本研究對於疑似新興傳染病、生物病原恐怖攻擊或感染急症之快速檢測，所進行之技術開發與應用研究，由於高傳染病的感染診斷一般需要將病患檢體送至微生物實驗室進行培養與核酸檢測，雖然市面上有部分快篩試劑產品，檢測靈敏度不足始終是最大的問題，因此開發現場可執行之高傳染性病原快速且靈敏度高的檢測方法是相當重要且迫切需要，可即時為患者提供適切的治療，並立即採取必要的感染管控措施，避免疫情擴散。我們建置一個簡單的方法可在採樣現場直接快速檢測血液檢體當中的病原，以解決目前現行檢測方法需要將檢體送入實驗室進行微生物培養與分析的不便性，首先利用鼠疫桿菌(Yersinia pestis)作為偵測標的物以確認方法的可行性，發現此法對於偵測鼠疫桿菌而言呈現高靈敏度，檢測極限可達100 CFU/mL，線性範圍很廣在102~107 CFU/mL之間。在此研究中我們採用自製的一維繞射感測器(one-dimensional diffraction grating sensor，簡稱ODGs)，即線型生物矽晶片，並以聚多甲基丙烯酸（PMAA）刷的頂端連接抗體，抗體可專一性地抓取目標病原體，不會抓取其他細胞或病原體，操作方式是將血液檢體滴加到一維繞射感測器上，將雷射光以45°的角度射入，並測量其反射繞射的強度，當晶片上有特定病原體存在時，反射繞射的強度會降低。我們發現當雷射光照射入晶片，且雷射光方向與溝槽平行，使雷射投影到晶片平面上時，在這樣的配置下偵測靈敏度更高。另外，2D和3D反射繞射的特點則是繞射階數的角度和振幅表現出對稱和不對稱的特性，這取決於晶片的方向，因此，可依雷射強度的變化作為特定病原體存在的指標。使用一維繞射感測器偵測微生物病原的優勢是僅需病原的專一性抗體，無需搭配任何螢光標記，儀器可輕易攜帶到實驗室以外的場域進行分析，且整個操作反應時間小於1小時。
另外，我們製作具有線陣列的一維繞射光柵晶片，透過乙基（二甲氨基丙基）碳二亞胺(EDC)和N-羥基琥珀醯亞胺(NHS)即EDC/NHS反應，將明膠(gelatin)選擇性地固定在具有2微米解析度的光刻模板溝槽陣列的醯胺基改質的基底上。已固定明膠的線陣列經過溴化後產生可用於原子轉移自由基聚合(ATRP)的大分子起始劑，再從大分子起始劑這一層開始接枝Poly(methacrylic acid) (PMAA)形成高分子刷線陣列。在接枝PMAA的不同聚合時間中，以雷射光束系統分析晶片，沿橫向磁極化(TE)和逆向電極化(TM) 45°分析觀察繞射效應的光學特徵，我們發現PMAA線陣列矽晶片隨著時間PMAA生長而增加了線刷的高度和寬度，導致反射繞射強度出現變化。通過用胰蛋白酶(trypsin)分解明膠，將不同接枝聚合時間下的PMAA刷從晶片基質上裂解下來，並通過膠體滲透層析儀分析它們的分子量。發現當PMAA分子刷的分子量在135到1475 kDa範圍下，PMAA刷的分子量與繞射強度的變化程度呈現線性關係，且相關係數高。使用反射繞射強度判斷聚合物刷分子量的測定方式，無需斷裂聚合物刷，提供可即時監測分子刷生長的簡單方法。

The focus of this dissertation is the applied research and development for rapid diagnosis of emerging infectious diseases, bioterrorism agents and acute and severe infectious diseases. Diagnosing potential contagious infections typically requires transporting patient specimens to microbiological laboratories for microorganism culture and/or molecular diagnosis. Although commercial rapid test kits (LFA) are available, their sensitivity is unsatisfactory. Therefore, a rapid and highly sensitive test at the point of care is important and urgently needed for the timely care of patients as well as for controlling the spread of infectious diseases. This research addresses the shortcomings of the methods widely used for detecting pathogens in human blood specimens, including their dependency on transporting the specimens to labs for microbial culture and analysis, and in response introduces herein a simple method that can deliver results quickly at the point of care. Through experiments with Yersinia pestis, the pathogen for plague, the method was shown to be highly sensitive, with LOD at 102 CFU/mL and linearity range between 102–107 CFU/mL. On the other hand, the LOD of immunofluorescence assay, commonly considered sensitive, but hardly to 103 CFU/mL, Moreover lower concentration would be undetectable under fluorescent microscopes. Major steps of the method include adding the specimens onto one-dimensional diffraction grating sensors (ODGs) made in-house, shining laser at them, and measuring the loss in the intensity of the reflective diffraction pattern caused by the presence of pathogen captured by its specific antibody, which was attached to the tip of the poly(methacrylic acid) (PMAA) brushes of the ODGs. The configuration for optimal sensitivity was found to be orienting the chip to align its trenches with the laser beam at 45-degree incident angle. Depending on the orientation, the diffraction orders’ angles and amplitudes exhibited symmetric and asymmetric properties, characteristic of the two- and three-dimensional reflective diffraction. The specific pathogen, if present, would be captured by the specific antibody and lead to the reduction in intensity of the diffraction orders. The advantages of detecting pathogenic microbes using diffraction grating include that the system only requires the specific antibody for the pathogen, is label-free for fluorescence and enzymes, and easily carried to point-of-care, where test results can be available within minutes of specimen collection.
The change in reflective diffraction intensity, as observed by analyzing the optical feature of the characteristic diffraction effect produced by shining a laser beam along the transverse magnetic and transverse electric polarization at 45° incident angle, was affected the heights and widths of the PMAA brush lines, which grew with grafting polymerization time. To monitor the growth without polymer brush cleavage, the molecular weights of the PMAA brushes were measured instead. It was made possible with a simple process: Selectively immobilize gelatin on the bottom, which were treated with ethyl(dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide reaction, of the trench array of a 2 μm resolution photoresist template. The gelatin-immobilized line array was brominated to produce a layer macroinitiator for atom transfer radical polymerization, to which PMAA brushes were grafted to form line arrays of one-dimensional diffraction gratings (DGs). After various polymerization time, the PMAA brushes were cleaved from the substrate by digesting gelatin with trypsin and weighted by gel permeation chromatography (GPC). The molecular weight of the PMAA brushes, within a wide range from 135 to 1475 KDa, was found to be highly correlated linearly with the change in diffraction intensity.

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