TWI395610B - Liquid filtering device and filtering method using the same - Google Patents
Liquid filtering device and filtering method using the same Download PDFInfo
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Description
本發明係關於一種液體過濾裝置及其過濾方法。The present invention relates to a liquid filtration device and a filtration method therefor.
血液擔負生物體內氧氣及能量傳輸的重要工作,係為生命系統正常運作不可或缺的元素之一。基於此點,臨床治療及醫療檢驗領域均發展出各式以血液為中心的應用技術,希望透過正確且迅速地取得/分析血液中所含的細胞或物質,進一步解決病痛帶來的不適,提昇人類生活品質。在此理念下,作為眾多進階應用基礎的血液分離或過濾技術一直被視為重點發展的項目之一。The blood is responsible for the important work of oxygen and energy transfer in the living body, and is one of the indispensable elements for the normal operation of the living system. Based on this, various blood-centered application technologies have been developed in the field of clinical treatment and medical examination. It is hoped that the cells or substances contained in the blood can be obtained/analyzed correctly and quickly to further solve the discomfort caused by the pain and improve. The quality of human life. Under this concept, blood separation or filtration technology, which is the basis of many advanced applications, has been regarded as one of the key development projects.
目前,已知分離血細胞與血漿的技術主要可分成四大類。第一種為離心技術,透過血細胞比重較大的特性,將全血血液置於試管中,以高速旋轉產生的離心力,達成將血細胞與血漿分離的目標。然而,由於部分血細胞之密度及沈澱速度與血漿成分非常接近,甚至相互重疊,導致離心技術在某些特殊應用上無法提供所需的純度。再者,此種技術通常要消耗大量的樣本及藥品,且處理上耗時甚長,整體成本偏高。At present, it is known that techniques for separating blood cells and plasma can be mainly classified into four categories. The first type is a centrifugal technique, in which the blood cells are placed in a test tube through the characteristics of a large proportion of blood cells, and the centrifugal force generated by the high-speed rotation is achieved to achieve the goal of separating blood cells from plasma. However, because the density and deposition rate of some blood cells are very close to, or even overlapping with, the plasma components, centrifugation techniques do not provide the required purity for certain applications. Moreover, this technology usually consumes a large amount of samples and medicines, and the processing takes a long time, and the overall cost is high.
其二係以介電泳力為基礎原理,搭配微機電製程,以特殊的儀器設備提供非均勻之交流電場,藉由血細胞與血漿間不同的導電度和介電常數,使兩者產生分離效果。但此技術目前仍受到步驟繁複以及所需設備造價較昂貴等條件限制,應用範圍略微狹隘。The second principle is based on the dielectrophoretic force principle, combined with the micro-electromechanical process, providing a non-uniform alternating electric field with special instruments and equipment, and the separation between the two is caused by the different conductivity and dielectric constant between the blood cells and the plasma. However, this technology is still limited by the complexity of the steps and the expensive equipment required, and the application range is slightly narrow.
非接觸式高波長雷射係近年來發展出的新技術,其係利用相反方向光壓形成一穩定的能量阱,以鉗住微小粒子。雖然,目前學說理論認為將此種工具方法用於分離血液將具備非接觸性、非侵入性等極佳的優點,讓非接觸式高波長雷射在此領域中受到非常大的期待,但是實際產業運用上還是難以克服設備成本過高的問題,推展遭遇相當困難。The non-contact high-wavelength laser system has developed a new technology in recent years, which uses a light source in the opposite direction to form a stable energy trap to clamp tiny particles. Although, the current doctrine theory believes that the use of such a tool method for separating blood will have the advantages of non-contact, non-invasive, etc., so that non-contact high-wavelength lasers are very much expected in this field, but the actual It is still difficult to overcome the problem of excessive equipment cost in industrial application, and it is quite difficult to carry out the exhibition.
深層過濾係四種技術中應用為較為普遍者,透過驅動血液以垂直方向流通過多層薄膜結構,使其中的血細胞等固體物質截留在薄膜表面。然而,此種技術最大的問題在於薄膜表面的濾餅形成,尤其隨通入血液量的增加,濾餅厚度會無可避免的對應增加,使得每作用一段時間就必須進行沖洗移除,耗費相當多的人力。除此之外,更重要的是,深層過濾往往會對血液中的血細胞產生較大的壓力,使得過濾過程中發生溶血現象,致使分離作業失敗。The deep filtration system is more commonly used in the four techniques. By driving the blood, it flows through the multilayer film structure in a vertical direction, so that solid substances such as blood cells are trapped on the surface of the film. However, the biggest problem with this technique is the formation of filter cake on the surface of the film, especially as the amount of blood introduced increases, the thickness of the filter cake will inevitably increase, so that it must be rinsed and removed every time it is used, which is quite expensive. More manpower. In addition, more importantly, deep filtration tends to exert greater pressure on blood cells in the blood, causing hemolysis during the filtration process, resulting in failure of the separation operation.
綜合上述,明顯可見習知分離血細胞取得血漿的技術難免有樣本消費量大、儀器設備昂貴不符合應用成本、作業耗時長及/或製程步驟繁瑣等問題,因此,如何提供一種設備成本低廉、結構簡單之液體過濾裝置,其不僅反應迅速,且所需樣品量少,運作符合經濟效益,更重要的是能有效避免濾餅形成及溶血現象產生,已成為一項重要的課題。In summary, it is obvious that the technique of separating blood cells to obtain plasma is inevitably subject to problems such as large sample consumption, expensive instrument equipment, inconsistent application cost, long operation time, and/or cumbersome process steps. Therefore, how to provide a device with low cost, The liquid filtering device with simple structure not only has a rapid reaction, but also requires a small amount of samples, and the operation is economical, and more importantly, it can effectively prevent the formation of filter cake and the phenomenon of hemolysis, which has become an important issue.
有鑑於上述課題,本發明之目的為提供一種設備成本低廉、結構簡單之液體過濾裝置,其不僅反應迅速,且所需樣品量少,運作符合經濟效益,更重要的是能有效避免濾餅形成及溶血現象產生。In view of the above problems, the object of the present invention is to provide a liquid filtering device which is low in cost and simple in structure, and which not only has a rapid reaction, but also requires a small amount of sample, and the operation is economical, and more importantly, it can effectively prevent the formation of filter cake. And hemolysis occurs.
為達上述目的,依據本發明之一種用於過濾一液體的裝置包括一流道以及一過濾薄膜。流道具有一流入口及一流出口。過濾薄膜具有複數孔洞。其中,流道係疊設於過濾薄膜,且液體於流過流道時,接觸過濾薄膜。在本發明實施例中,液體係實質上平行流過過濾薄膜。To achieve the above object, a device for filtering a liquid according to the present invention comprises a first-class track and a filter film. The runners have excellent entrances and first class exits. The filter membrane has a plurality of pores. Wherein, the flow channel is stacked on the filter film, and the liquid contacts the filter film when flowing through the flow channel. In an embodiment of the invention, the liquid system flows substantially parallel through the filter membrane.
在本發明之一實施例中,裝置係為微型晶片。其中,液體係為血液,且液體經過裝置過濾得到一血漿。In one embodiment of the invention, the device is a microchip. Wherein, the liquid system is blood, and the liquid is filtered through the device to obtain a plasma.
在本發明實施例中,流道係呈螺旋狀或渦狀。In the embodiment of the invention, the flow channel is spiral or spiral.
在本發明實施例中,該等孔洞之孔徑範圍係為1微米至50微米。在本發明之一實施例中,該等孔洞之孔徑較佳為1微米。In the embodiment of the invention, the pores have a pore size ranging from 1 micrometer to 50 micrometers. In an embodiment of the invention, the apertures of the holes are preferably 1 micron.
在本發明實施例中,過濾薄膜具有一第一表面及一第二表面。其中,第一表面具有複數弧面,且該等孔洞設置於該等弧面之間。第二表面對應該該等孔洞具有複數凹陷區。In an embodiment of the invention, the filter film has a first surface and a second surface. Wherein, the first surface has a plurality of curved surfaces, and the holes are disposed between the curved surfaces. The second surface corresponds to the holes having a plurality of recessed regions.
在本發明實施例中,裝置更包括一包覆殼體。流道以及過濾薄膜容置於包覆殼體,且流道之流入口及流出口外露於包覆殼體之一表面。其中,裝置更包括一收集槽。收集槽容置於包覆殼體,且對應流道設置於過濾薄膜之另一側。流道與收集槽透過過濾薄膜之孔洞相連通。In an embodiment of the invention, the device further includes a cover housing. The flow channel and the filter film are accommodated in the covering case, and the flow inlet and the outflow port of the flow channel are exposed on one surface of the covering case. Wherein, the device further comprises a collecting trough. The collecting tank is placed on the covering shell, and the corresponding flow channel is disposed on the other side of the filtering film. The flow channel and the collecting tank communicate with each other through a hole of the filter film.
在本發明實施例中,包覆殼體具有一上流道部及一下收集部。流道設置於上流道部,收集槽設置於下收集部,且過濾薄膜夾設於流道及收集槽。In an embodiment of the invention, the cladding housing has an upper flow channel portion and a lower collection portion. The flow channel is disposed in the upper flow channel portion, the collection groove is disposed in the lower collection portion, and the filter film is sandwiched between the flow channel and the collection groove.
在本發明一實施例中,裝置更包括一封裝部。封裝部覆蓋包覆殼體之至少一部分。In an embodiment of the invention, the device further includes an encapsulation portion. The encapsulation portion covers at least a portion of the cladding housing.
在本發明一實施例中,裝置更包括驅動單元。驅動單元連接流道,且驅動液體與過濾薄膜相對移動。In an embodiment of the invention, the apparatus further includes a drive unit. The driving unit is connected to the flow path, and the driving liquid moves relative to the filtering film.
為達上述目的,依據本發明之一種液體過濾方法,其係透過將一液體輸入依據本發明揭示之裝置,且收集該液體通過過濾薄膜之部分。在本發明實施例中,液體係為血液,且該液體通過過濾薄膜之部分係為血漿。To achieve the above object, a liquid filtration method according to the present invention is obtained by introducing a liquid into a device according to the present invention and collecting the liquid through a portion of the filtration film. In an embodiment of the invention, the liquid system is blood and the portion of the liquid that passes through the filter membrane is plasma.
在本發明之一實施例中,液體係連續地輸入裝置。In one embodiment of the invention, the liquid system is continuously input to the device.
承上所述,因依據本發明之裝置及其過濾方法可透過流道與過濾薄膜的結構搭配,使目標液體在流道中流過時,能與過濾薄膜接觸,並藉由過濾薄膜上的微小孔洞,提供目標液體中的液態成分通過,而截留住固體物質,從而達到過濾分離的目的,故可適於包括血液等含有懸浮微粒的液體使用。更重要的是,由於本發明裝置的結構係可供液體以平行過濾薄膜的狀態持續地流動,符合掃流原理,故可於流道內產生相對應之剪切應力。如此,當應用於例如過濾血液時,能有效降低濾餅形成的問題,避免孔洞阻塞以及溶血現象,而為一種可靠度高且不需時常維護的血液分離裝置。According to the above, the device according to the present invention and the filtering method thereof can be matched with the structure of the filter film through the flow channel, so that the target liquid can contact the filter film when flowing through the flow channel, and the micropores on the filter film are filtered. The liquid component in the target liquid is passed, and the solid substance is trapped to achieve the purpose of filtration separation, so it can be suitably used for a liquid containing suspended particles such as blood. More importantly, since the structure of the apparatus of the present invention allows the liquid to continuously flow in a state of parallel filtering of the film, in accordance with the sweeping principle, a corresponding shear stress can be generated in the flow path. Thus, when applied to, for example, filtering blood, it is effective in reducing the problem of filter cake formation, avoiding hole clogging and hemolysis, and is a blood separation device which is highly reliable and does not require frequent maintenance.
與習知技術相較,本發明不僅結構簡單,製程容易,可大量應用在含有懸浮物質之液體過濾。另外,依據本發明之裝置更易於以生物晶片的方式生產,不僅具有運送方便的優點,且每次操作時所需的樣本消耗量較少,有利於各等級的醫療院所或研究單位使用。又以時間成本的角度而言,利用本發明之裝置只需要選定配合的過濾薄膜,再簡單地將液體輸入,即可迅速地取得結果,沒有繁瑣的處理過程,避免例如傳統血液分離過程過度冗長的問題。Compared with the prior art, the present invention is not only simple in structure, but also easy in process, and can be widely applied to liquid filtration containing suspended substances. In addition, the device according to the present invention is easier to produce in the form of a bio-wafer, which not only has the advantage of convenient transportation, but also requires less sample consumption per operation, and is advantageous for use in various grades of medical institutions or research units. In terms of time cost, the apparatus of the present invention only needs to select a matching filter film, and then simply input the liquid, and the result can be quickly obtained without complicated processing, thereby avoiding, for example, excessive lengthy process of the traditional blood separation process. The problem.
以下將參照相關圖式,說明依本發明較佳實施例之液體過濾裝置及其過濾方法,其中相同的元件將以相同的元件符號加以說明。DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, a liquid filtering device and a filtering method thereof according to a preferred embodiment of the present invention will be described with reference to the accompanying drawings, wherein the same elements will be described with the same reference numerals.
圖1為依據本發明第一實施例之一種液體過濾裝置的示意圖,而圖2為圖1所示之液體過濾裝置的分解示意圖。請參考圖1所示,依據本實施例之一種裝置1,係用於過濾一液體,且此液體係例如含有懸浮微粒、顆粒或其他小型固體物質的可流動物質。在此,本實施例之裝置1所過濾的液體係以全血或含有血細胞的血液為例,其中懸浮有統稱為血細胞之紅血球、各種白血球及/或血小板。另外,需特別說明的是,本實施例中所稱之「過濾」一詞意指透過既存的孔洞,以在液體通過時,將其中指定的懸浮微粒、顆粒或其他小型固體物質因為尺寸大小的限制因素,停滯或截留於孔洞之一端,而與流通到達孔洞之另一端的液體成分分離。另外,本實施例所稱之過濾,並非限制於完全地分離,而係涵蓋因製造瑕疵、少數特殊狀況、或學說實作上所能允許的誤差。1 is a schematic view of a liquid filtering device according to a first embodiment of the present invention, and FIG. 2 is an exploded perspective view of the liquid filtering device shown in FIG. 1. Referring to FIG. 1, a device 1 according to the present embodiment is for filtering a liquid, and the liquid system is, for example, a flowable substance containing suspended particles, particles or other small solid matter. Here, the liquid system filtered by the apparatus 1 of the present embodiment is exemplified by whole blood or blood containing blood cells in which red blood cells collectively referred to as blood cells, various white blood cells and/or platelets are suspended. In addition, it should be particularly noted that the term "filtering" as used in this embodiment means passing the existing holes to specify the suspended particles, particles or other small solid materials in the liquid as it passes through the size. The limiting factor is stagnant or trapped at one end of the hole and separated from the liquid component that circulates to the other end of the hole. In addition, the filtration referred to in the present embodiment is not limited to complete separation, but covers errors that can be allowed due to manufacturing defects, a few special conditions, or a doctrine.
依據前述定義,本實施例之裝置1係可例如用於將包括紅血球、各種白血球及/或血小板的血細胞停滯或截留於孔洞之一端,而與通達孔洞之另一端的不含血細胞的血液部分(即血漿)分離。當然,在本發明其他實施例中,液體過濾裝置1亦可用於過濾懸浮有膠體粒子的水溶液,例如含有醫藥組合物的水溶液,本發明在此不限。According to the foregoing definition, the device 1 of the present embodiment can be used, for example, to stagnant or trap blood cells including red blood cells, various white blood cells, and/or platelets at one end of a hole, and a blood cell-free blood portion at the other end of the access hole ( That is, plasma) is separated. Of course, in other embodiments of the present invention, the liquid filtering device 1 can also be used to filter an aqueous solution in which colloidal particles are suspended, such as an aqueous solution containing a pharmaceutical composition, and the present invention is not limited thereto.
請同時參考圖1及圖2所示,在本實施例中,用於液體過濾的裝置1可以為一微型裝置,例如微型生物晶片,其外觀呈一薄型長方體。就細部結構而言,裝置1包括一包覆殼體11、一流道12、一收集槽13以及一過濾薄膜14。其中,包覆殼體11可更進一步具有一上流道部111及一下收集部112。上流道部111及下收集部112可以為一體成形或分離的兩塊體,且兩者尺寸大小可以相同或不同。在本實施例中,上流道部111與下收集部112係為獨立製成的兩部分,但長度、寬度及高度均分別為4公分、2.5公分及0.5公分。上流道部111與下收集部112在形成後,透過密封結合形成包覆殼體11。當然,除上述實施例外,兩者的尺寸亦可隨應用所需進行調整,非為限制條件。Referring to FIG. 1 and FIG. 2 simultaneously, in the embodiment, the apparatus 1 for liquid filtration may be a micro device, such as a micro biochip, which has a thin rectangular parallelepiped appearance. In terms of the detailed structure, the apparatus 1 includes a cladding housing 11, a flow path 12, a collection tank 13, and a filter film 14. The cover case 11 can further have an upper flow path portion 111 and a lower collection portion 112. The upper flow path portion 111 and the lower collection portion 112 may be two pieces integrally formed or separated, and the sizes thereof may be the same or different. In the present embodiment, the upper flow path portion 111 and the lower collecting portion 112 are two separate parts, but the length, width and height are respectively 4 cm, 2.5 cm and 0.5 cm. After the upper flow path portion 111 and the lower collecting portion 112 are formed, the coating case 11 is formed by sealing and sealing. Of course, in addition to the above implementations, the size of the two can also be adjusted as required by the application, not a limitation.
包覆殼體11及其上流道部111與下收集部112的材質可例如為聚甲基丙烯酸甲酯(Polymethylmethacrylate,PMMA)、聚雙甲基矽氧烷(Poly-dimethylsiloxane,PDMS)、環氧樹脂(Epoxy)、金屬或玻璃,當然,其他具備較佳機械強度以及高生物相容性特性的高分子材料亦可應用之。在本實施例中,包覆殼體11及其上流道部111與下收集部112的材質係以聚雙甲基矽氧烷(PDMS)為例,其不具細胞毒性,適合作為與活體生物樣本接觸的材料。另外,聚雙甲基矽氧烷還具有透光性佳,方便觀測等特性。The material of the cladding case 11 and the upper flow channel portion 111 and the lower collecting portion 112 may be, for example, polymethylmethacrylate (PMMA), poly-dimethylsiloxane (PDMS), epoxy. Epoxy, metal or glass. Of course, other polymer materials with better mechanical strength and high biocompatibility properties can also be used. In the present embodiment, the material of the coating casing 11 and its upper flow channel portion 111 and the lower collecting portion 112 is exemplified by polydimethyl methoxy oxane (PDMS), which is not cytotoxic and is suitable as a living biological sample. Contact material. In addition, polydimethyl oxa oxane also has good light transmittance and is easy to observe and other characteristics.
流道12、收集槽13以及過濾薄膜14均容置於包覆殼體11。其中,流道12設置於上流道部111,收集槽13設置於下收集部112,且過濾薄膜14夾設於流道12及收集槽13之間。流道12係為連續的液體通路,且除底側係為開放,其餘上側及左右兩側共三面則係為封閉。流道12兩端對外開口,例如本實施例中外露在包覆殼體11之一表面113而呈圓形的開口。流道12的開口即分別為液體輸入的流入口121及輸出的流出口122,其可分別連接例如鐵氟龍(polytetrafluoroethene,PTFE)橋接頭,以便於再與注射針筒連結,避免待過濾的液體在出入流道12時發生外漏。流道12的整體路徑並不限定形狀,在此係以螺旋狀或渦狀為例,其可在一定的面積範圍內,形成距離較長的液體通路,有利於液體過濾作業發揮較佳的功效。然而,在其他實施例中,流道12亦可以呈簡單的直線或鋸齒狀,端視過濾需求以及液體所含之成分,而能確實將指定的顆粒或固體物質與液體分離為原則。The flow path 12, the collection tank 13, and the filter film 14 are housed in the cladding casing 11. The flow channel 12 is disposed in the upper flow channel portion 111, the collection groove 13 is disposed in the lower collection portion 112, and the filter film 14 is interposed between the flow channel 12 and the collection channel 13. The flow channel 12 is a continuous liquid passage, and the bottom side is open, and the other upper side and the left and right sides are closed on three sides. Both ends of the flow path 12 are open to the outside, for example, an opening that is exposed in a circular shape on one surface 113 of the covering casing 11 in this embodiment. The openings of the flow channel 12 are respectively a liquid input flow inlet 121 and an output flow outlet 122, which can respectively be connected with a polytetrafluoroethene (PTFE) bridge joint, for example, so as to be connected with the injection syringe to avoid filtering. The liquid leaks when entering and exiting the flow path 12. The overall path of the flow channel 12 is not limited in shape. Here, it is a spiral or a spiral shape, which can form a long distance liquid passage within a certain area, which is beneficial to the liquid filtration operation. . However, in other embodiments, the flow channel 12 can also be in the form of a simple straight or serrated shape, depending on the filtration requirements and the components contained in the liquid, and can indeed separate the specified particles or solid materials from the liquid as a principle.
在本實施例中,流道12係以灌膠成形的方式設置於包覆殼體11之上流道部111。詳細而言,可選用具有流動性膠體性質的聚雙甲基矽氧烷覆蓋於母模,待膠體凝固後,將聚雙甲基矽氧烷形成的部分與母模分離,即可形成設置有流道12的包覆殼體11之上流道部111。圖3為圖2所示之流道的放大示意圖。請參考圖3所示,流道12係設置於上流道部111之中心位置,且流道12整體(以下以掃流區稱之)概略呈螺旋狀或渦狀。掃流區直徑d1約0.8公分。流道12的通道寬度d2約為50微米,流道的結構高度約為100微米。當然,上述尺寸均非本發明之限制性條件,而可隨實際應用需要調整,在其他實施例中,流道12的通道寬度d2可以由約50至500微米,例如為100或200微米,而流道12的結構高度可以由約10至500微米,例如20或200微米。另外,在流道12形成的過程中,同時透過例如模具的設計使包覆殼體11之上流道部111形成對外開口的流入口121與流出口122,在此,兩者均為細長管體(圖3中未示)。In the present embodiment, the flow path 12 is provided on the flow path portion 111 above the cladding casing 11 by means of potting. In detail, the polydimethyl methoxy alkane having a fluid colloidal property may be used to cover the master mold, and after the colloid is solidified, the portion formed by the polydimethyl siloxane is separated from the master mold to form a set. The flow path 12 covers the flow path portion 111 above the casing 11. Figure 3 is an enlarged schematic view of the flow path shown in Figure 2. Referring to FIG. 3, the flow path 12 is provided at the center of the upper flow path portion 111, and the entire flow path 12 (hereinafter referred to as a swept area) is substantially spiral or spiral. The sweeping area diameter d1 is about 0.8 cm. The channel 12 has a channel width d2 of about 50 microns and a channel structure height of about 100 microns. Of course, the above dimensions are not the limiting conditions of the present invention, but may be adjusted according to practical applications. In other embodiments, the channel width d2 of the flow channel 12 may be from about 50 to 500 microns, for example, 100 or 200 microns. The structural height of the flow channel 12 can be from about 10 to 500 microns, such as 20 or 200 microns. In addition, in the process of forming the flow path 12, the flow path portion 111 on the cladding casing 11 is formed into the outwardly opening inlet port 121 and the outflow port 122 through the design of, for example, a mold, where both are elongated tubes. (not shown in Figure 3).
請參考圖2所示,本實施例之收集槽13亦可以依據上述相同方式而設置於下收集部112,且對應流道12設置於過濾薄膜14之另一側。其中,收集槽13可以為一直徑0.8公分之圓形凹槽,且結構高度為200微米。當然,收集槽13的尺寸亦可隨例如過濾液體的量而調整,在其他實施例中,其結構高度可介於10至500微米,例如,結構高度可以為20或200微米。Referring to FIG. 2 , the collecting groove 13 of the embodiment may be disposed in the lower collecting portion 112 according to the same manner as described above, and the corresponding flow channel 12 is disposed on the other side of the filtering film 14 . The collecting groove 13 may be a circular groove having a diameter of 0.8 cm and a structural height of 200 μm. Of course, the size of the collection trough 13 can also be adjusted, for example, by the amount of filtered liquid. In other embodiments, the height of the structure can be between 10 and 500 microns, for example, the height of the structure can be 20 or 200 microns.
在本實施例中,掃流區、收集槽13以及過濾薄膜14三者的中心可例如實質上重疊,且過濾薄膜14夾設於流道12以及收集槽13間,換言之,過濾薄膜14亦係夾設於上流道部111及下收集部112間。過濾薄膜14的尺寸及構型並無特別限制,原則上係以配合掃流區為原則。In this embodiment, the centers of the sweeping zone, the collecting tank 13 and the filter film 14 may be substantially overlapped, for example, and the filter film 14 is interposed between the flow channel 12 and the collecting tank 13, in other words, the filtering film 14 is also It is interposed between the upper flow path portion 111 and the lower collection portion 112. The size and configuration of the filter film 14 are not particularly limited, and in principle, it is based on the principle of cooperating with the sweeping zone.
圖4a為圖2所示之過濾薄膜的部分放大示意圖,而圖4b為圖4a所示之過濾薄膜於剖面線B-B位置的示意圖。請同時參考圖4a及圖4b所示,在本實施例中,過濾薄膜14可為直徑1公分的圓形薄膜,其上具有複數孔洞141。過濾薄膜14具有一第一表面142及一第二表面143,其分別為過濾薄膜14之上表面及下表面。在本實施例中,巨觀下觀察之過濾薄膜14的第一表面142及第二表面143均近似平整表面,而無凹凸起伏變化(如圖2所示)。然而,請參考圖4b所示,若進一步以微觀角度觀察,則第一表面142具有複數向上凸起的弧面144,而孔洞141設置於弧面144之間,且第二表面143對應孔洞141,具有複數凹陷區145。4a is a partially enlarged schematic view of the filter film shown in FIG. 2, and FIG. 4b is a schematic view of the filter film shown in FIG. 4a at a position along the line B-B. Referring to FIG. 4a and FIG. 4b simultaneously, in the present embodiment, the filter film 14 may be a circular film having a diameter of 1 cm and having a plurality of holes 141 thereon. The filter film 14 has a first surface 142 and a second surface 143, which are the upper surface and the lower surface of the filter film 14, respectively. In the present embodiment, the first surface 142 and the second surface 143 of the filter film 14 observed under the macroscopic view are both approximately flat surfaces without undulations (as shown in FIG. 2). However, referring to FIG. 4b, if further observed at a microscopic angle, the first surface 142 has a plurality of upwardly convex curved surfaces 144, and the holes 141 are disposed between the curved surfaces 144, and the second surface 143 corresponds to the holes 141. There are a plurality of recessed regions 145.
詳細再說明上述結構。請同時參考圖4a及圖4b所示,在本實施例中,弧面144可例如為圓弧面,且包括頂端及底端,底端設置於孔洞141的周邊。凹陷區145可以為圓形,且面積大於孔洞141之面積。此外,孔洞141係為連通過濾薄膜14之第一表面142至第二表面143的圓形穿孔,其直徑大小可例如為1微米。然在本發明其他實施例中,孔洞141亦可以為其他形狀及/或尺寸,例如由1至50微米,原則上係依據目標溶液的組成及選定過濾之懸浮微粒或固體物質的大小而調整。舉例而言,以過濾分離全血中的血細胞為例,孔洞141的較佳直徑為1微米。The above structure will be described in detail. Referring to FIG. 4a and FIG. 4b simultaneously, in the embodiment, the curved surface 144 can be, for example, a circular arc surface, and includes a top end and a bottom end, and the bottom end is disposed at a periphery of the hole 141. The recessed area 145 may be circular and have an area larger than the area of the hole 141. Further, the holes 141 are circular perforations that communicate with the first surface 142 to the second surface 143 of the filter film 14, and may have a diameter of, for example, 1 micrometer. However, in other embodiments of the present invention, the holes 141 may be of other shapes and/or sizes, for example, from 1 to 50 microns, and are in principle adjusted depending on the composition of the target solution and the size of the selected suspended particulate or solid material. For example, the blood cells in the whole blood are separated by filtration, and the diameter of the holes 141 is preferably 1 micrometer.
過濾薄膜14可以為合金材質,其製造可以透過包括微影黃光製程與電鑄(electroforming)等數個步驟。首先,可先提供一基板,再於基板之一表面上形成一光阻層。接續,於光阻層形成複數個光阻圖樣,並顯露於基板之部分表面。設置一光罩於光阻層上方,其中,光罩具有複數個相對應光阻圖樣之圖樣。其後,進行曝光及顯影,以形成本實施例所示之圓形光阻圖樣。利用電鑄法將一合金層形成於光阻圖樣及基板上。最後,將合金層與光阻圖樣及基板分離開來,即形成本實施例之過濾薄膜14。The filter film 14 may be an alloy material, which can be manufactured through several steps including a lithography process and electroforming. First, a substrate may be provided first, and then a photoresist layer is formed on one surface of the substrate. Subsequently, a plurality of photoresist patterns are formed on the photoresist layer and exposed on a part of the surface of the substrate. A photomask is disposed above the photoresist layer, wherein the photomask has a plurality of patterns corresponding to the photoresist patterns. Thereafter, exposure and development are performed to form a circular photoresist pattern as shown in this embodiment. An alloy layer is formed on the photoresist pattern and the substrate by electroforming. Finally, the alloy layer is separated from the photoresist pattern and the substrate to form the filter film 14 of the present embodiment.
圖5為圖1所示之裝置於剖面線A-A位置的示意圖。請參考圖5所示,在本實施例中,由於流道12係實質上平行疊設於過濾薄膜14之第一表面142上,因此當液體L通入並流過流道12時,必然會有部分期間與過濾薄膜14接觸,且係以實質上平行過濾薄膜14的方式流過過濾薄膜14上方。流道12藉由本身底側為開放的構型,而與收集槽13透過過濾薄膜14之孔洞141相連通,是以,當液體L於流道12中流動時,會受到重力作用而由第一表面141的弧面144流至孔洞141(圖中因為巨觀角度,故仍呈平整狀,詳細結構可參照圖4b),使液態物質的部份順利通過孔洞141,至於其中液體L中所含的例如微粒或顆粒大小超過孔洞141尺寸的固體物質均會被孔洞141截留,達到分離過濾的效果。Figure 5 is a schematic illustration of the apparatus of Figure 1 at a section line A-A. Referring to FIG. 5, in the embodiment, since the flow path 12 is substantially vertically stacked on the first surface 142 of the filter film 14, when the liquid L enters and flows through the flow path 12, it is inevitable. A portion of the film is in contact with the filter film 14 and flows over the filter film 14 in a manner substantially parallel to the filter film 14. The flow path 12 communicates with the collecting hole 13 through the hole 141 of the filtering film 14 by the configuration in which the bottom side is open, so that when the liquid L flows in the flow path 12, it is subjected to gravity. The curved surface 144 of a surface 141 flows to the hole 141 (the figure is still flat due to the giant angle, and the detailed structure can be referred to FIG. 4b), so that the liquid substance portion passes through the hole 141 smoothly, and the liquid L therein The solid matter containing, for example, particles or particles having a size larger than the size of the pores 141 is trapped by the pores 141 to achieve the effect of separation filtration.
值得特別說明的是,藉由本發明之裝置1結構,可使液體L符合掃流過濾的原理,產生平行剪切應力,從而掃除過濾過程中堆積於例如過濾薄膜14之第一表面142的微粒或顆粒大小超過孔洞141尺寸的固體物質,避免過濾速度受到孔洞141上被過濾物質堆積的影響,造成操作阻力的增加。為產生較佳的平行剪切應力及過濾效果,液體L的流速範圍約由0.05 mL/min至0.5 mL/min,其中,又以較高的流速可取得的過濾效果較好,例如以0.5 mL/min。It should be particularly noted that, by the structure of the apparatus 1 of the present invention, the liquid L can be made to conform to the principle of sweep filtration to generate parallel shear stress, thereby sweeping particles deposited on the first surface 142 of the filter film 14 during filtration or The solid matter having a particle size exceeding the size of the hole 141 prevents the filtration speed from being affected by the accumulation of the filtered material on the hole 141, resulting in an increase in the operational resistance. In order to produce better parallel shear stress and filtration effect, the flow rate of liquid L ranges from about 0.05 mL/min to 0.5 mL/min, and the filtration effect obtained at a higher flow rate is better, for example, 0.5 mL. /min.
圖6係為利用本發明第一實施例之裝置進行全血過濾以分離血細胞時的流道內部分放大示意圖。請參考圖6所示,特別係用於全血過濾以分離血細胞時,透過本發明的設計,血液BL能以平行過濾薄膜14的方式於流道12內流動,且依據上述原理,不僅使白血球WC、紅血球RC以及血小板PL與血漿SR分離,完成收集血漿SR的目的,同時還能有效降低濾餅的形成,防止發生阻塞以及溶血現象。Fig. 6 is a partially enlarged schematic view showing the flow path when whole blood is filtered by the apparatus of the first embodiment of the present invention to separate blood cells. Referring to FIG. 6 , especially when used for whole blood filtration to separate blood cells, blood BL can flow in the flow channel 12 in parallel with the filter film 14 according to the design of the present invention, and according to the above principle, not only white blood cells are used. WC, red blood cell RC and platelet PL are separated from plasma SR to complete the purpose of collecting plasma SR, and at the same time, it can effectively reduce the formation of filter cake and prevent occlusion and hemolysis.
圖7係為依據本發明第二實施例之裝置的示意圖。請參考圖7所示,在本實施例中,用於液體過濾之裝置7的結構與元件組成大致與前述實施例所述相同,故以下僅就尚未提及之處說明。本實施例之裝置7更包括一驅動單元75,用以提供動力驅動液體於流道72內流通。其中,驅動單元75連接流道72之流入口721,較佳地係透過鐵氟龍橋接頭76與流入口721連接,且設置於包覆殼體71之上側。驅動單元75可例如以微型注射幫浦,啟動後可持續將由外接式儲存裝置(圖未示)輸入裝置7之液體向前推動,且使其維持慣性前進,從而形成與過濾薄膜74間的相對移動。依據此條件,驅動單元75當然可以為其他能提供動力的模組或元件,例如抽吸器、手動操作注射針筒或其他相似裝置,亦或於流入口721及流出口722形成氣體壓力差或真空狀態,使液體能夠被推動的模組或元件。Figure 7 is a schematic illustration of a device in accordance with a second embodiment of the present invention. Referring to FIG. 7, in the present embodiment, the structure and component composition of the apparatus 7 for liquid filtration are substantially the same as those described in the foregoing embodiment, and therefore, only the descriptions have been made below. The device 7 of the present embodiment further includes a driving unit 75 for providing power to drive the liquid to circulate in the flow channel 72. The driving unit 75 is connected to the inflow port 721 of the flow channel 72, preferably connected to the inflow port 721 through the Teflon bridge connector 76, and disposed on the upper side of the cladding case 71. The driving unit 75 can be, for example, a micro-injection pump, which can continuously push the liquid of the input device 7 from the external storage device (not shown) forward after starting, and maintain the inertia advancement, thereby forming a relative relationship with the filter film 74. mobile. According to this condition, the driving unit 75 can of course be other power-providing modules or components, such as an aspirator, a manually operated syringe or the like, or a gas pressure difference or at the inflow port 721 and the outflow port 722. A vacuum, a module or component that enables a liquid to be pushed.
另外需說明的是,依據本發明之裝置可以利用封裝技術另外加以包覆及保護,例如,在本發明第三實施例中,裝置具有與前述實施例大致相同的結構與元件組成,且更包括一封裝部。封裝部係以高分子材料環氧樹脂(Epoxy)為封裝材料,且覆蓋包覆殼體之至少一部分,例如包覆殼體的上表面。In addition, it should be noted that the device according to the present invention can be additionally coated and protected by using a packaging technology. For example, in the third embodiment of the present invention, the device has substantially the same structure and component composition as the foregoing embodiment, and further includes A package. The encapsulating portion is made of a polymer material epoxy resin (Epoxy) and covers at least a part of the covering case, for example, covering the upper surface of the casing.
本發明另揭露一種過濾方法,其係將液體輸入前述本發明之裝置,以分離液體中的微粒、顆粒或固體物質,再收集通過液體通過過濾薄膜的部分。舉例而言,本發明過濾方法可用於將血液連續輸入,以過濾血液中的血細胞,收集血液通過過濾薄膜後的血漿部分。The present invention further discloses a filtration method for introducing a liquid into the apparatus of the present invention to separate particulates, particles or solid matter in a liquid, and collecting a portion passing through the filtration membrane through the liquid. For example, the filtration method of the present invention can be used to continuously input blood to filter blood cells in the blood and collect blood plasma portions after passing through the filtration membrane.
為驗證本發明裝置及其過濾方法之可行,以下將舉人類血液為一實驗例,說明操作本發明裝置分離血液中的血細胞,且收集血漿之步驟。In order to verify the feasibility of the device of the present invention and the filtration method thereof, human blood is taken as an experimental example to explain the steps of operating the device of the present invention to separate blood cells in blood and collect plasma.
依據前述方式製成的本發明裝置,在此為一種微型生物晶片。首先,以1 mL針筒量取人類全血血液0.5 mL。利用鐵氟龍橋接頭連結注射針筒將全血血液注入本發明裝置中。調整微量注射幫浦,使流速維持在0.05 mL/min至0.5 mL/min的範圍內。在此使用的數組流速設定可以為0.5 mL/min、0.3 mL/min、0.1 mL/min、0.07 mL/min及0.05 mL/min。持續輸入大約10分鐘內即可注射完畢。藉由光學顯微鏡觀察過濾結果,如圖8所示,在10倍顯微鏡下可觀察到血液流通流道C,而通過過濾薄膜發生血漿與血細胞分離的情況(如箭號D所指)。The device of the invention made in the manner previously described is herein a microbiochip. First, 0.5 mL of human whole blood was taken from a 1 mL syringe. Whole blood is injected into the device of the present invention using a Teflon bridge connector to connect the syringe. Adjust the microinjection pump to maintain the flow rate in the range of 0.05 mL/min to 0.5 mL/min. The array flow rate used here can be set to 0.5 mL/min, 0.3 mL/min, 0.1 mL/min, 0.07 mL/min, and 0.05 mL/min. The injection can be completed within about 10 minutes of continuous input. The filtration result was observed by an optical microscope. As shown in Fig. 8, the blood flow path C was observed under a 10-fold microscope, and plasma and blood cells were separated by a filter film (as indicated by arrow D).
綜上所述,因依據本發明之裝置及其過濾方法可透過流道與過濾薄膜的結構搭配,使目標液體在流道中流過時,能與過濾薄膜接觸,並藉由過濾薄膜上的微小孔洞,提供目標液體中的液態成分通過,而截留住固體物質,從而達到過濾分離的目的,故可適於包括血液等含有懸浮微粒的液體使用。更重要的是,由於本發明裝置的結構係可供液體以平行過濾薄膜的狀態持續地流動,符合掃流原理,故可於流道內產生相對應之剪切應力。如此,當應用於例如過濾血液時,能有效降低濾餅形成的問題,避免孔洞阻塞以及溶血現象,而為一種可靠度高且不需時常維護的血液分離裝置。In summary, the device according to the present invention and the filtering method thereof can be matched with the structure of the filter film through the flow channel, so that the target liquid can contact the filter film when flowing through the flow channel, and the micropores on the filter film are filtered. The liquid component in the target liquid is passed, and the solid substance is trapped to achieve the purpose of filtration separation, so it can be suitably used for a liquid containing suspended particles such as blood. More importantly, since the structure of the apparatus of the present invention allows the liquid to continuously flow in a state of parallel filtering of the film, in accordance with the sweeping principle, a corresponding shear stress can be generated in the flow path. Thus, when applied to, for example, filtering blood, it is effective in reducing the problem of filter cake formation, avoiding hole clogging and hemolysis, and is a blood separation device which is highly reliable and does not require frequent maintenance.
與習知技術相較,本發明不僅結構簡單,製程容易,可大量應用在含有懸浮物質之液體過濾。另外,依據本發明之裝置更易於以生物晶片的方式生產,不僅具有運送方便的優點,且每次操作時所需的樣本消耗量較少,有利於各等級的醫療院所或研究單位使用。又以時間成本的角度而言,利用本發明之裝置只需要選定配合的過濾薄膜,再簡單地將液體輸入,即可迅速地取得結果,沒有繁瑣的處理過程,避免例如傳統血液分離過程過度冗長的問題。Compared with the prior art, the present invention is not only simple in structure, but also easy in process, and can be widely applied to liquid filtration containing suspended substances. In addition, the device according to the present invention is easier to produce in the form of a bio-wafer, which not only has the advantage of convenient transportation, but also requires less sample consumption per operation, and is advantageous for use in various grades of medical institutions or research units. In terms of time cost, the apparatus of the present invention only needs to select a matching filter film, and then simply input the liquid, and the result can be quickly obtained without complicated processing, thereby avoiding, for example, excessive lengthy process of the traditional blood separation process. The problem.
以上所述僅為舉例性,而非為限制性者。任何未脫離本發明之精神與範疇,而對其進行之等效修改或變更,均應包括於後附之申請專利範圍中。The above is intended to be illustrative only and not limiting. Any equivalent modifications or alterations to the spirit and scope of the invention are intended to be included in the scope of the appended claims.
1、7...裝置1, 7. . . Device
11、71...包覆殼體11, 71. . . Covered housing
111...上流道部111. . . Upper runner
112...下收集部112. . . Lower collection department
113...表面113. . . surface
12、72...流道12, 72. . . Runner
121、721...流入口121, 721. . . Inflow
122、722...流出口122,722. . . Outflow
13...收集槽13. . . Collection tank
14、74...過濾薄膜14, 74. . . Filter film
141...孔洞141. . . Hole
142...第一表面142. . . First surface
143...第二表面143. . . Second surface
144...弧面144. . . Curved surface
145...凹陷區145. . . Sag area
75...驅動單元75. . . Drive unit
76...鐵氟龍橋接頭76. . . Teflon bridge connector
A-A、B-B...剖面線A-A, B-B. . . Section line
BL...血液BL. . . blood
C...流道C. . . Runner
D...箭號D. . . Arrow
d1...直徑D1. . . diameter
d2...寬度D2. . . width
PL...血小板PL. . . Platelet
RC...紅血球RC. . . erythrocyte
SR...血漿SR. . . plasma
WC...白血球WC. . . leukocyte
圖1為依據本發明第一實施例之一種液體過濾裝置的示意圖;1 is a schematic view of a liquid filtering device according to a first embodiment of the present invention;
圖2為圖1所示之液體過濾裝置的分解示意圖;Figure 2 is an exploded perspective view of the liquid filtering device shown in Figure 1;
圖3為圖2所示之流道的放大示意圖;Figure 3 is an enlarged schematic view of the flow path shown in Figure 2;
圖4a為圖2所示之過濾薄膜的部分放大示意圖;Figure 4a is a partially enlarged schematic view of the filter film shown in Figure 2;
圖4b為圖4a所示之過濾薄膜於剖面線B-B位置的示意圖;Figure 4b is a schematic view of the filter film shown in Figure 4a at a position along the line B-B;
圖5為圖2所示之裝置於剖面線A-A位置的示意圖;Figure 5 is a schematic view of the device of Figure 2 taken along the line A-A;
圖6係為利用本發明第一實施例之裝置進行全血過濾以分離血細胞時的流道內部分放大示意圖;Figure 6 is a partially enlarged schematic view of the inside of the flow channel when the whole blood is filtered by the device of the first embodiment of the present invention to separate blood cells;
圖7係為依據本發明第二實施例之裝置的示意圖;以及Figure 7 is a schematic illustration of a device in accordance with a second embodiment of the present invention;
圖8為本發明第一實驗例之結果於10倍顯微鏡下觀察的照片圖。Fig. 8 is a photographic view of the results of the first experimental example of the present invention observed under a 10x microscope.
1...裝置1. . . Device
11...包覆殼體11. . . Covered housing
111...上流道部111. . . Upper runner
112...下收集部112. . . Lower collection department
113...表面113. . . surface
12...流道12. . . Runner
121...流入口121. . . Inflow
122...流出口122. . . Outflow
13...收集槽13. . . Collection tank
14...過濾薄膜14. . . Filter film
Claims (16)
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RU2753239C2 (en) * | 2017-02-17 | 2021-08-12 | Штат Пил Аг | Filtering device |
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EP0420765B1 (en) * | 1989-09-28 | 1995-11-22 | Terumo Kabushiki Kaisha | Blood plasma-separating membrane and blood plasma separator using the membrane |
TW200510059A (en) * | 2003-04-23 | 2005-03-16 | Asahi Medical Co | Body fluid treating device of hollow fiber membrane type |
CN101394917A (en) * | 2006-03-02 | 2009-03-25 | 真锅征一 | Porous diffusion type flat-film separating device, flat-film condensing device, regenerated cellulose porous film for porous diffusion, and non-destructive type flat-film inspecting method |
CN100556516C (en) * | 2007-05-25 | 2009-11-04 | 浙江伏尔特医疗器械有限公司 | Nuclear pore filter membrane for precision medicine liquid filter and preparation method thereof |
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EP0420765B1 (en) * | 1989-09-28 | 1995-11-22 | Terumo Kabushiki Kaisha | Blood plasma-separating membrane and blood plasma separator using the membrane |
TW200510059A (en) * | 2003-04-23 | 2005-03-16 | Asahi Medical Co | Body fluid treating device of hollow fiber membrane type |
CN101394917A (en) * | 2006-03-02 | 2009-03-25 | 真锅征一 | Porous diffusion type flat-film separating device, flat-film condensing device, regenerated cellulose porous film for porous diffusion, and non-destructive type flat-film inspecting method |
CN100556516C (en) * | 2007-05-25 | 2009-11-04 | 浙江伏尔特医疗器械有限公司 | Nuclear pore filter membrane for precision medicine liquid filter and preparation method thereof |
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