis (IVD) for clinical blood test is the most critical fields for POCT development. Harnessing the advance of complementary metal-oxide-semiconductor(CMOS) technology, CMOS-based biomedical system has great potential to realize the vision of future POCT platform system. In this dissertation, a complete overview of POCT is first given, followed by introduction of CMOS-based biosensors and fluidic actuator for bio-diagnosis system. This bio-diagnostic system consists of clinical blood sample handling, silicon-based sensor device and the built-in interface circuit. It can serve as a SoC sensor product for POCT personal healthcare application. Three different fully-integrated CMOS SoCs are respectively implemented and designed for biomolecular detection, microfluidic actuation, and biosample diagnosis platform. First chip is the bottom-gate biodiagnosis system-on-chip (BG-bioSSoC) for biomarker detection in clinical serum samples. In blood test application, the biomolecular analyses in serum is essential information to diagnose patient status. For the development of the POCT blood diagnosis device, the background interferences within serums are the major challenges to be conquered. To overcome this obstacle, this BG-bioSSoC presents a fully integrated bottom-gate poly-silicon nanowire (poly-Si NW) biosensor SoC implemented in a 0.35μm CMOS process from a semiconductor foundry. By applying electrical potential at the bottom gate under poly-Si NW biosensor, the biosensor SoC response of cardiac-specific Troponin I (cTnI) biomarker can be improved by 26 folds in 50% phantom serum samples. This enhancement can be contributed to the electrostatic interactions between target biomolecules and the applied bottom gate voltage. Here, this is the first time for a fully integrated poly-Si NW CMOS biosensor, which shows feasibilities of biomarker detection in serum samples. The second SoC is integrated by an on-chip micropump and related driving circuitry for fluidic actuation. To develop a practical bio-diagnosis system, since most of the biological clinical samples are in liquid phase, the microfluidic pump is an essential component in POCT applications. Here, a low-power microfluidic pump SoC based on travelling-wave electroosmosis (TWEO) is reported for blood sample actuation. This CMOS TWEO pump SoC is fabricated by 0.35 μm Bio-MEMS standard process which characterized with mass production, miniaturized size, low power consumption, and easy to integrate with various CMOS based biosensors. This on-chip TWEO pump SoC is first successfully developed and driven by a monolithically integrated low-power circuit. This SoC has the ability to actuate the clinical diluted serum sample with the flow velocity of nearly 51 μm/s at 1.5V driving voltage. Furthermore, the power consumption of this TWEO pump SoC to drive diluted serum sample is 1.74mW which is appreciated as the actuator for potential POCT system in blood test applications. To further develop a powerful CMOS SoC bio-diagnosis platform, a monolithically integrated micro-fluidic biosensor system-on-chip (μBio-SSoC) is successfully realized in standard 0.35 μm CMOS processes. Furthermore, this is the first time that the on-chip CMOS-based TWEO pump to drive the diluted whole blood samples for biomarker diagnosis. This μBio-SSoC is composed of a TWEO pump, a poly-SiNW biosensor, and driving/sensing circuits. With 1.5V driving voltage, the μBio-SSoC has the ability to drive diluted whole blood sample to biosensing area with nearly 10 μm/s flowing velocity. After sample liquid pumping, the detection limit of the integrated nanowire biosensor is experimentally verified at 3.2pM for cTnI protein in diluted whole blood sample. This μBio-SSoC successfully demonstrates the high-sensitivity poly-SiNW biosensor equipped with the ability of microfluidic whole blood sample handling. This technique shows a feasibility of a CMOS biodiagnosis SoC can be implemented and realized in personalized healthcare blood test application.