CN106457251A - 用于反应的过程和设备 - Google Patents

用于反应的过程和设备 Download PDF

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CN106457251A
CN106457251A CN201580014421.2A CN201580014421A CN106457251A CN 106457251 A CN106457251 A CN 106457251A CN 201580014421 A CN201580014421 A CN 201580014421A CN 106457251 A CN106457251 A CN 106457251A
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piece
reaction
hrm
aforementioned
reaction vessel
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N·拿撒雷特
D·艾德格
A·泰勒
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BG Research Ltd
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Abstract

一种除热模块片，构造成服务一排反应容器，所述片为导热材料块的形式，在片的边缘具有一排反应站，在片的一端为液体入口歧管，而在片的另一端为液体出口歧管；并且换热器液体通道与所述反应站相邻并且在两个歧管之间延伸。通过多个类似的片，所述片被构造来形成用于结合至反应设备和过程中的热减少模块，反应通常地为PCR反应。

Description

用于反应的过程和设备
技术领域
本发明涉及生物的、化学的和生物化学的反应，具体而言是在纳升至微升级别进行的那些反应，并且甚至可包括在皮升级别进行的那些反应。它包括涉及热循环的那些反应，诸如聚合酶链式反应(PCR)以及等温反应。
它还具体地涉及一种设备，在该设备中同时进行大量的减小体积的反应，多个反应容器被同时容纳在一个反应设备中。例如，在微升级别，反应容器可以是托盘的形式，该托盘被称为微滴定板，该托盘包括容器的阵列。在一个标准的微滴定板中，96个容器被设置在包括12×8行的一个阵列中。其它的板然后通常构造在96×n的基部上，其中n为整数。
背景技术
具体在PCR的现场，其中在尽可能短的时间内实现完整的反应会是有价值的，热可以被传入和传出样品的速率是很重要的。这意味着不仅考虑传热介质和最佳的基部温度，而且还要考虑加热介质和冷却介质相对样品的接近度。在96n微升阵列的情况下，其中也特别希望对每个容器中的反应进行单独的控制，如可优选的那样，如果冷却是利用单独的块在基部温度处操作，则保证相同的基部温度对每个容器始终都是可用的是至关重要的。
一个这样的单独的块是如PCT专利申请PCT/GB07/003564中描述的除热模块(HRM)。该模块是单独的块，具有形成在其中的复杂的通道，冷却剂可从通道中流过。模块被形成来容纳微滴定反应容器。然而，尽管在该专利申请中所述的系统中冷却设施是相当有效的，但是另一方面，加热设施却不那么有效。
PCT专利申请WO2012063011记载了一种反应容器容纳站，该反应容器容纳站具有反应容器容纳部分、加热器部分和冷却部分，后者被布置成将站锚固在除热模块中。包括围绕容器容纳部分缠绕的线的加热器部分是特别有效的。
本发明提供一种除热系统，能够满足来自每一个反应容器的一致的冷却的需求。
发明内容
根据本发明，提供了一种构造成服务一排反应容器的除热模块片，所述片是导热材料块的形式，在片的边缘具有一排反应站，在片的一端是液体入口歧管，而在片的另一端是液体出口歧管；换热器液体通道与反应站相邻并且在两个歧管之间延伸。
反应容器容纳站优选限定反应容器支架可被安装在内的凹部，优选为过盈配合。
根据本发明的特征，随着歧管从片的一个面至另一个面延伸，片可被构造成面对面地装配成类似的这样的片的阵列，从而每个片的歧管形成连续的歧管入口管和出口管，并且每个片可结合定位及连接装置，从而片可被准确地互相定位和连接。
通过多个如所定义的片的装配形成除热模块的重要的优点是便于制造，对每一个反应站获得高效率的和一致的冷却，以及相对便宜地拆卸和更换部件，部件例如在反应容器容纳部件故障的情况下的片。在一个12×8的井式阵列系统中，优选所述片被构造成服务一排八个站。
记住，除热模块上方的区域可能会相当拥挤，与从片形成除热模块的设施相关联的另一个优点是，片可被制造来结合用于电气导管的凹槽以连接至反应容器支架，用于为其加热器供电和传送来自其的传感器(诸如温度传感器)信号。这些导管可被形成在印刷电路板(PCB)上，实际上是形成在被构造成安装在凹槽中、理想地为卡(click)在凹槽中的印刷电路板上。这也能够有利于热减少模块的制造，因为在反应容器支架被安装在站内，每一个结合有加热器和温度传感器，以及专用的印刷电路板在适当位置的情况下，加热器和传感器与导管的连接可相对简单。典型地，导管在细管中终止，传感器和加热器的引线可被反馈并且焊接或者简单地夹持(卷)在细管中的合适的位置。
在片的制造中，首先切出形状，形成必要的孔并且磨出用于PCB的凹槽，以及靠着片的与凹槽相反的一侧将片夹持在合适模型的夹具中，安装容器支架，PCB随后卡入合适的位置并且容器支架传感器和加热器线连接至PCB导管终端。随后硅树脂被提供在容器支架的周围以绝缘所述容器支架加热器线圈，以及辅助维持整体性。为了尽可能地绝热，每个站相互之间具有间隙(例如切口)，间隙可被形成在片的每个站之间，并且所述片可相对于相邻的片是缩进的。
通常的标准微滴定12×8板用井中心在9.0mm中心构造。反应容器是由碳载塑料材料形成的微滴定容器，并且具有2cm的整体长度。它包括，以从上到下的顺序，盖容纳边，填料部分和具有基部的反应腔。填料部分具有7mm的最大外径和5mm的深度。反应腔从3mm向下逐渐变细为2.5mm，整个具有0.8mm的壁厚。因此反应容器基本上是毛细管尺寸。
因此，HRM片可以是9.00mm厚。为了结合14.00mm的歧管以及它们的连接至冷却剂管的相关联的连接器(优选是柔性的)，片可以是11-12cm长以及4-5cm深。换热器液体通道可具有大约3-4mm的孔。典型地，片由较纯的铝形成。这样的铝易加工，并且具有足够高的热导率，同时与例如铜和塑料材料相比要足够地抗机械变形，并且比例如不锈钢更便宜。铝还可通过阳极氧化为容易被保护的并且足够抗氧化。
然后应当理解，标准的HRM模块将包括12个HRM片加上结合了冷却剂管连接器的端部夹持元件。
这样的HRM典型地安装在反应设备中，在这里它可以在装载站和操作站之间移动。装载站可从设备中突出出来，在这里模块可容纳装载了96个装有反应部件的反应井的微滴定板。然后马达收缩模块并将模块抬起至操作站，在这里机械压力引起每个井和它的容器支架维持接触，同时期望的反应发生。该设备可结合感测装置，用于指示期望的接触压力已经达到并且维持。反应设备将通常也具有布置用于监测反应的结果的设施，通常地是光学设施。
在反应过程中，通过导管的电力供应可被布置来根据预定的程序加热所述井，而其他的导管传送与井中的温度相关的信号。
加热循环可被布置来针对HRM 50中的冷却剂环境而发生，其优选固定在高于室温的某个温度，例如在30℃至45℃之间。具有较高的HRM温度允许达到较高的加热速率——至通常的96℃的最大值。相反HRM温度越低，冷却速率将会越快。期望的平均值是40℃，这个温度通常高于室温，并且是加热效率和冷却效率的中点。
该设备特定地适合于对各井中的反应循环的单独控制。
附图说明
现在将参考附图以示例的形式描述本发明的实施例，附图中：
图1是热减少模块片的等轴视图；
图2是具有安装的PCB的片的等轴视图；
图3是具有安装的PCB和反应容器支架的片的等轴视图；
图4是安装有PCB的片的前视图，示出了反应容器支架的位置和结构；
图5是装配的HRM的平面图；
图6是反应设备的示意图；以及
图7和图8是替代的片的等轴视图。
具体实施方式
图1-5中示出的是除热模块片10。由铝形成，除热模块片10在顶边缘处具有多个反应站11，冷却剂液体入口12和出口13歧管孔在每个端部处穿过除热模块片10，并且一系列的凹槽14沿着一个面从除热模块片10的顶部边缘至底部边缘延伸。换热器液体通道15与反应站11相邻，在歧管孔之间延伸。
反应站11是圆形的空洞，尺寸设置为反应容器支架40的基部在其中过盈配合。小孔16从每个站11的基部通至凹槽14，用于当容器支架被放入时，允许气体(空气)从站11中逸出。
在片的一个面上围绕每个歧管的是用于O型密封圈的凹槽17，并且更外侧是滑动连接孔18，每个孔18具有定位套19。
在一个面的每一个底角处是分离缩进(rebate)20，布置来在需要的时候辅助分离所述片。在每个站11之间，具有布置来最大化每个站11之间的热隔离的切口21。在每个片10的一侧上的缩进22也为相同的目的而形成。
印刷电路板(PCB)30被制造成卡入凹槽14内，并且在所述片10上面和下面突出。PCB 30承载加热器和传感器电气导管，该传感器电气导管在PCB 30顶部的连接器31中和底部的连接器32中终止。PCB 30的宽度为凹槽14的深度。
如在图3和图4中具体示出的，反应容器支架40安装至每个反应站11中。反应容器支架40包括反应容器容纳部分41、加热器部分42和冷却部分43，后者布置成将站锚固在除热模块中。也由铝销钉状地形成的支架40的大小和形状可被放入反应站11。容器容纳部41的形状为贴合地容纳微滴定反应容器(未示出)，并且在其壁中放置有温度传感器44。加热器部分42具有围绕其的螺旋状的凹槽，其中布设有加热器线圈45。
在片的制造中，首先切出形状，形成必要的孔，并且磨出用于PCB的凹槽，以及靠着片的与凹槽相反的一侧将片夹持在合适模型的夹具中，安装容器支架，PCB随后卡入合适的位置并且容器支架传感器和加热器线连接至PCB导管终端。
为了形成用于通常的96(12×8)井式托盘的除热模块50，12个HRM片10被安装在一起，如图5和图6所示，通过连接器板51夹持并夹持在连接器板51之间，该连接器板51具有冷却剂液体入口和出口接头52和53。模块50在电动传送机上被结合入反应设备(未示出)内，通过该电动传送机，该模块可在装载位置和设备内的操作位置之间移动，在装载位置，该模块从设备中突出，在操作位置可以发生反应。柔性的管(未示出)通过泵(未示出)将接头52、53与散热器冷却剂存储器(未示出)连接。
图6示出了模块50和承载反应井61的井式微滴定托盘96或板60的组件。反应容器61是微滴定容器，由碳载塑料材料形成，并且整体长度为2cm。以从上到下的顺序，它包括盖容纳边、填料部分和具有基部的反应腔。填料部分具有7mm的最大外直径和5mm的深度。反应腔的直径从3mm向下逐渐变细为2.5mm，整个具有0.8mm的壁厚。因此反应容器基本上是毛细管尺寸的。
托盘60适于安装在支架的阵列上，并且反应设备被布置来均匀地将井压入支架内。反应设备具有结合了光学设施的光学盒62，该光学设施布置来监测井61内的反应的进展。光学盒还具有维持支架40内的井61的压力的功能。设备结合传感器(未示出)以指示所述均匀压力的达到和维持。
在图7和图8中示出的可替代的片100中，相同的附图标记指代相同的部件。片100与片10的区别在于片100是由矩形的空洞101形成的，空洞101从缩进的基部102延伸至刚好在站11的基部的下方，并且从入口管12至出口管13。安装至缩进的基部102中的止动件103用于密封空洞101。空洞101因此布置来在入口管12和出口管13之间传送冷却剂。该空洞101因此代替了片10中的管15，并且提供了改进的冷却剂流动和效率。
在反应过程中，通过导管的电力供应被布置来根据预定的程序加热井61，而其他的导管传送与井中的温度相关的信号。针对每个井，该程序被预先确定，从而该设备特别适于在每个井61中执行完全独立的反应。因此，在反应包含加热-冷却循环的情况下，如在作为示例的PCR的情况中，一个井61可处于加热阶段，而另一个处于冷却阶段，一个在闲置而另一个在完成。
加热循环被布置来针对HRM 50内的冷却剂环境而发生，HRM 50被固定在40℃，通常高于室温并且是加热效率和冷却效率的中点。

Claims (29)

1.一种除热模块片，所述除热模块片被构造成服务一排反应容器，所述片是导热材料块的形式，在所述片的边缘处具有一排反应站，在所述片的一端处具有液体入口歧管，而在所述片的另一端处具有液体出口歧管；并且换热器液体通道与所述反应站相邻并且在所述两个歧管之间延伸。
2.如权利要求1所述的片，并且其中所述反应容器容纳站限定凹部，反应容器支架能够被安装在凹部中。
3.如权利要求2所述的片，并且其中所述凹部被布置成以过盈配合来容纳反应容器支架。
4.如权利要求1-3中任一项所述的片，并且其中，歧管从所述片的一个面延伸至另一个面，片被构造成面对面地装配成类似的这样的片的阵列，从而每个片的歧管形成连续的歧管入口管和出口管，并且每个片结合有定位及连接装置，从而片能够被准确地互相定位和连接。
5.如前述任一项权利要求所述的片，并且被构造成服务在12×8的井式阵列中的一排的八个站。
6.如前述任一项权利要求所述的片，并且结合用于电气导管的至少一个凹槽以连接至反应容器支架，用于为反应容器支架的加热器供电和传送来自反应容器支架的传感器信号，所述传感器诸如温度传感器。
7.如权利要求6所述的片，并且具有相关联的印刷电路板(PCB)，所述印刷电路板承载有电气导管并且构造成安装在所述至少一个凹槽中。
8.如权利要求7所述的片，并且其中所述导管在细管中终止，所述传感器和加热器引线能够被反馈并且焊接或者简单地夹持在细管中的合适的位置。
9.如前述任一项权利要求所述的片，并且具有安装在片中的容器支架。
10.如前述任一项权利要求所述的片，并且具有安装在片中的八个容器支架。
11.如权利要求9或者10所述的片，并且具有围绕所述容器支架的硅树脂套。
12.如前述任一项权利要求所述的HRM片，并且片为9.00mm厚。
13.如前述任一项权利要求所述的片，并且其中所述歧管具有直径14.00mm的孔。
14.如前述任一项权利要求所述的片，并且片为11-12cm长，4-5cm深。
15.如前述任一项权利要求所述的片，并且其中所述换热器液体通道具有大约3-4mm直径的孔。
16.如前述任一项权利要求所述的片，并且由相对纯的铝形成。
17.一种包括多个片以及端部夹持元件的HRM模块，每个片为如前述任一项权利要求所述，端部夹持元件包含冷却剂管连接器。
18.如权利要求17所述的HRM模块并，且包括12个HRM片。
19.一种结合有如权利要求17或者18所述的HRM模块的反应设备。
20.如权利要求19所述的反应设备，并且其中所述HRM模块被布置为能够在装载站和操作站之间移动。
21.如权利要求20所述的反应设备，并且其中在所述装载站处，所述HRM模块被布置来容纳装载有96个反应井的微滴定板，所述96个反应井装有反应部件。
22.如权利要求21所述的反应设备，并且具有用于在期望的反应发生时，施加机械压力以维持每个井与井的容器支架之间的接触的装置。
23.如权利要求20至22中任一项所述的反应设备，并且具有布置来收缩所述模块并且将模块抬升至操作站的马达。
24.如权利要求20至23中任一项所述的反应设备，并且具有布置用于监测所述反应的结果的设施。
25.如权利要求24所述的反应设备，并且其中监测设施是光学的。
26.一种使用如权利要求20至25中任一项所述的设备的生物的、化学的或者生物化学的过程。
27.一种基本上如上文参考所述附图描述的HRM片。
28.一种基本上如上文参考所述附图描述的HRM模块。
29.一种基本上如上文参考所述附图描述的反应设备。
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