利用CMOS生物感測技術檢驗臨床心臟疾病的血清生物分子

Abstract

個人化醫療在近年來一直是一個非常重要的議題，利用床邊檢驗幫助臨床醫師與病患治療疾病，隨著科技的發展，有越來越多的工具可以使用。另一方面，對於醫師資源短缺的地區或國家來說，使用此床邊檢驗可以幫助未能親自前往的醫師幫忙診斷及重症疾病，進而做醫療決策轉送至後邊大型醫院接受治療，個人醫療診斷平台開發越益重要且其具有相當大的潛力。另一方面，由於全球半導體技術快速的成熟及發展，我們可以進一步利用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。 根據美國心臟病協會(American Heart Association, AHA) 的調查顯示，在美國每三個人之中就有一個人會死於心血管疾病：包括冠狀動脈硬化、心律不整、心肌梗塞、中風等。臨床資料顯示，目前台灣的心血管相關疾病的罹患比率已經和美國相去不遠，主要和生活習慣已逐漸西化有關，常見的抽菸、不規律的運動、飲食習慣不良等都會增加罹患的風險。預防心血管疾病的發生，首先就是要先了解引發的因子。現代人的心血管疾病大多是因為冠狀動脈病變所引起，在臨床上，心血管疾病的血清標記在救治病人與時效性方面的意義都非常的重要。重要的心血管疾病包括了冠狀動脈疾病，心肌梗塞，與心臟衰竭。此三種疾病都有對應的血清標記，若能早期偵測，早期預防，不良心血管事件與死亡率皆能大幅降低與改善。在臨床上，這些心血管血清標記已被大幅使用於診治病人，但是它們的準確性與敏感度仍然是科學界努力的目標。 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，也將介紹所開發系統單晶片並且實際應用於臨床血液檢體樣本。此系統單晶片分別為高靈敏度生物分子感測系統，並可同時檢測三種重要的血清標記，用以診斷嚴重的心血管疾病與其臨床預後。以下為所研發之生醫系統單晶片的摘要介紹： 高靈敏度Biodiagnosis system-on-chip (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，可針對心血管疾病，急性心肌梗塞，與心臟衰竭，檢測相對應的interleukin-6、cardiac Tropnin-I和N-termianl proBNP。對於個人醫療診斷而言，如何正確而即時檢測血液中三種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，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血管疾病特異蛋白組件檢測SoC晶片系統。經由實驗結果證實，interleukin-6、cardiac Tropnin-I和N-terminal proBNP在稀釋的血清樣本中，仍能有效偵測此三種血清蛋白。此結果顯示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。

Doctor shortage remains a critical problem across the world. To solve this issue, point-of-care testing (POCT) platform shows significant potential in diagnostic function, owing to its merits in clinical healthcare application. Among various POCT devices, in vitro diagnosis (IVD) for clinical blood test is the most critical field for POCT development. Harnessing the advantages 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 was first given, followed by introduction of CMOS-based biosensors for bio-diagnosis system. The bio-diagnostic system consisted of clinical blood sampler and silicon-based sensor device. It could serve as a SoC sensor product for POCT personal healthcare application. The CMOS SoCs was implemented and designed for biomolecular detection and biosample diagnosis platform. According to the American Heart Association (AHA) survey, one out of every three people in the United States dies of cardiovascular disease: coronary atherosclerosis, myocardial infarction, stroke, and more. Clinical data show that at present the incidence of cardiovascular-related diseases in Taiwan is not far from the United States. It is mainly due to the gradual westernization of living habits. Common smoking, irregular exercise and poor eating habits all increase the risk of cardiovascular disease. Prevent the occurrence of cardiovascular disease, the first is to first understand the trigger factor. Modern cardiovascular diseases are mostly caused by coronary artery lesions. In clinical practice, the significance of serum markers of cardiovascular diseases in the treatment of patients and the timeliness are very important. Important cardiovascular diseases include coronary artery disease, myocardial infarction, and heart failure. All three diseases have corresponding serum markers. If early detection, early prevention, adverse cardiovascular events and mortality can be significantly reduced and improved. Clinically, these cardiovascular serum markers have been widely used in the diagnosis and treatment of patients, but their accuracy and sensitivity remain the goal of the scientific community. The chip was the biodiagnosis system-on-chip (BioSSoC) for biomarker detection in clinical serum samples. In blood test application, the biomolecular analyses in serum provided essential information to diagnose patient status. For the development of the POCT blood diagnosis device, this BioSSoC presented a poly-silicon nanowire (poly-Si NW) biosensor SoC implemented in a 0.35μm CMOS process from a semiconductor foundry. The biosensor SoC could respond to three biomarkers of cardiac disease in phantom serum samples. The enhancement could be contributed to the electrostatic interaction among target biomolecules. This was the first time for a fully integrated poly-Si NW CMOS biosensor to demonstrate feasibility of biomarker detection in serum samples.