TW200528179A - High sensitive multi-channel air-virus-counting device and method - Google Patents
High sensitive multi-channel air-virus-counting device and method Download PDFInfo
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五、發明說明(1) 【發明所屬之技術領域】 一種多通道高靈敏度的空氣縣 置,用以精確的計算出在定量空$ =病毒計數(偵測)裂 別是指使用時將定量的空氣檢5 =病毒的數量^特 離檢體中的病毒’並加以計數的檢:j =進口,自動去分 【先前技術】V. Description of the invention (1) [Technical field to which the invention belongs] A multi-channel, high-sensitivity air station is used to accurately calculate the quantitative empty $ = virus count (detection) split refers to the quantitative Air test 5 = the number of viruses ^ the virus in the test specimens and counted: j = import, automatic separation [previous technique]
近年來生物氣膠的健康危害漸受 居亞熱帶地區,氣候溫暖潮濕,終 估。台灣^ 以上,溫度平均介於2。。卜3(^之:相=度平均在7〇% 生長,尤豆在今客你螢尸悴由― 十刀適合微生物含 i因存在著相當高濃度的生物素 發”用之生物氣膠環境债測技術以獲得具代; 性的樣本,是相當重要的課題。 生物氣膠泛指懸浮於空氣中的生物微粒,其來源十分 廣泛’其中包括:病毒、細菌、放射菌(8(^111〇1115^46)、 真菌(fungal)、苔(moss)及蕨(f e r η)之孢子;蕩類In recent years, the health hazards of biogas rubber have gradually been affected by subtropical regions, and the climate is warm and humid. Above Taiwan ^, the average temperature is between 2. . Bu 3 (^ of: phase = degree average growth at 70%, You Dou in this guest your firefly 悴 悴 10 knife suitable for microorganisms containing i because of the existence of a relatively high concentration of biotin hair "bio aerosol environment Debt measurement technology to obtain a representative sample is a very important subject. Biogas gel refers to biological particles suspended in the air, which come from a wide range of sources, including: viruses, bacteria, radioactive bacteria (8 (^ 111 〇1115 ^ 46), fungal, moss, and fern (fer η) spores
(algal)及植物之細胞;昆蟲及其碎片與***物;來自 動、植物之蛋白質;生物科技製造之酵素、抗生素、及其 他產物;革蘭氏陰性細菌之内毒素(Endotoxin);真菌產 生之黴菌毒素(mycotoxin)及醣類(glucan)。病毒症目前 並無有效之藥物可治療及預防,唯一有效的辦法就是隔絕 病毒入侵。 過去的研究選定衝擊瓶、薄膜濾紙及果膠濾紙三種常(algal) and plant cells; insects and their fragments and excreta; proteins from animals and plants; enzymes, antibiotics, and other products made by biotechnology; endotoxins from Gram-negative bacteria; Mycotoxin and glucan. There is currently no effective medicine to treat and prevent viral disease. The only effective way is to isolate the virus from invasion. Past research has selected three types of impact bottles, membrane filter paper and pectin filter paper.
第11頁 200528179 五、發明說明(2) 使用的生物氣膠接接 子(採樣流量、室評估,探討物理性因 性因子(生物氣膠本身ς耐23甘採樣時間)與生物 採樣效率(入口效率此隹丨)對其採集細菌的物理性 回收率:菌落存活效率及相對存活率樣效率(總 〇公共侑生學院環境衛生組郝玫芝^胃參考台 樣技術之評估) 字之珊生物氣膠採 大的=耐;2強弱是決定採樣器生物採樣效率影麼最 八扪U于抓集大腸桿菌時,衝墼溆沾门^亦田千&響敢 落存活效率約為5 % ) , ^ ^ ' 率最好(其菌 差;而衝擊瓶和薄 氏、二、、、的回收率約較衝擊瓶 Η , 仁用4膜濾紙採集大腸桿菌時,撻接士 是一個影響因子,#杯卢]R八#勝枰国^如樣時間則 不大。 最好在Η 以内,採樣流量的影響都 在採集枯草桿菌的時候,衝 近,但薄臈據紙的回收率約σ右=果膠慮紙回收率相 左右,並不受氣擊瓶和果膠據紙的7〇% 在低濃产洛m二^辰度、採樣、机量和採樣時間的影塑。而 在低辰度乳膠環境時,採樣時 =: 採不到的情形。 J +且苁短,否則會發生 以上的收集生物氣膠的方式並不適用於料來# ^ h 上收集時間過長,所以不县右:::於微形化的機制’加 採樣收隼。另U:不易有效使用於-般環境進行現場 少提及,、所技,氣懸浮病毒的採集技術甚 本毛月特別提出微形化的靜電沉隼妒置來改 收集效革並促其成為手持式裝Ϊ,可容易Page 11 200528179 V. Description of the invention (2) Biogas adhesive connector used (sampling flow rate, room evaluation, discussion of physical factors (the biogas adhesive itself can withstand 23 gan sampling time) and biological sampling efficiency (inlet Efficiency 隹 丨) The physical recovery rate of the bacteria it collects: colony survival efficiency and relative survival rate-like efficiency (total 〇 Evaluation of Environmental Health Group Hao Meizhi ^ Stomach Reference Bench-like Technology) Large = resistant; 2 strong and weak is to determine the biological sampling efficiency of the sampler. When the E. coli is collected, it will be washed at the door ^ Yitian Qian & Xiang Dangluo survival efficiency is about 5%), ^ ^ 'The rate is the best (its bacteria are poor; and the recovery rate of the impact bottle and thinner, two ,, and is about that of the impact bottle. When collecting Escherichia coli with 4-membrane filter paper, tart is a factor, #cup卢] R 八 # 胜 枰 国 ^ This time is not large. It is best to be within Η, the impact of the sampling flow is close when collecting B. subtilis, but the recovery rate of thin paper is about σ right = fruit The recovery rate of adhesive paper is about the same, and it is not affected by 70% of the rubber paper is produced in the low-concentration product, the sampling time, the amount of the machine, and the sampling time. In the low-temperature latex environment, the sampling time =: The situation where it is not available. J + And it is short, otherwise the above method of collecting bio aerosol does not apply to the material. The collection time on the material is too long, so it is not right: :: The mechanism for miniaturization is to add sampling and collect. Another U: It is not easy to use it effectively in ordinary environment. It is rarely mentioned on the spot. The technology of aerosol virus collection is very similar to that of Mao Maoyue. It specially proposes a miniaturized electrostatic sinking jealousy to change the collection effect and promote it to be handheld. Can be easily installed
第12頁 先前 單位的濃 微粒混合 粒數目, 間接計數 assay ) 紅血球結 與一系列 hemaggul 撕 79 於一般環境進行現場採樣收集與即時分析,同時也可 空氣懸浮病毒來處置。 一般針對收集的病毒檢測方式多使用聚合?連鎖力 (簡稱PCR )檢測技術。利用具有專一性之聚合?連鎖 應引子,依照各病毒之DNA聚合? 一致性基因所設計, 僅以該檢測病毒之基因為模板時,才會產生相對鹼基 酸片段,利用引子對病毒的專一性從而檢測出是否感 毒0 但使用P C R檢測方式費時,且須在實驗官中進杆 Γ般公司機關或家庭可自行備置,V:其至費中用進:較 昂三為此,本發明[病毒計數裝置]可讓一般公司機關 庭藉由自行備置的檢驗裝置快速而較低成本的檢驗出 空氣的品質是重度感染、輕度感染或無感染(亦即單 積空氣内的病毒數量多募),立即採取有效治療手段 防因時間延誤造成的傷害。 “Page 12 Previous units of concentrated microparticles, mixed particle number, indirect counting assay) Red blood cell knots and a series of hemaggul tears 79 On-site sampling collection and instant analysis in general environments, and can also be treated with airborne viruses. Do you generally use aggregation for virus detection methods? Linkage (PCR) detection technology. Use specific aggregations? Chain Should primers be polymerized according to the DNA of each virus? Consistent genes are designed to generate relative base acid fragments only when the virus-detecting gene is used as a template. The specificity of the primers to the virus is used to detect whether the virus is susceptible. However, the PCR detection method is time-consuming and requires The experimental officer can be prepared by the company organization or the family by itself. V: It is used to the expense: More than three. For this reason, the present invention [virus counting device] allows a general company organization to use a self-provided inspection device. A quick and low-cost test of the quality of the air is whether it is severely infected, mildly infected, or non-infected (that is, the number of viruses in a single accumulation of air is more recruited), and effective treatment is immediately taken to prevent injuries caused by time delay. "
计數病毒的方法有直接計數和間接測量病一 度。直接計數的方法是將病毒與已知濃度έ ’利用電子顯微鏡下觀察並算出數病毒數I 將計數結果與乳膠微粒濃度換算成病毒濃Z 最常見為凝血分析法(hemagglutination ,當病毒數與紅血球數比值足夠大時,病毒 合形成網狀,造成懸浮液沉澱或凝集,將系 病毒稀釋液混合’造成凝血的最高稀釋倍逢 ination titer ,此方法可正確快速定^ 針對 ^應 反 當 的核 染病 ,並 高 或家 周圍 位容 ,以 感染 乳膠 與微 t與 血球 即為 毒 200528179 五、發明說明(4) 數。 終點方法(e n d ρ 〇 i n t m e t h 〇 d )是將病毒懸浮液經一 系列稀釋後,接種至動物上,將每種稀釋度造成的動物致 死量做成曲線,找出造成5 0 %動物死亡的終點稀釋 度。LD50 (Lethal dose)與 ID50 (Infectious dose)即 是指在此稀釋度含有足夠劑量,可造成5 〇 %動物致死或感 染。 溶菌斑分析法(plaque assay)是將不同稀釋倍數的 噬菌體或動物病毒與宿主細胞混合,平舖於平板表面,當 病毒粒在一大片宿主細胞上引發感染時,會造成細胞被溶 解而形成溶菌斑,每個溶菌斑係由一個病毒粒所造成,計 算溶菌斑數目再乘以稀釋倍數,即可得知原來的病毒感染 單位的濃度。 在 nW0 02/052246 A2 Method and Device forThe methods for counting viruses include direct counting and indirect measurement of disease. The method of direct counting is to compare the number of viruses and known concentrations under an electron microscope and calculate the number of viruses I. The counting result and the concentration of latex particles are converted to the concentration of virus Z. The most common method is hemagglutination. When the number of viruses and red blood cells When the ratio is large enough, the virus will form a network, causing the suspension to precipitate or agglutinate. Mixing the virus dilutions will cause the highest dilution of blood clotting to occur in the titer. This method can be accurately and quickly determined. Infected, and high or around the home, the infection with latex and microt and blood cells is a poison 200528179 V. Description of the invention (4) Number. The end method (end ρ 〇intmeth 〇d) is a series of dilution of the virus suspension Then, inoculate the animals, and draw the curve of the animal lethality caused by each dilution to find the endpoint dilution that caused 50% of the animal's death. LD50 (Lethal dose) and ID50 (Infectious dose) refer to here The dilution contains sufficient doses, which can cause 50% of the animals to be lethal or infected. Plaque assay is to dilute different dilutions Several phages or animal viruses are mixed with the host cells and spread on the surface of the plate. When the virus particles cause infection on a large area of host cells, the cells will be lysed to form bacterial plaques. Each plaque is caused by a virus particle. As a result, calculate the number of plaques and multiply by the dilution factor to get the concentration of the original virus infection unit. In nW0 02/052246 A2 Method and Device for
Detecting and Identifying Bio-aerosol particles in the airn 生物氣膠粒子在粒子流中經過AT0FMS(aerosol time - of - flight mass spectrometer),利用榮光技術加 以選擇’而且以MALDI(matrix-assisted laser desorpt ion/ionizat ion)將選到的生物氣膠粒子離子化, 之後,所形成的離子因此被偵測到,所以生物氣膠粒子可 以被鑑定出來。但此法需要極昂貴的儀器設備。 由上所幾種方法得知要計算病毒的數量,有些要稀 釋,有些則利用顯微鏡觀察,有些需要昂貴的儀器設備, 而這些過程只會讓過程更複雜,變數更多而已,而利用本Detecting and Identifying Bio-aerosol particles in the airn ATOFMS (aerosol time-of-flight mass spectrometer) in the particle flow, selected using glory technology 'and using MALDI (matrix-assisted laser desorpt ion / ionizat ion ) The selected aerosol particles are ionized. After that, the formed ions are detected, so the aerosol particles can be identified. However, this method requires extremely expensive equipment. It is known from the above methods that the number of viruses needs to be calculated, some are diluted, some are observed with a microscope, and some require expensive equipment. These processes will only make the process more complicated and have more variables.
200528179 五、發明說明(5) 一 發明所製作之裝置不但不需要繁瑣的pCR過程,並也不需 要利用人工的方式去觀察病毒數量,本發明只需將檢體引 入裝置中即y準確的將病毒計算出來。跟先前技術相比, 本毛月不仁操作簡易,一般沒党過訓練的人即可使用,而 且觀察的準確性也高的多,另外價格也便宜。 【内容】 本發明的目 量的多寡, 本發明的目 測在一般的 去做繁瑣的 本發明的目 成,使用者 本發明的目 發出警告, 本發明的目 置,使用半 本發明的目 上,供日後 本發明的目 測多種不同 的之一 預防人 的之二 公司機 檢測方 的之三 無須專 的之四 立即採 的之五 導體製 的之六 分析及 的之七 的病毒200528179 V. Description of the invention (5) The device made by an invention does not only need a cumbersome pCR process, but also does not need to use a manual method to observe the amount of virus. The invention only needs to introduce the specimen into the device, that is, y will accurately The virus figured it out. Compared with the previous technology, Ben Maoyue is easy to operate. Generally, people without party training can use it, and the accuracy of observation is much higher, and the price is cheaper. [Content] The amount of the present invention, the visual inspection of the present invention is generally done in the tedious objective of the present invention, the user of the present invention issues a warning, the objective of the present invention, using half of the objective of the present invention For the purpose of visual inspection of the present invention in the future, one of the two different types of prevention of the company ’s two company ’s testers, three of which are not required, four of which are immediately collected, five of the five-conductor analysis, and seven of the viruses
’可快速的得出環境中空氣懸浮病毒襄 群受到病毒感染。 ,改善現有的病毒檢測技術,使病毒拍 關或家庭就可以做到,不必拿到實驗室 法。 ,,從取樣到檢测計數到判讀,一體完 業生化知識即可操作。 跑^即時判識是否有病毒感染的危險, 取有效措施。’It can be quickly concluded that the airborne virus cluster in the environment is infected with the virus. Improve the existing virus detection technology, so that virus detection or home can do it, without having to get a laboratory method. , From sampling to detection and counting to interpretation, one can complete the operation of biochemical knowledge. Run to identify if there is any danger of virus infection and take effective measures.
r提Γ厂種可整合成晶片形式的讀取裝 粒,與微機電製程來完成。 追蹤。 儲存於任何可攜式媒體 ,利用晶Μ μ夕, 。 上夕組獨立流道,可同步檢The r Γ plant can be integrated into the chip loading and loading, and the micro-electromechanical process to complete. track. Store in any portable media, using Crystal M μ ,. The independent flow channel of the eve group can be detected simultaneously
第15頁 200528179 五、發明說明(6) 技術内容 空氣懸 過程一、取 檢體的取得 下的無菌濾 微小粒子, 過程二、前 流通空氣的 足夠電荷, 電的病毒至 動牽引含病 讓病毒移動 過程三、病 進入檢驗分 _的電極施 的中央,而 電極的接點 極的區域; 過程四、病 將擁有病毒 再將液滴封 過程五、二 經第一次分 了達到精確 浮病毒計數晶片完整的 得樣本1 乃是將利用真空抽氣定 膜過濾,經過此步驟後 從待測環境中取得定容 處理(充電與靜電沉澱) 病毒,必要時可先加以 接著利用靜電沉澱的方 純水中,切換電極的接 毒的液體到液滴封包電 至其後的檢驗分析裝置 毒分離3 析裝置後第一階段會經 一高頻的交流電,使病 其他不是病毒的部分會 ’使電場改變慢慢移動 流程顯示在圖一 時間定流量經過5 // m以 了渡掉大部分之灰塵和 積的空氣; 2 父流充電,使病毒帶上 法’使高靜電場吸附帶 點’使電場改變慢慢移 極的區域,以便自動的 過分離電極,在兩旁交 毒被介電力排斥到流道 被吸附在電極上,切換 牽引病毒到液滴封包電 毒牽引4 之溶液經由電極轉換,使液滴形成液滴封包, 包送往離子通道的區域; 次分離5 離後會有少許的病毒殘留在分離電極區域,為 計數的目的,可做二次分離,當病毒經由牵引 圖Page 15 200528179 V. Description of the invention (6) Technical content Air suspension process 1. Sterile filtration of micro particles obtained from the specimen. Process 2. Sufficient charge in the air before circulation. The electric virus will move to the traction and contain the disease to make the virus. During the moving process, the disease enters the center of the electrode, and the electrode is in the area of the electrode pole. During the process, the disease will have the virus, and then the droplet is sealed. Counting the complete wafer to obtain sample 1 is to use a vacuum pump to fix the membrane to filter. After this step, obtain the constant volume treatment (charging and electrostatic precipitation) from the environment to be tested. Viruses can be used first if necessary, followed by electrostatic precipitation. In the switch, the poisoned liquid of the electrode is switched to the droplet encapsulation and the subsequent analysis and analysis device is separated. The first stage of the analysis device will pass a high-frequency alternating current, so that other parts that are not viruses will 'change the electric field. The slowly moving process shows that at a time, a constant flow rate of 5 // m passes through 5 // m to get rid of most of the dust and accumulated air; 2 The parent stream charges, making the disease Put on the method of “making the high electrostatic field adsorption band point” to make the electric field change the area that moves slowly to the pole, so as to automatically pass through the separation electrode, the poisoning on both sides is repelled by the dielectric force to the flow channel and it is adsorbed on the electrode, and the traction virus is switched to The solution of electroporation traction 4 of the droplet package is converted by the electrode, so that the droplet forms a droplet package, and the packet is sent to the area of the ion channel. After the separation 5, a small amount of virus will remain in the area of the separation electrode. For counting purposes, Can do secondary separation, when the virus passes the traction map
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第16頁 200528179 五、發明說明(7) 電極形成液滴 過第一次分離 會有少 分離, 病毒離 四的步 過程六 當病毒 下降; 過程七 電流下 道的病 部分之 首先將 開電極 驟把剩 、病毒 通過離 才=後會再經由第二段分離 再做-次分離,、經由分離電:^能 八雜币1 所以必要時可做多次 刀離電極電場釋放,使少 文少口丨为吸附在電極之 再她加電場做二次分齙, ^ ^ ^ ^ 入刀離’依過程三和過糕 了病毋送到病毒計數離子通道中,· 計數6 子通道時會使孔道部 1^ 七 < °丨切阻塞,造成離子電流 、檢測 降的次 毒數量 結果分析7數I I二:ί確的計算出在多組獨立檢測通 乂達到病毋計數的目的。 病毒採集裝置 由於懸浮空氣病毒主要以約_ 娇以若#用一蝌本 > 丄h 微未大小的液滴存在, 所以右便用一彳政水左右的過濾梦 a涡噹奘菩品么、+ + 〜展置,可能使病毒液滴停留 於過/愿表置而無法有效被收隼, ,看紙及果狀:奢祕楚. 一另外可能的衝擊瓶、薄膜 給分析F詈带” 士义、、、 動的讓病毒移動至其他的檢 驗为析展置,所以本發明特別撻 沾闲莴靜雷π成^桃而 敌出使用靜電沉澱的方法’ 使用同靜電%吸附帶電的病毒 ^ ^ ^ /L Ζ., 母主純水中,以便自動的讓病 毒移動至其他的檢驗分析裝置。 對於生物氣膠本身帶電荷不足者,可使用交流電場充Page 16 200528179 V. Description of the invention (7) Electrode formation droplets will be less separated after the first separation. The virus is separated from the four steps of the process. When the virus drops; the process of the current is to open the electrode first. After leaving the virus, the virus will pass through the second stage, and then it will be separated by the second stage and then separated again, and the electricity will be separated: ^ can be miscellaneous coins 1 Mouth 丨 For the second adsorption, she applied an electric field to the electrode. ^ ^ ^ ^ "Into the knife" according to the process of the third and the disease is not sent to the virus counting ion channel, · When counting 6 subchannels will make The channel section 1 ^ 7 < ° 丨 clogged, causing the number of secondary currents and the detection of the number of secondary poisons. The results were analyzed. II: Calculate the number of independent tests in multiple groups to achieve the goal of disease-free counting. Because the virus in the air collection device is mainly in the form of _ Jiao Yi Ruo # 用 一 本本> 丄 h micro-sized droplets, so the right side will use a filter of political water about a dream to vortex when it is a lotus root. , + + ~ Display, may cause the virus droplets to stay in the past / wish to be placed and cannot be effectively collected, see paper and fruit-like: extravagant. Another possible impact bottle, film for analysis F belt ”Shi Yi ,,,, and the movement of the virus to other tests are analyzed and displayed, so the present invention is particularly tart with lettuce and thunder π into ^ peach, and the method of electrostatic precipitation is used. Virus ^ ^ ^ / L Zn., Pure water of mother and master, so that the virus can be automatically moved to other inspection and analysis devices. For those who are not sufficiently charged with biogas gel, they can use AC electric field to charge
200528179 五、發明說明(8) 電器(charger),參考文獻 Μ· Lackowski,A. Jaworek, A. Krupa, "Current-voltage characteristics of alternating electric field charger", J. of Electrostatics,58(2003) 77-89, 一般所施加的頻率約 5 0 -40 0 Hz, 電場大小約lkV/cm -lOkV/cm,由於本發明 目的是將糸統微小化’所以形成電場充電的電極距離相車父 於參考文獻可能小於50 Oum,為使生物氣膠帶電並且不會 於充電中偏離至電極板上,本發明不使用直流充電,如參 考文獻[1] Mainelis,Gediminas; Adhikari,Atin; W i1 1 eke, Klaus; Lee, Shu-An; Reponen, Tiina; Grinshpun,Sergey A. "Collection of airborne microorganisms by a new electrostatic precipitator” Journal of Aerosol Science Volume: 33, Issue: 10, October, 2002, pp· 1417-1432 與[2]Mainelis, Gediminas; Willeke, Klaus; Baron, Paul; Reponen, Tiina; Grinshpun, Sergey A.; "Electrical charges on airborne microorganisms" Journal of Aerosol Science Volume: 32, Issue: 9, September, 2001, pp· 1087-1110 o 影響電暈(Corona)放電之最小電壓Vmin的因素主要 有二個: 1·空氣的Dielectric strength :太約是3 kV/mm. 2. 電極的形狀··曲率越大,或曲率半徑R越小,貝彳Vmi η 越低,反之則越高。200528179 V. Description of the invention (8) Electric appliance (charger), references MLackowski, A. Jaworek, A. Krupa, " Current-voltage characteristics of alternating electric field charger ", J. of Electrostatics, 58 (2003) 77 -89, the generally applied frequency is about 50-400 Hz, and the electric field size is about lkV / cm-10kV / cm. Since the purpose of the present invention is to miniaturize the system, the electrode forming the electric field charge is at a distance from the car reference. The literature may be less than 50 Oum. In order to charge the biogas tape and not deviate to the electrode plate during charging, the present invention does not use DC charging, such as reference [1] Mainelis, Gediminas; Adhikari, Atin; W i1 1 eke, Klaus; Lee, Shu-An; Reponen, Tiina; Grinshpun, Sergey A. " Collection of airborne microorganisms by a new electrostatic precipitator "Journal of Aerosol Science Volume: 33, Issue: 10, October, 2002, pp. 1417-1432 And [2] Mainelis, Gediminas; Willeke, Klaus; Baron, Paul; Reponen, Tiina; Grinshpun, Sergey A .; " Electrical charges on airborne microorganism s " Journal of Aerosol Science Volume: 32, Issue: 9, September, 2001, pp · 1087-1110 o There are two main factors affecting the minimum voltage Vmin of Corona discharge: 1. Dielectric strength of air: too It is about 3 kV / mm. 2. The shape of the electrode: · The larger the curvature, or the smaller the radius of curvature R, the lower the Vm η and the higher the opposite.
第18頁 200528179 五、發明說明(9) 若以針狀電極對平板(n e e d 1 e〜t。η 1 ^、 ^ ^ ^ ^ > Al , t0 —Plate)的電暈(Corona) 放電l置而吕,在針狀電極表而p斗 衣面附近的電場最強:Page 18, 200528179 V. Description of the invention (9) If a needle electrode is used for a flat plate (need 1 e ~ t. Η 1 ^, ^ ^ ^ ^ > Al, t0 —Plate), the corona discharge is set. And Lu, the electric field is the strongest near the needle electrode surface and p bucket surface:
Emax=V/R kV/mm X R = Vmin af, 當 Emax > 3 kV/mm,即 V > 會發生電暈放電. Ί此模型估算,各種曲率半徑❻ hlOOiim, Vmin = 30 0V; R = i〇 r/m v . mvmin ^ hEmax = V / R kV / mm XR = Vmin af, when Emax > 3 kV / mm, that is V > corona discharge will occur. ΊThis model estimates various radius of curvature❻ hlOOiim, Vmin = 30 0V; R = i〇r / mv. mvmin ^ h
Vuin,。 ㈣,Vl"in = 30V; R = 1,, 因此以微型化與可攜帶的設 過500 _,所施電壓以 、二,:極的間距不超 這當然可以用微機電技衔支針尖直徑要小於3 _ 、 电孜術來製作,另外一鲂佔砧每你古 f^使用叢集的奈米碳f陣列來達成,盆理由二用太米 、理來解釋,•米碳管平面顯:器 攝粉·而本發"明/只奴官發出的電子能直接撞擊陽極板的 於空氣中的生物氣膠,//曰厌官主發出的電子能撞擊附著 荦,"太黃榮堂等之中華民國發明專利申請 二電μ電裝置",圓/觀9’申請案號 使充二流電的頻率提高至,,驗’以 基本上,不管靜電::,二盪的距離。 电/儿歲,或交流充電,其運動行為乃根據 第19頁 200528179Vuin ,. ㈣, Vl " in = 30V; R = 1, so with miniaturization and portable settings over 500 _, the applied voltage is two, two: the distance between the poles does not exceed this. Of course, microelectromechanical technology can be used to pin the tip diameter. It should be less than 3 _, produced by electrosurgery, and the other one uses an array of nano carbon f arrays to achieve this. The second reason is explained by using rice and reason. • The carbon tube plane shows: Camera powder and the hair " The electrons issued by the Ming / Slave officials can directly hit the biogas glue in the air of the anode plate, // The electrons emitted by the disgusting official can impact the attachment, " Tai Huang Rongtang, etc. The Republic of China invention patent application for the second electric μ electric device " Yuan / Guan 9 'application number increases the frequency of charging the second electric current to, and the test is based on basically, regardless of the static electricity ::, the distance between the two swings. Electricity / children's age, or AC charging, the movement behavior is based on page 19, 200528179
下列公式 md(dx/dt)/dt mg 71 ^ rcx(u-dx/dt) 式中g是重力加速度,q粒子電荷量,m粒子質i 黏滯性,cx拖良(drag)係數。 、 ”乳體 ^考圖三’將含有病毒之生物氣膠的氣體藉由以 ^acuum Pump)引入晶片入口,使氣體流速達到礼邦 - lm/sec,首先經過交流充電區,使生 ,電荷,接著通過靜電沉澱區,由於生物氣膠%有面帶 何’因此在直流電場的作用下將會受 / °電 :物= =槽置放液體,較佳為去:二 浦= iff於水中。取樣的過程全由真空抽氣邦 即可:25 定取樣體積的多募,-般約6°cm3 器,以阻於、岛女=可ί進氣口加裝5微米以下的過濾 —方&告==、火塵等非生物氣膠的粒子進入水中,另 生物氣:“ί氣邦浦不運作時’過據器也可減少已收集 疏水性^面^ =液與外界的擴散交流。由於凹槽的下游為 說明 > 、、机道,並具有形成液滴的機制(參見下節的 游:于後:Γ;集生物氣膠的水溶液將可--輸送至下 尖ΪΓΐΐ 步的病毒分離與計數。 需時間為生負離子去撞擊生物氣膠使其帶負電,充電所The following formula md (dx / dt) / dt mg 71 ^ rcx (u-dx / dt) where g is the acceleration of gravity, the amount of charge of the q particles, the viscosity of the m particles, and the viscosity of the cx drag. "" Mammary ^ "Figure 3" The virus-containing bio aerosol gas is introduced into the wafer inlet by the ^ acuum Pump), so that the gas flow rate reaches Libang-lm / sec, first through the AC charging area to generate, charge , And then through the electrostatic precipitation area, because the biogas glue% has a face, so under the action of the DC electric field / ° electricity: object = = tank to place liquid, preferably to: Erpu = iff in water The process of sampling is all done by vacuum pumping: 25 sets of sampling volume,-about 6 ° cm3, to prevent, island girl = can be installed with a filter below 5 microns at the inlet-side & Announcement ==, fire dust and other non-biological aerosol particles enter the water, and another biogas: "When Qi Bangpu is not in operation, the passing device can also reduce the hydrophobicity of the collected ^ surface ^ = diffusion of the liquid from the outside world communicate with. Because the downstream of the groove is for explanation, the machine path, and the mechanism of forming droplets (see the next section of the tour: after the next: Γ; the aqueous solution containing bio aerosol will be able to be transported to the lower tip ΪΓΐΐ Virus isolation and counting. It takes time for negative ions to strike the biogas gel to make it negatively charged and charge the office.
第20頁 200528179 — 五、發明說明(11) dq/dt = 3 7rn(t) //E(t)r*r *[l-q(t)( er + 2)/12 7Γ eOE(t)r*r* er] *[1 -q ⑴(er + 2)/12 7Γ εΟΕ ⑴ r*r* er] 式中r是粒子半徑,ε r是粒子相對介電性(r e 1 a t i v e permittivity) ,// 是離子運動性(m〇bi 1 i ty) ,n 是充 £的空間電何绝、度,與β是電場。經過無窮時間的充電^ 粒子所吸收的飽和電荷為Page 20, 200528179 — V. Description of the invention (11) dq / dt = 3 7rn (t) // E (t) r * r * [lq (t) (er + 2) / 12 7Γ eOE (t) r * r * er] * [1 -q ⑴ (er + 2) / 12 7Γ εΟΕ ⑴ r * r * er] where r is the particle radius, and ε r is the relative permittivity of the particle, // Is ion mobility (m0bi 1 ity), n is the space electric charge, degree, and β is the electric field. Charged after infinite time ^ The saturated charge absorbed by the particle is
qs = 12 7Γ ε Or*r*Em* ε r/( ε r + 2 ) 式中Em是交流電場的振幅 參考圖四,針狀電極對平板(needle —t〇_pUte)或針對 的電暈放電裝置的製作可利用MEMS製程或陣列奈米碳 術,利用MEMS製程如下所述 议 如 二、首先選用P_Type(100)料晶石夕作為基材qs = 12 7Γ ε Or * r * Em * ε r / (ε r + 2) where Em is the amplitude of the AC electric field. Refer to Figure 4. Needle-shaped electrode to flat plate (needle — t〇_pUte) or targeted corona The discharge device can be manufactured by using MEMS process or array nano-carbon technology. The use of MEMS process is as follows. First, P_Type (100) material crystal stone is selected as the substrate.
步驟二、利用光微影蝕刻技術對基材的上半平面以軟 刻的,式㈣出圖帛,如圖四⑻,接著將基材置於85' 的A氧化钾(K0H)中,一邊塘採一、嘉, u t 逭筏件邊蝕刻,利用單晶矽其 材的特性蝕刻出54· 74度斜角的槽,如圖四(c) " 步驟三、利用丙酮將光阻洗去,如圖四(d) 步驟四、制電鑄的方法在基材表面沉積一層Ni金屬,Step 2: Use the photolithography etching technique to softly engrav the upper half of the substrate, and use the formula shown in Figure 4 below, and then place the substrate in 85 ′ potassium oxide (K0H). Tong Caiyi, Jia, ut 逭 raft edge etching, using the characteristics of single crystal silicon material to etch a 54.74 degree inclined groove, as shown in Figure 4 (c) " Step 3, using acetone to wash away the photoresist As shown in Figure 4 (d) Step 4, the method of making electroforming deposits a layer of Ni metal on the surface of the substrate,
第21頁 200528179 五、發明說明(12) 圖四(e) 步驟五、接著將基材連同…金屬置於 (K0H)中,一邊授拌一邊敍刻,將所剩餘的氧化奸 如圖四(f ) 幻餘的基材蝕刻掉, 利用光微影蝕刻技術在…金屬層 (spacer),最後再利用步驟一至五 田n隔态 屬層連結在間隔器(spacer)上形成封閉暖狀故離’。將另—Ni金 利用奈米碳管製程如下所述 步驟 步驟二 步驟三 步驟四 步驟五 利用光阻塗佈機在基材上旋塗上一犀 利用光為影#刻技術達到奈米碳管‘ ^二 利用蒸鍍機將觸媒金屬(Ni,c〇 F 形狀。 利㈣e-off技術完成觸媒金屬陣二上^ 於 利用鬲溫爐將觸媒金屬退火或還原,你^贫^ 米及金屬或矽化物。 ’、使八成為奈 步驟六、再以乙炔甲烷等碳氫氣 碳管。 ^仃化子軋相生成奈米 M h ί t為了成本考量,也可使用網版印刷將奈米舻# 轉卩成陣列形狀,再經高溫處理即可。 一 A & ’ 病毒分離裝置 如圖五所示,要達到分離的目的,首 的特性,;® m 元而要知道病毒 =I·生而要利用介電力DEp達到分丙毋 幻”電特性,導電性是需要知道的,在 毋 里/則病毒介電係數Page 21 200528179 V. Description of the invention (12) Figure 4 (e) Step 5: Then place the base material together with the metal in (K0H), and engraving while mixing, and then oxidize the remaining oxide as shown in Figure 4 ( f) The substrate is etched away, and the photolithographic etching technology is used to ... on the metal layer (spacer), and finally, steps 1 to 5 are used to connect to the spacer to form a closed and warm space. '. The other—Ni gold using nano carbon control process is as follows: Step 2 Step 3 Step 4 Step 5 Use a photoresist coater to spin-coat a rhino on the substrate and use light for shadow #etching technology to reach the nano carbon tube. '^ The catalyst metal (Ni, coF shape) was deposited by an evaporation machine. The catalyst metal array was completed using the e-off technology. ^ The catalyst metal was annealed or reduced by using a high temperature furnace. And metal or silicide. ', Make eight into Nai step six, and then use carbon, hydrogen and other carbon tubes such as acetylene methane. ^ Homogeneous rolling phase to generate nanometer M h For cost considerations, you can also use screen printing to Nai米 舻 # It can be turned into an array shape, and then it can be processed at high temperature. A A & 'Virus separation device is shown in Figure 5. To achieve the purpose of separation, the first characteristic; · Born to use the dielectric power DEp to achieve the "unlimited" electrical characteristics, electrical conductivity needs to be known, in the case of / the virus dielectric constant
第22頁 200528179 五、發明說明(13)Page 22 200528179 V. Description of the invention (13)
的機制中,可以採用兩種方法,一種是R0T量測,可參考 文獻如 M Changes in Friend murine er y t hr o 1 eukaem i a cell membranes during induced differentiation determined by electrorotation,f , Biochimica et Biophysica Acta 1193(1994) 330-344 ,和 丨丨 Differences in the A V electrodynamics of viable and non-v i ab1e yeast cells determined through combined dielectrophoresis and electrorotation studies", Phys .Med. Biol.,1992, Vol. 37, No 7, 1499-1517·另一種就是利用Levitator量測,參考文獻如 Integrated planar concentric ring dielectrophoretic (DEP) levitator", Journal of Electrostatics 55(2002)65-79,利用此兩種方法求出 cell permittivity,以便於整合晶片上之分離所要提供 之電場頻率。在量測中需要有相當高的精密度,例如··空 氣中的雜質、室溫、已經細胞培養時間之長短、介質溶液 的特性(高滲透壓溶液、低滲透壓溶液及等張溶液)、電極 的清潔與否,都足以影響到量測的結果。In the mechanism, two methods can be used. One is ROT measurement, which can be referenced as M Changes in Friend murine er yt hr o 1 eukaem ia cell membranes during induced differentiation determined by electrorotation, f, Biochimica et Biophysica Acta 1193 (1994 ) 330-344, and Diferences in the AV electrodynamics of viable and non-v i ab1e yeast cells determined through combined dielectrophoresis and electrorotation studies ", Phys. Med. Biol., 1992, Vol. 37, No 7, 1499- 1517 · The other is to use Levitator to measure. References such as Integrated planar concentric ring dielectrophoretic (DEP) levitator ", Journal of Electrostatics 55 (2002) 65-79, use these two methods to find the cell permittivity to facilitate integration on the wafer. The frequency of the electric field to be provided for the separation. Requires a high degree of precision in the measurement, such as ... impurities in the air, room temperature, the length of the cell culture time, the characteristics of the medium solution (high osmotic pressure solution, low osmotic pressure solution and isotonic solution), Whether the electrodes are clean or not is enough to affect the measurement results.
利用DEP使病毒分離的方法在文獻中,如"Separation of Submicron Bioparticles by Dielectrophoresis'丨, Biophysical Journal Volume 77 July 1999 516-525 和 f, D i e 1 ec t rophore t i c Trapping of Dissociated Fetal Cortical Rat Neurons", IEEE Trans, on Biomedical Engineering, Vol. 48, NO· 8, AUG 2001 921-930 和Methods for using DEP to isolate viruses in the literature, such as " Separation of Submicron Bioparticles by Dielectrophoresis' 丨, Biophysical Journal Volume 77 July 1999 516-525 and f, D 1 1 ec t rophoretic tic Trapping of Dissociated Fetal Cortical Rat Neurons " , IEEE Trans, on Biomedical Engineering, Vol. 48, NO · 8, AUG 2001 921-930 and
第23頁 五、發明說明(14)Page 23 V. Description of Invention (14)
Trapping in AC Electrode cages, Journal 〇fTrapping in AC Electrode cages, Journal 〇f
Electrostatics 50 (20 0 0 ) 1 7-2 9 中均有人研究,還有 其他相關的文獻中均有提到,他們發現不同檢體之間,有 不同的介電特性與導電性,因此本發明就利用這項特性, 藉由外加電場產生介電力,並利用不同的介電頻率和不同 檢體間頻率改變會產生極性變化的原理,再藉由微機電製 程技術做出電極2 3,在所設計的電極上,加上一交流電, 使其產生電磁效應,再利用頻率改變,使不同檢體在不同 的頻率下會產生不同的介電特性,在電極上加上正負不同 之電場,會使極性不同之檢體區分開來,以達到分離的目 的。 本發明是利用交錯排列的電極2 4利用外部分壓電路所 形成之電場並用相位落後的方式使電場可以帶動微粒(含 病毒),先利用介電力將欲測之微粒21驅趕至流道的中 央,而檢體中其他之物質22將被會被吸附在電極上。利用 微粒牽引裝置,再利用相位落後的方法,如文獻以“”, F.F., Wang, , Huang, Y., Pethig, R., Vykoukal, J., and Gascoyne, P.R.C.. Proc. Natl. Acad. Sci., USA· 92 ·· 860-864,1 9 95,將欲計數之微粒2i集中在流道 中央,使其沿著流道被牽引至微粒(含病毒)牽引電極26的 位置,因在微粒牵引裝置區域為疏水诖,所以當檢體經分 離電極流至牽引電極時將因疏水性的關係使檢體滯留在疏 水線2 7右側,在利用電極切換使溶液形成液滴牽引至下一 200528179 五、發明說明(15) 病毒牽引裝置 參考文獻丨’Towards Digital Microfluidic Circuits: Creating, Transporting, Cutting and Merging Liquid Droplets by Electrowetting-based Actuation" IEEE MEMS 2002,中提到當液體在疏水性表 面時,會因表面張力而形成圓形液滴。藉由介電力對液體 的牽引,電極會造成液滴兩邊接觸角不對稱而使得液體流 動。利用電極on-off切換如圖六(a〜e)可以使液滴產生分 離、融合、移動等效果,便可應用在晶片中的液體輸送及 病毒牽引,見圖七 COS ㊀(V)-cose e〇(V2)/2(rLG)tSome people have studied in Electrostatics 50 (20 0 0) 1 7-2 9 and other related literatures have mentioned that they found that different specimens have different dielectric properties and conductivity, so the present invention Based on this feature, the dielectric field is generated by applying an external electric field, and the principle that different dielectric frequencies and frequency changes between different specimens will cause a polarity change, and then the electrodes 2 3 are made by microelectromechanical process technology. An alternating current is added to the designed electrode to generate an electromagnetic effect, and then the frequency is changed so that different specimens will have different dielectric characteristics at different frequencies. Adding different positive and negative electric fields to the electrode will cause Samples with different polarities are distinguished to achieve the purpose of separation. The invention uses the staggered electrodes 24 to make use of the electric field formed by the external partial voltage circuit and makes the electric field drive the particles (including viruses) in a phase backward manner. First, the particles 21 to be tested are driven to the flow channel by the dielectric power. The center, and the other substances 22 in the specimen will be adsorbed on the electrode. Use particle traction device, and then use the method of backward phase, such as "", FF, Wang, Huang, Y., Pethig, R., Vykoukal, J., and Gascoyne, PRC. Proc. Natl. Acad. Sci ., USA · 92 ·· 860-864, 1 9 95, the particles 2i to be counted are concentrated in the center of the flow channel, so that they are drawn along the flow channel to the position of the particle (including virus) traction electrode 26, The area of the traction device is hydrophobic, so when the sample flows through the separation electrode to the traction electrode, the sample will stay on the right side of the hydrophobic line 2 7 due to the relationship of hydrophobicity. The electrode formation is used to pull the solution forming droplets to the next 200528179. V. Description of the invention (15) References for virus traction devices 丨 'Towards Digital Microfluidic Circuits: Creating, Transporting, Cutting and Merging Liquid Droplets by Electrowetting-based Actuation " IEEE MEMS 2002, mentioned that when a liquid is on a hydrophobic surface, it will Round droplets are formed due to surface tension. By the traction of the liquid by the dielectric force, the electrode will cause the contact angle of the two sides of the droplet to be asymmetric, which will cause the liquid to flow. Using electrode on-off switching, as shown in Figure 6 (a ~ e), the droplets can be separated, fused, and moved. They can be used for liquid transport and virus traction in the wafer. See Figure 7. COS ㊀ (V) -cose e〇 (V2) / 2 (rLG) t
其中’ r LG為表面張力,ε介電層介電係數,ε〇為真空中介 電韦數之’t為介電層厚度,0為介電力引起之液體移動角 度。由式中可知,若要提高電極牵引的效率,則要降低介 電層的厚ft ’選擇介電係數大的介電層,或者提高施加 電C °但右施加的電壓太高會使得整體裝置的成本增加, 因此可藉由減少介電層厚度及選用高介電係數的材料來達 人广本明則利用此種特性,當分離機制將所要之微粒 各病毋)分離開之後,並利用行進波介電力(traveling一Where 'r LG is the surface tension, the dielectric constant of the ε dielectric layer, ε0 is the dielectric dimension in vacuum,' t is the thickness of the dielectric layer, and 0 is the angle of liquid movement caused by the dielectric force. It can be known from the formula that if the efficiency of electrode traction is to be improved, the thickness of the dielectric layer must be reduced ft 'Select a dielectric layer with a large dielectric coefficient, or increase the applied electric C ° but the voltage applied to the right will make the overall device too high The cost increases, so it can be achieved by reducing the thickness of the dielectric layer and selecting materials with high dielectric constants. Guang Benming took advantage of this characteristic. After the separation mechanism separates the desired particles from each other, the traveling wave is used to separate them. Electricity
第25頁 200528179 五、發明說明(16) wave-di electrophoretic force)將微粒牽引至分離電極 最W端’用上述的方法將有微粒之溶液形成液滴封包,液 滴封包中將會有病毒存在,再利用程式化的電極控制,可 精準的控制液體移動方向及速度,使液滴可在疏水性區域 中移動,便可藉此將液體中的微粒(含病毒)牽引至所需位 置。 如圖八顯示電極施加方式,圖八(a)所示,當分離電 極將微粒分離好並利用行進波介電力^””丨丨叫—^^一 (^electrophoretic f0rce)將微粒牵引至分離電極最前 端’其中0和1代表電極通電狀況,〇代表L〇w,1代表 Higji,當微粒被集中在分離電極最前端時,利用將壓電材 2施加一電壓,會使壓電材料體積改變產生一擠壓的力 量,配合介電質上之電濕潤(electrowetting-on- 1 ec t r i c)方式將整電極施加如圖八(匕)所示,可將檢體 ^壓並吸引至液滴封包之疏水通道中,當檢體進人疏水區 ^ ’也會順便將微粒帶入疏水區,並利用電極將液滴吸引 $ i然後放掉壓電材料之電壓,使壓電材料體積回復至原 :小’此時檢體會被拉回分離電極區,而被液滴封包吸 主的液體將形成一液滴封包如圖八(c)所示。 明利ί ί ΐ i:每一站均有不同導電度之介質溶液,本發 Γ γΠ蝌來達到控制溶液導電度的目的,如圖八 離的:/液滴被牽引至下一站的時候會和周圍溶液有隔 離的效果,不會破壞介質溶液之導電度。Page 25 200528179 V. Explanation of the invention (16) Wave-di electrophoretic force) The particles are drawn to the end of the separation electrode. The solution with the particles is formed into a droplet package by the above method, and a virus will be present in the droplet package. Then, the stylized electrode control can be used to precisely control the direction and speed of liquid movement, so that the liquid droplets can move in the hydrophobic area, so that the particles (including viruses) in the liquid can be pulled to the desired position. Figure 8 shows the electrode application method. As shown in Figure 8 (a), when the separation electrode separates the particles and uses the traveling wave dielectric power ^ "" 丨 丨 called — ^^ 一 (^ electrophoretic f0rce) to pull the particles to the separation electrode. Front end, where 0 and 1 represent the electrode current, 0 represents L0w, and 1 represents Higji. When the particles are concentrated at the forefront of the separation electrode, applying a voltage to the piezoelectric material 2 will cause the volume of the piezoelectric material to change. A squeezing force is applied in conjunction with the electrowetting-on-1ec tric method on the dielectric to apply the entire electrode as shown in Fig. 8 (dagger), which can compress the sample and attract it to the droplet package. In the hydrophobic channel, when the specimen enters the hydrophobic area ^ ', it will also bring particles into the hydrophobic area, and use the electrode to attract the droplets and then release the voltage of the piezoelectric material, so that the volume of the piezoelectric material returns to the original: At this time, the specimen will be pulled back to the separation electrode area, and the liquid absorbed by the droplet package will form a droplet package as shown in Figure 8 (c). Mingli ί ΐ ΐi: Each station has a medium solution with different conductivity. The hair Γ γΠ 蝌 is used to achieve the purpose of controlling the solution conductivity, as shown in Figure 8: / When the droplet is drawn to the next station, it will It has the effect of isolation from the surrounding solution and will not destroy the conductivity of the medium solution.
200528179 五、發明說明(17) 計數的機制 西元1 953年Coulter提出··當一非導體的粒子在導 電的溶液中流經一細毛細管的瞬間,會增加毛細管中的阻 值’而且阻值改變的大小與非導體粒子的大小相關,本發 明則利用此原理,如圖九所示,為本發明所使用的多離子 通道計數裝置示意圖,主要是運用多個奈米通道的一側置 入氯化鉀(KC1)或氯化鈉等氣化鹽,將病毒導引通過奈米 通道,由於病毒對通道有阻塞作用,致使鉀離子流經通道 的頻率,即離子流,有所不同,因而可以計算出通過病毒 之數量。本發明也利用多個通道可同時進行病毒計數的動 作,增加計數的速度。 虽粒子流經毛細管所造成電導率(c 〇 n d u c t a n c e)改變的關 係式如下式所示:200528179 V. Explanation of the invention (17) Counting mechanism 1953 AD Coulter proposed that when a non-conductive particle flows through a thin capillary in a conductive solution, it will increase the resistance in the capillary. The size is related to the size of the non-conducting particles. The present invention uses this principle. As shown in Figure IX, it is a schematic diagram of a multi-ion channel counting device used in the present invention. It mainly uses one side of a plurality of nano-channels to place chlorination. Vaporized salts, such as potassium (KC1) or sodium chloride, guide the virus through the nanochannel. Because the virus has a blocking effect on the channel, the frequency of potassium ions flowing through the channel, that is, ion flow, is different, so it can be calculated. Number of passed viruses. The present invention also uses multiple channels to perform virus counting simultaneously, increasing the counting speed. Although the relationship between the change in conductivity (c 0 n d u c t a n c e) caused by particles flowing through the capillary is shown in the following formula:
△ g = 2 Ilr^r^r σ/L △ g :電導變化率 r :粒子半徑 σ :溶液導電度 L : 通道長度 因此利用晶片將病 當病毒通過奈米通 流產生變化,因而 的。 毒先行分離出所要檢 道時,便會因阻值改 可得知病毒通過的數 測的病毒種類,在 變而使得量測的電 目,達到計數的目△ g = 2 Ilr ^ r ^ r σ / L △ g: Conductivity change rate r: Particle radius σ: Solution conductivity L: Channel length Therefore, the chip will be used to change the disease when the virus passes through the nanometer flux, and therefore. When the virus first isolates the desired path, it will know the type of virus that the virus passed through due to the change in the resistance value, which will change and make the measured electricity meter reach the goal of counting.
第27頁 200528179 五、發明說明(18) [通道粒 當粒 子通道, 引電極極 下電極5 5 方式可有 示。不同 同,適用 排序 方之柱狀 的電場強 到高密度 電極 子通道下 的電極設 電磁模擬 圖十二所 【實施方 分離電極 步驟一、 膠基材6 2 步驟二、 子排 子流 以便 為重 及離 多種 的排 的粒 遷引 高密 度及 電場 之外 方流 計所 軟體 )|々 〇 序遷引 經離子 偵測通 要。排 子通道 ,茲舉 列方式 子類型 電極利 度電場 特殊電 區作用 型設計 道中之 形成的 找出電 完成之 電極] 通道時 道中之 序遷引 所在之 出較佳 所產生 及應用 用介電 區5 8, 場分佈 產生而 將會影 所有粒 電場遷 極排列 電極外 ,必需將 電流變化 機制主要 薄膜層5 6 的五種實 之電場方 也有所差 力將粒子 如圖十一 ’流經附 一穩定加 響電場分 子往離子 引方向亦 方式及外 型設計如 其排序 ’因此 結構分 ’電極 施例子 向及電 異。 遷引至 所示。 近的所 速度通 佈情形 通道方 不相同 型設計 圖十三 且穩定通過離 通道之排序遷 為上電極5 4、 間的相對排列 ’如圖十所 場分佈均不相 離子通道5 7下 由於柱狀電場 有粒子5 9會受 過離子通道。 ’電場須將離 向集中,不同 。本發明透過 ,模擬結果如 所示。 式】 的製作 利用 塑膠射出技術射出含有流道與儲存槽67 參考圖十四(a), 之塑 接著作光微影並利用濺鍍機Page 27 200528179 V. Description of the invention (18) [Channel particles When particles are in the channel, the lead electrode and the lower electrode 5 5 can be shown. The difference is that the columnar electric field of the ordering square is as strong as the electrode arrangement under the high-density electrode sub-channel. The electromagnetic simulation is shown in Figure 12. [Implementing the method of separating the electrode step 1, the glue substrate 6 2 step 2, the sub-flow sub-flow for weight and separation A variety of rows of particle migration and high density and electric field software outside the flow meter) | Rows of sub-channels, in a row of sub-types, electrode type, profitability, electric field, special electric zone, design path, find the electrically-completed electrode], when the order of the channel in the channel is better, the dielectric is generated and applied. Area 5 8: The field distribution is generated and will affect all particles. The electric field will be arranged outside the electrodes. The five real electric fields of the main thin film layer 5 6 of the current change mechanism must also be ineffective to flow the particles as shown in Figure 11 '. Attached to a stable sounding electric field molecules are directed in the direction of the ion and the design is such as the order 'so the structure is divided' and the electrode examples are oriented and electrically different. Relocate to as shown. The near velocity distribution situation is different. The design of the channels is different. Figure 13 and the stability of the relative arrangement of the upper electrodes 5 4 through the sorting of the channels are not shown. In a columnar electric field, particles 5 and 9 will pass through ion channels. ’The electric field must focus on the off direction, different. Through the present invention, the simulation results are shown. Formula] The plastic injection technology is used to shoot the flow channel and storage tank 67. Refer to Figure 14 (a). The photolithography is used and the sputtering machine is used.
第28頁 200528179 五、發明說明(19) " (sputter)在基材的上半平面濺鍍上一層鉻(Cr)再濺鍍一 層金(Au)作為電極層63,並利用Li ft 〇f f製程技術將所需 要的圖形留下’以作為提供電場及量測訊號的上電極之 用’其中鉻金屬層主要的作用在於增加金與塑膠基材的附 著力,所以並不需要太厚; 步驟三、參考圖十四(b),再利用光微影蝕刻技術,將所 要的光阻61殘留下來當間隔(Spacer)用,如圖十四(c)所 不 ,Page 28 200528179 V. Description of the invention (19) " (sputter) Sputtering a layer of chromium (Cr) on the upper half of the substrate and then a layer of gold (Au) as the electrode layer 63, and use Li ft ff The process technology leaves the required pattern 'for the purpose of providing an electric field and an upper electrode for the measurement signal'. The main role of the chromium metal layer is to increase the adhesion between gold and the plastic substrate, so it does not need to be too thick; 3. Referring to FIG. 14 (b), the photolithography etching technology is used to leave the desired photoresist 61 as a spacer, as shown in FIG. 14 (c).
步驟四、最後再披覆(coating) —層薄薄的tefl〇n 6〇當介 電層用; 步驟五、參考圖十四(d),選用ΙΤ0玻璃66當密封流道與 儲存槽67之材料,因為ΙΤ0玻璃表面有一層透明的氧化銦 錫6 5可以當電極用; 步驟六、參考圖十四(e)與(f ),利用機械加工技術如喷 衫(文獻 ’ A N 〇 v e 1 L 〇 w L 〇 s s w a f e r - L e v e 1 P a c k a g i n g of the RF-MEMS Devices 20 02 IEEE )或雷射穿孔在 IT〇 玻璃上開出我們所需要的進入孔和逃氣孔;Step 4. Finally, coating — a thin layer of teflon 60 is used as the dielectric layer. Step 5. Referring to FIG. 14 (d), select ITO glass 66 as the sealing channel and storage tank 67. Material, because the ITO glass surface has a layer of transparent indium tin oxide 65, which can be used as an electrode; Step VI, referring to Figures 14 (e) and (f), using mechanical processing techniques such as spray shirts (document 'AN 〇ve 1 L 〇w L 〇sswafer-Leve 1 Packaging of the RF-MEMS Devices 20 02 IEEE) or laser perforation to make the required entry holes and escape holes on the IT〇 glass;
步驟七、參考圖十四(S) ’利用Lift off製程技術在ιτο玻 璃的背面上錢鍵上一層鉻(Cr)再錢鍵一層金(au)作為電極 層68,用來和離子通道的電極層接合用; 步驟八、參考圖十四(S)再披覆一層teflon當介電層在IT0 玻璃上; 步驟九、參考圖十四(h) ’利用UV膠把加工好之〖το玻璃和 基材連結起來使流道與儲存槽67形成密封狀態。Step 7. Refer to FIG. 14 (S) 'Using the Lift off process technology, a layer of chromium (Cr) and a layer of gold (au) are used as electrode layers 68 on the back of the glass on the back of the glass, which is used for the electrode of the ion channel. For layer bonding; Step 8. Refer to Figure 14 (S) and cover it with a layer of teflon as the dielectric layer on IT0 glass. Step 9: Refer to Figure 14 (h) 'Use UV glue to process the glass and The base materials are connected to form a sealed state between the flow path and the storage tank 67.
200528179200528179
[離子孔道的電子電路] 離子流過奈米孔道的電流,依孔道的孔徑大小而定, 其電流大小約數nano到數百nano安培,習知的技 大型的儀器或電子電路,為了能將其縮小並整合於晶片之 上,本發明將其重新設計成積體電路,說明二;ΘΒ[Electronic circuit of ion channel] The current flowing by ions through the nano channel depends on the pore size of the channel, and its current is about nano to hundreds of nano amps. Conventional large-scale instruments or electronic circuits. Reduced and integrated on the chip, the present invention redesigns it into an integrated circuit, description two; ΘΒ
參考圖十五(a),nano安培電流量測電子電路可概分成五 個獨立的次電路,包括1 ·電流/電壓轉換器(I 一 V converter) 2·直流電場電壓 3·交流電場電壓 4 三 位元高速類比數位轉換器 5 ·微控制器等。 · 一 電流/電壓轉換器所用的低雜訊運算放大器,參考圖十五 (b ) ’透過—電流放大和一轉阻放大的二級串接電路所組 成’其輸入的偏流約為6 η A〜6 0 η A,頻寬約為1 〇 μ Η z增益 約 lOMega〜IMega。Referring to Fig. 15 (a), the nano ampere current measurement electronic circuit can be roughly divided into five independent sub-circuits, including 1 · current / voltage converter (I-V converter) 2 · DC electric field voltage 3 · AC electric field voltage 4 Three-bit high-speed analog-to-digital converter 5 · Microcontroller, etc. · Low-noise operational amplifier used in a current / voltage converter, refer to Figure 15 (b) 'through-current amplification and a transimpedance amplification of a two-stage series circuit' whose input bias current is about 6 η A ~ 6 0 η A, bandwidth is about 10 μ〇 z gain is about lOMega ~ IMega.
由於所使用的電流/電壓轉換器71,目的在將數nA到數百 nA的電流訊號轉成數mv電壓訊號,在此需要增益的轉組放 大器電路中,若使用常見的〇p放大器外家電組的結構將會 使用到非常大的電阻,在晶片化的過程中勢必佔用到大片 的面積。因此,為避免此大電阻的使用,在電路結構上將 不採用傳統的電壓模式的0P運算放大器,而已低輸入阻抗 之電路架構取而代之。第一級電流放大711將數nA至數百 nA之電流放大1〇〇〜1〇〇〇倍,第二級712則使用轉阻放大器 放大約1 0 0 0 0倍,故二級總合起來的放大增益約為 1MegaVo1t/A 〇Due to the current / voltage converter 71 used, the purpose is to convert a current signal of several nA to several hundreds of nA into a voltage of several mv. In this transfer amplifier circuit that requires gain, if a common oop amplifier is used for external appliances The structure of the group will use a very large resistance, which will inevitably occupy a large area during the waferization process. Therefore, in order to avoid the use of this large resistance, the traditional 0P op amp in voltage mode will not be used in the circuit structure, and the circuit structure with low input impedance will be replaced. The first stage current amplifier 711 amplifies currents ranging from several nA to hundreds of nA by 100-1000 times, and the second stage 712 uses a transimpedance amplifier to put about 100 thousand times, so the two stages are combined. The amplification gain is about 1 MegaVo1t / A.
第30頁 200528179 五、發明說明(21) 將二位元或更高位元之高速類比數位轉換器7 2,目的在將 多種不同病毒所相對應的多個電壓位準以及一參考位準, 例如若是未阻塞時的電壓位準共六個,就需要轉成三位 元’基本架構為快閃式(flash)電路(參考D· A. johns and K. Martin, 1997, Analog Integrated Circuit Design, pp· 50 7-5 1 3 ),位準之間的電阻,因應多個不同 病毒以及未阻塞時電壓位準的不同而調整之,其轉換速度 為100MHz-5 0 0MHz可使用多工方式讀取多個通道。 直流電場電壓7 8,目的在電極加上DC偏壓,使病毒經過電 極上設置的通道,為了減少雜訊的影響(參考Hami i i et. al., 1981, Pfluegers Arch. Eur. J. Physiol. 391:85-100 ) ’提供一個降低病毒通過奈米孔的速度,使 每一病毒能暫停於奈米孔之中,不受擴散的影響,有時間 讓離子可通過,基本上將取樣時間控制在1微秒,其電壓 位準約為60- 1 50mV。 ' 此直流電場電壓可經由圖七的電流電壓轉換器7丨來施 加,透過電流訊號端I去產生局部電場電壓,而在第二級 放大器,由差分放大器取出離子電流丨.的放大值。Page 30 200528179 V. Description of the invention (21) A high-speed analog-to-digital converter 72 with two or more bits is used to convert multiple voltage levels and a reference level corresponding to different viruses, for example, If there are a total of six voltage levels when unblocked, it needs to be converted into a three-bit 'basic architecture as a flash circuit (refer to D. A. johns and K. Martin, 1997, Analog Integrated Circuit Design, pp · 50 7-5 1 3), the resistance between the levels is adjusted according to different viruses and the voltage level when it is not blocked. Its conversion speed is 100MHz-5 0 0MHz, which can be read by multiplexing. Multiple channels. The DC electric field voltage is 78. The purpose is to apply a DC bias voltage to the electrode so that the virus passes through the channel provided on the electrode in order to reduce the influence of noise (see Hami ii et. Al., 1981, Pfluegers Arch. Eur. J. Physiol. 391: 85-100) 'Provide a way to reduce the speed of virus passing through the nanopore, so that each virus can be suspended in the nanopore, not affected by diffusion, have time to let ions pass, basically control the sampling time At 1 microsecond, its voltage level is about 60-1 50mV. 'This DC electric field voltage can be applied via the current-to-voltage converter 7 丨 shown in Fig. 7 to generate a local electric field voltage through the current signal terminal I. In the second stage amplifier, the amplified value of the ion current is taken out by the differential amplifier.
微控制器73的功能包括:調整交流電場電壓的電壓位 準與頻率,直流電場電壓的位準、同步訊號的導通時間與 不通時間長度,與二位元高速類比數位轉換器的溝通,基 因序列碼的轉換與儲存,或與記憶體76儲存已知疾病的基 因序列比對,並顯示於顯示器(LCD)74,或暫存基因序列" 碼,透過RS-232的通訊協定77,轉存至外界的電腦75。微The functions of the microcontroller 73 include: adjusting the voltage level and frequency of the AC electric field voltage, the level of the DC electric field voltage, the on-time and the off-time length of the synchronization signal, the communication with the two-bit high-speed analog digital converter, and the gene sequence The conversion and storage of the code, or the comparison with the gene sequence of the known disease stored in the memory 76, and display on the display (LCD) 74, or the temporary gene sequence " code, which is transferred through the RS-232 communication protocol 77, To an external computer 75. micro-
第31頁 200528179Page 31 200528179
控制器也可選用市 以外加的記憶體擴 的病毒數目並可以 的大小或判斷初始 售的產品,而内建的 充之,可讀取的通道 δ己錄電流下降之程度 否有病毒以外之物質 記憶體7 6也可另 數目與每通道讀取 ,可用來比較病毒 參雜。 [離子通道之製作8〇] 步驟一、 參考圖+ >,昔止、辟 谇认抑曰^十,、百先選用Ρ一 Type (100)、厚 $ h 為接著在基材上以低壓化學 Α/〇.〇ΛΤ,Ν 在土材雙面沉積一層 50nm - 100nm 的虱化矽(Si3N4)薄膜82,如圖十六(a); 二驟 > 考圖十,、,利用光微影蝕刻技術對基材的上半 平=乾式㈣的方式㈣出圖t,接著將基材置於85。( 的虱軋化鉀(K0H)中一邊攪拌一邊蝕刻至剩下薄膜,利用 單晶矽基材81的特性蝕刻出54. 74度斜角的槽,如圖十六 (b); 步驟二、接著在基材上層以再以Lpcvi)的方式沉積一層 2 0 0nm-25〇nm的氮化矽(Si3N4)薄膜82,如圖十六(c); 步驟四、利用光微影蝕刻技術對基材的下半平面以乾式蝕 刻的方式钱刻出圖案’如圖十六(d ); 步驟五、接著作光微影製程並利用濺鍍機(sputter)在基 材的下平面均濺鍍上一層鉻(Cr) 83,再濺鍍一層金(au) 84,作為下電極,如圖十六(e); 步驟六、在上層以光微影製程把所需要的厚膜光阻8 5留下 當作遮罩,如圖十六(f);並利用濺鍍機(sputter)在基材The controller can also choose the number of viruses expanded by external memory and the size of the virus or determine the initial sale of the product, and the built-in, the readable channel δ has recorded a decline in the current level of the virus. Material memory 76 can also be read with another number and per channel, which can be used to compare virus contamination. [Production of ion channel 8〇] Step I, refer to the figure + >, the past and the last one, select ^ ten, one hundred first choose P-Type (100), thick $ h for the next low pressure on the substrate Chemistry Α / 〇.〇ΛΤ, Ν deposits a layer of silicon silicate (Si3N4) film 50nm-100nm on both sides of the soil material, as shown in Figure 16 (a); Second step > The photoetching technique draws out the pattern t on the upper half of the substrate = dry type, and then sets the substrate at 85. (The lice rolled potassium (K0H) was etched while stirring to the remaining film, and the characteristics of the single crystal silicon substrate 81 were used to etch a 54.74 degree beveled groove, as shown in Figure 16 (b); Step two, Next, a layer of silicon nitride (Si3N4) film of 200 nm to 25 nm is deposited on the substrate in the manner of Lpcvi), as shown in FIG. 16 (c); The lower half plane of the material is engraved with a pattern by means of dry etching, as shown in Figure 16 (d); Step five, the photolithography process is followed, and the lower plane of the substrate is sputtered by a sputtering machine. A layer of chromium (Cr) 83, and then a layer of gold (au) 84, as the lower electrode, as shown in Figure 16 (e); Step six, in the upper layer, the required thick film photoresist 8 5 As a mask, as shown in Figure 16 (f); and using a sputter on the substrate
第32頁 200528179Page 32 200528179
的上平面均濺鍍上一層鉻(Cr)83,再濺鍍一層金(Au)84, 作為上電極,如圖十六(g);將厚膜光阻移除掉,如圖十 六(h);上平面的電極以作為提供電場及加以直流電壓之 ,,下平面則用來加以交流電量測pic。級安培的離子電流 量測電路’其中鉻金屬層83主要的作用在於增加金以與矽 基材81的附著力,所以並不需要太厚; ” 步驟七、在下層以光微影製程把所需要的厚膜光阻^5 當作絕緣層,如圖十六(i );The upper plane of the substrate is sputtered with a layer of chromium (Cr) 83, and then a layer of gold (Au) 84, as the upper electrode, as shown in Figure 16 (g); remove the thick film photoresist, as shown in Figure 16 ( h); The electrodes on the upper plane are used to provide the electric field and the DC voltage, and the lower plane is used to measure the AC power pic. Grade Ampere Ion Current Measurement Circuit 'The main role of the chrome metal layer 83 is to increase the adhesion of gold to the silicon substrate 81, so it does not need to be too thick;' Step 7: The photolithography process is used in the lower layer. The required thick film photoresist ^ 5 is used as an insulating layer, as shown in figure sixteen (i);
步驟八、以乾式钱刻的方式把 薄膜82蝕刻剩下約70 0A,如圖 步驟九、用e-beam writter在 小孔’最後在下半平面之氮化 式打出一奈米孔道80。 下層周圍的氮化石夕(Si3N4) 十六(j)。 下半平面上之光阻寫一奈米 石夕薄膜8 2上用乾式餘刻的方 整體晶片之製作 圖^十七為整體晶片之***圖,整體晶片包含電極厣 口離子通道層10〇,在電極層中包括分離電極,^ 亟,其中91為含有流道與儲存槽67之塑膠基材,Step 8. The film 82 is etched with dry money to leave about 70 0A, as shown in the step. Step 9. Use an e-beam writter to form a nano-channel 80 in the small hole and finally in the lower half of the nitride. Nitride stone around the lower layer (Si3N4) XVI (j). The photoresist on the lower half plane is used to make a monolithic wafer with a dry type on the nano-silicon film 82. Figure 17 is an exploded view of the monolithic wafer. The monolithic wafer contains an electrode port ion channel layer 100. A separate electrode is included in the electrode layer. Among them, 91 is a plastic substrate containing a flow channel and a storage tank 67.
^極!63,在電極層上利用光阻所製程之流道61 枯卞Γ ^上盍上一ΙΤ〇玻璃66,玻璃背面則利用1ife-〇f 之接合電極68,圖十八(b)在玻璃66上所製作· 電極68知示意圖,在離子通道層1〇() 作 :Γ:Γ,圖十八⑻為…之製程完二J: 視圖,其中68和96主要是利用覆晶封裝的方法讓破壤和^ Extreme! 63. The photoresist-made flow channel is used on the electrode layer. 61 ITO glass 66 is placed on the top, and 1ife-〇f bonding electrode 68 is used on the back of the glass. Figure 18 (b) is on glass 66. The electrode 68 made above is shown in the schematic diagram of the ion channel layer 10 (): Γ: Γ, Figure 18 is the second process of J: view, where 68 and 96 are mainly made by flip-chip packaging. Ripped and
200528179 五、發明說明(24) 道上之電極接合,再利用底部填膠1 2 1將空隙填滿以增加 接合強度。1 0 0則是離子通道層,在離子通道上做有可計 算量測出病毒數量之電子電路7 0如圖十八(a)所示。 _ 當離子通道層的電極84和玻璃層之電極68相接合後,上下 電極間會形成6 7密閉空間如圖二十,圖二十為延圖十九 (c)剖面線a之剖面圖,本發明則利用此方法製作出在離子 通道中之流道,當病毒被牽引至離子通道層的時候會經由 此流道而流經計數的奈米孔道(n a η 〇 - ρ 〇 r e ),經由奈米孔 道(nano-pore)則可算出病毒在溶液中的個數。200528179 V. Description of the invention (24) The electrodes on the road are bonded, and then the bottom filler is used to fill the gap to increase the bonding strength. 1 0 0 is an ion channel layer, and an electronic circuit 70 capable of calculating and measuring the number of viruses on the ion channel is shown in Fig. 18 (a). _ When the electrode 84 of the ion channel layer and the electrode 68 of the glass layer are joined, a sealed space of 67 will be formed between the upper and lower electrodes, as shown in Fig. 20, and Fig. 20 is a sectional view extending along section 19 of Fig. 19 (c). The present invention uses this method to create a flow channel in the ion channel. When the virus is drawn to the ion channel layer, it will flow through the nano channel (na η 〇-ρ 〇re) through the flow channel. Nano-pore can calculate the number of viruses in solution.
第34頁 200528179 圖式簡單說明 圖一整體晶片檢測的流程圖 圖二分離技術示意圖 圖三病毒牽引示意圖 圖四液滴封包示意圖 圖五計數機制示意圖 圖六分離電極的製作流程圖 圖七離子通道的電子電路示意圖 圖八液滴封包形成不意圖 圖九離子通道之製作流程圖 圖十排序遷引電極排列示意圖 圖十一柱狀電場示意圖 圖十二電場分佈模擬圖 圖十三排序遷引電極外型示意圖 圖十四整體晶片封裝建構圖 圖十五電流放大訊號電路示意圖 圖十六離子通道製程示意圖 圖十七整體晶片之***示意圖 圖十八瑪道與電極封裝之剖面示意圖 圖十九晶片完成不意圖 圖二十晶片完成剖面圖Page 34 200528179 Brief description of the diagram Figure 1 Flow chart of overall wafer detection Figure 2 Schematic diagram of separation technology Figure 3 Schematic diagram of virus pulling Figure 4 Schematic diagram of droplet packing Figure 5 Schematic diagram of counting mechanism Schematic diagram of electronic circuit Fig. 8 Intentional formation of droplet package Fig. 9 Flow chart of ion channel production Fig. 10 Schematic diagram of sorting and relocating electrode Fig. 11 Schematic diagram of columnar electric field Fig. 12 Simulation of electric field distribution Schematic diagram Figure 14 Overall chip package construction diagram Figure 15 Current amplification signal circuit diagram Figure 16 Ion channel process schematic diagram Figure 17 Schematic diagram of the overall chip explosion Figure 18 Schematic diagram of the cross section of the electrode package and the electrode package Figure 20 Wafer complete sectional view
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