CN1693478A - 用于制作dna微阵列的点样装置和使用该装置点样的方法 - Google Patents
用于制作dna微阵列的点样装置和使用该装置点样的方法 Download PDFInfo
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- CN1693478A CN1693478A CNA2004101049191A CN200410104919A CN1693478A CN 1693478 A CN1693478 A CN 1693478A CN A2004101049191 A CNA2004101049191 A CN A2004101049191A CN 200410104919 A CN200410104919 A CN 200410104919A CN 1693478 A CN1693478 A CN 1693478A
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- Apparatus Associated With Microorganisms And Enzymes (AREA)
Abstract
本发明提供了用于制作DNA微阵列的点样装置及用该装置点样的方法。这种用于在DNA微阵列表面上滴落和固定生物分子溶液的装置包括:管形的第一微通道;供给单元,用于给第一微通道提供生物分子溶液;生物分子溶液液滴形成单元,它横向连接第一微通道,并通过定期向第一微通道中流动的生物分子溶液喷射气体而形成预定大小的生物分子溶液液滴;第二微通道,它连接第一微通道且直径大于第一微通道;冷却单元,它包围第二微通道的至少一部分以冷冻通过第二微通道的生物分子溶液液滴;点样单元,它将冷冻的生物分子溶液液滴解冻并滴落到DNA微阵列的表面。该装置可在制作DNA微阵列时形成相同形状的点,使温度对生物分子的影响最小,并轻松操作生物分子。
Description
技术领域
本发明涉及一种用于制作DNA微阵列的点样装置和使用该装置点样的方法。更具体地说,本发明涉及一种点样装置和使用该装置点样的方法,该点样装置用于在DNA微阵列表面上滴落和固定生物分子溶液,例如,核酸(如探针DNA、mRNA和肽核酸(PNA))和蛋白质,以制作一种DNA微阵列。
技术背景
随着人类基因组计划的发展,对于快速提供关于诊断、治疗和预防遗传性疾病的大量基因信息的方法的需求大大增加。虽然直到Sanger等人的当时已经用于分析碱基序列的Sange方法通过聚合酶链反应(PCR)复制DNA及其自动化的发展而得到稳步改进,但是因为分析过程复杂、耗时、昂贵并需要高度的技能,该方法不能分析大量基因。因此,一直需要一种用于分析碱基序列的新系统。根据时代的需要,近几年在制作DNA微阵列和使用该DNA微阵列的技术上取得了进步。
“DNA微阵列”通常是指,将寡核苷酸探针附着到固体表面的成百个或数十万个预定位置以形成微阵列,所述探针的碱基序列已知并且具有最小几个到最大几百个的碱基,所述固体例如硅树脂、表面改性的玻璃、聚丙烯、以及活化的聚丙烯酰胺。在将有待分析的目标DNA片段结合到DNA微阵列时,根据附着到DNA微阵列上的探针的碱基序列和目标DNA片段的碱基序列之间的互补程度发生各种杂交,这些杂交通过光学方法或放射化学方法观察和分析,以发现目标DNA的碱基序列(杂交测序;SBH)。
使用DNA微阵列制作的DNA芯片可以实现DNA分析系统的微小化,使用仅仅超微量的样本进行基因分析并且在目标DNA上各个位置同时检查碱基序列。因此,DNA芯片费用不高且可快速提供遗传信息。而且,DNA芯片可以同时快速地分析大量的基因信息,并弄清基因之间的关系,于是,可以应用于很多领域,如遗传性疾病和癌症的诊断、突变的搜索、病原性细菌和真菌的检测、基因表达的分析以及药物开发。而且,DNA芯片可以用于生物技术以促进发展。例如,它可以用作微生物和环境污染的传感器以发现中和毒药的物质的基因,并且基因重组技术用于这里以大量生产中和毒药的物质或者生产医用植物和低脂肪肉。
DNA微阵列根据所使用的探针类型可以划分为寡核苷酸芯片和cDNA芯片,根据制作方法可以划分为光蚀刻(photolithography)芯片、使用针(pin)的点样芯片以及使用喷墨(inkjet)的点样芯片。图1和图2分别显示了使用针和喷墨制作DNA微阵列的传统点样方法。在这些方法中,生物分子溶液,例如,核酸(如探针DNA、mRNA和PNA)和蛋白质被滴落并固定在DNA微阵列表面。这些方法中是使用的所有生物分子都为液态。
考虑到制作DNA微阵列的传统点样装置以及使用该装置的点样方法,如果使用针,因为针被用于点样生物分子溶液并随后冲洗该溶液,然后用于点样另一种生物分子溶液,将有99%或者更多的生物分子溶液未经使用就被废弃。而且,点(spot)的大小不均匀,针偶尔堵塞,针的寿命不长,生物分子溶液的浓度根据点样时间而变化,并且需要很长时间点样生物分子溶液。如果使用喷墨,泡沫喷射方法(bubble jet method)立刻就需要(momentarily require)超高的热量,于是一部分对热敏感的生物分子可能受到热的影响。而且,喷嘴偶尔堵塞。
发明内容
本发明提供了一种点样装置和使用该装置的点样方法,当制作生物芯片或DNA微阵列时,该点样装置能比传统的点样装置产生具有更相同形状的点,使温度对生物分子的影响减到最小,并轻松操纵生物分子。
本发明也提供了一种能够显著减少制作生物芯片或DNA微阵列所需时间的点样装置和使用该装置的点样方法。
根据本发明的一个方面,它提供了一种点样装置,该点样装置用于在DNA微阵列表面上滴落(drop)和固定生物分子,例如,核酸(如探针DNA、mRNA和肽核酸(PNA))和蛋白质的溶液以制作一种DNA微阵列,该点样装置包括:管形的第一微通道、供给单元、生物分子溶液液滴形成单元(dropletfotming unit)、第二微通道、冷却单元和点样单元,其中,所述供给单元用于给第一微通道提供生物分子溶液;生物分子溶液液滴形成单元横向连接(cross-linked)到第一微通道,并通过定期向第一微通道中流动的生物分子溶液喷射气体而形成具有预定尺寸的生物分子溶液液滴;第二微通道连接到第一微通道并且具有比第一微通道更大的直径;冷却单元包围第二微通道的至少一部分以冷冻通过第二微通道的生物分子溶液液滴;而点样单元将生物分子溶液液滴解冻并将已解冻的生物分子溶液液滴滴落到DNA微阵列的表面。
点样单元包括:第三微通道、释放器(discharger)和第四微通道,其中第三微通道具有微阀(microvalve)用于开、关冷冻的生物分子溶液液滴所通过(pass through)的通道,并在零下温度(sub-zero temperature)贮存冷冻生物分子溶液液滴;释放器连接到第三微通道并通过打开微阀将冷冻的生物分子溶液液滴从第三微通道释放;第四微通道连接到第三微通道并被加热器加热到预定的温度,使第三微通道释放的冷冻的生物分子溶液液滴解冻。
所述预定的温度是20至200℃,且所述零下温度是-5至-30℃。通常,隔热通道安装在第三微通道和第四微通道之间,以防止热从第四微通道传到第三微通道。
而且,释放器是安装在第三微通道上方的微激励器(microactuator),并且大量点样单元可以规则布置以减少制作时间。
供给单元包括贮液器和第一微泵(micropump),其中贮液器连接到第一微通道以贮存生物分子溶液;第一微泵将贮存在贮液器中的生物分子溶液泵入到第一微通道中。
并且,气体是空气且生物分子溶液液滴形成单元包括贮存空气的储气器和第二微泵,该第二微泵将贮存在储气器中的空气定期向第一微通道中流动的生物分子溶液喷射。
生物分子溶液液滴的预定尺寸可以是直径2000μm到1nm。
并且,冷却单元可以还包括用于贮存冷冻的生物分子溶液液滴的冷冻生物分子溶液液滴贮液器。
根据本发明的另一个方面,它提供了一种用于在DNA微阵列表面上滴落和固定生物分子,例如,核酸(如探针DNA、mRNA和肽核酸(PNA))和蛋白质的溶液以制作一种DNA微阵列的点样方法,该点样方法包括:(a)允许生物分子溶液流入管形的第一微通道;(b)定期向第一微通道中流动的生物分子溶液喷射气体以形成具有预定尺寸的生物分子溶液液滴;(c)使通过第二微通道的生物分子溶液液滴冷冻以贮存冷冻的生物分子溶液液滴,其中第二微通道连接到第一微通道并且具有比第一微通道更大的直径;和(d)将冷冻的生物分子溶液液滴解冻并将解冻的生物分子溶液液滴滴落到DNA微阵列的表面。
在操作(c)中,冷冻的生物分子溶液液滴的贮存可以在保持在-5至-30℃的第三微通道中完成。
在操作(d)中,当通过由加热器保持在20至200℃并且连接到第三微通道的第四微通道时,冷冻的生物分子溶液液滴可以解冻。
在操作(b)中,气体是空气且液滴的预定尺寸通常是直径2000μm到1nm。
在操作(d)中,冷冻的生物分子溶液液滴可以由大量规则布置的点样单元同时释放,由此减少制作DNA微阵列的时间。
附图说明
结合附图阅读下面详细说明的典型实施例,可以更清楚地了解到本发明的上述以及其它特性和优点,其中:
图1说明了一种使用针制作DNA微阵列的传统点样方法;
图2说明了一种使用喷墨制作DNA微阵列的传统点样方法;
图3说明了一种按照本发明实施例的用于制作DNA微阵列的点样装置,用于描述生物分子溶液的冷冻过程;
图4是图3中所示点样装置的点样单元的一个示意性剖面图;
图5A和5B是用于说明使用图3中所示点样装置进行点样实验的过程的图表;和
图6A至6C说明了图5A和5B的实验结果。
具体实施方式
现在将参考显示本发明实施例的附图更完整地说明本发明。
图3是按照本发明实施例的用于制作DNA微阵列的点样装置的图,用于描述生物分子溶液的冷冻过程,图4是图3中点样装置的点样单元的一个示意性剖面图。如图3和图4所示,根据本发明的实施例的用于制作DNA微阵列3的点样装置1包括:管形的第一微通道10、供给单元20、生物分子溶液液滴形成单元30、第二微通道40、冷却单元50和点样单元60,其中供给单元20给第一微通道10提供生物分子溶液5,所述生物分子例如,核酸(如探针DNA、mRNA和肽核酸(PNA))和蛋白质;生物分子溶液液滴形成单元30横向连接到第一微通道10并通过向第一微通道10中流动的生物分子溶液5定期喷射气体而形成具有预定尺寸,通常是2000μm至1nm之间直径的生物分子溶液5的液滴;第二微通道40连接到第一微通道10并且具有比第一微通道10更大的直径;冷却单元50包围第二微通道40的至少一部分以冷冻通过第二微通道40的生物分子溶液5的液滴;点样单元60使冷冻生物分子溶液液滴71解冻,并将已解冻的生物分子溶液液滴滴到DNA微阵列3的表面。并且单独设置有用于贮存已在冷却单元50中冷冻的生物分子溶液液滴71的生物分子溶液液滴贮液器70。
用于给第一微通道10提供生物分子溶液5的供给单元20包括贮液器22和第一微泵21,其中贮液器22连接到第一微通道10并贮存生物分子溶液5,而第一微泵21将贮存在贮液器22中的生物分子溶液5注入到第一微通道10中。
横向连接到第一微通道10的生物分子溶液液滴形成单元30包括贮存空气33的储气器32和第二微泵31,该第二微泵31将贮存在储气器32中的空气33向第一微通道10中流动的生物分子溶液5定期喷射。如果空气33由隔膜型(diaphragm type)第二微泵31基本垂直于第一微通道10喷射,那么第一微通道10中流动的生物分子溶液5就变为具有预定尺寸的液滴。虽然在这里使用的是空气,但是也可以使用其它合适的气体。
连接到第一微通道10的第二微通道40具有比第一微通道10更大的直径。因此,由空气33形成的具有预定尺寸的生物分子溶液5的液滴,以接触第一微通道10内表面的状态在第一微通道10中流动,然后以与第二微通道40内表面分离的状态在内径比第一微通道10更大的第二微通道40中流动,在那里因为表面张力而形成基本上为球形的液滴。
冷却单元50是一种低温装置,包括低温装置体51和冷却管52,一种低温液体,即低温液氮在冷却管52中流动。冷却单元50包围第二微通道40的一部分以冷冻通过第二微通道40的生物分子溶液液滴。
使用这种结构的点样装置均匀而精细地冷冻生物分子溶液液滴的过程如下所述。生物分子溶液5通过第一微泵21从贮液器22注入第一微通道10。使用隔膜型第二微泵31将储气器32中容纳的空气33以基本垂直的方向定期注入第一微通道10。生物分子溶液5的液滴尺寸由空气33的注入速率所决定。也就是说,如果空气33被快速注入,就形成生物分子溶液5的小液滴,如果空气33被缓慢注入,就形成生物分子溶液5的大液滴。而且,生物分子溶液5的液滴尺寸可以因生物分子溶液5的流速而不同。也就是说,如果生物分子溶液5流动快,就形成生物分子溶液5的大液滴,如果生物分子溶液5流动慢,就形成生物分子溶液5的小液滴。因此,通过控制空气33的注入速率和生物分子溶液5的流速,就可以形成预期尺寸的生物分子溶液5的液滴。当通过第二微通道40时,所形成的生物分子溶液5的液滴基本上为球形。然后,当通过由冷却单元50维持低温的第二微通道40时,生物分子溶液5的液滴被冷冻,其中低温液体,如低温液氮在冷却单元50中流动。冷冻的生物分子溶液液滴71被贮存在冷冻生物分子溶液贮液器70中。
点样单元60包括第三微通道61、释放器63、第四微通道65和隔热通道64,其中,第三微通道61贮存经冷冻的生物分子溶液液滴并且维持在大约-5℃至-30℃的零下温度;释放器63连接到第三微通道61,用于将冷冻的生物分子溶液液滴71从第三微通道61释放出;第四微通道65被加热器加热到20-200℃以解冻从第三微通道61释放出的生物分子溶液液滴71;隔热通道64安装在第三微通道61和第四微通道65之间,以防止热从第四微通道65传到第三微通道61。用于开、关冷冻的生物分子溶液液滴71所通过的通道的微阀62安装在第三微通道61中。释放器63是安装在第三微通道61上方的微激励器,可以通过机械方法、压电方法(piezo method)或电场感应方法(electric field inducing method)来操作。
已在冷却单元50中冷冻并贮存在冷冻生物分子溶液液滴贮液器70中的生物分子溶液液滴71随后被贮存在第三微通道61中。当微阀62被微激励器打开时,已经贮存在第三微通道61中的冷冻生物分子溶液液滴71逐一分离并向外释放。当通过包含加热器的第四微通道65时,释放的生物分子溶液液滴被解冻。然后,液态生物分子溶液液滴被滴落在生物芯片或DNA微阵列3的表面,并且滴落的生物分子溶液液滴在生物芯片或DNA微阵列3的表面被固定和被生物分子化(biomoleculated),从而完成制作DNA微阵列3的点样过程。当大量点样单元60被规则地布置,由此数滴生物分子溶液液滴被同时滴落并固定在生物芯片或DNA微阵列3上时,点样过程所需要的时间可以显著减少。
现在将参考图5A和5B以及图6A至6C更详细地说明根据本发明一种实施例的用于制作DAN微阵列的点样装置的点样操作实例。
实例
点样试验的条件如下。
首先,制备探针DAN寡聚物(oligomer)。在图5B中,完全匹配的探针DNA寡聚物(WP MODY3 EXON3-6,C6NH2-5’-CGGAGGAACCGTTTC-3’)被分配到1、2、5、6、9、10、13和14,不匹配的探针DNA寡聚物(MP MODY3EXON3-6,C6NH2-5’-CGGAGGAACCATTTC-3’)被分配到3、4、7、8、11、12、15和16。
然后,制备100uM的DNA寡聚物、100uM的PEG、3uM的Cy5活化酯(activate ester)和一种DMSO溶液。
接下来,使用根据本发明一种实施例的用于制作DNA微阵列的点样装置形成液滴,在-20℃冷冻该液滴,然后使用50uM的Mody3 Exon3作为目标DNA进行杂交。在这时,杂交时间是16小时并且杂交温度是32℃。
清洗后,在绿色模式下以532nm波长使用PMT573(Scanner GenePix4000B,Axon Instruments,Inc.)对结果进行扫描。
图6A是杂交后点的照片,图6B和6C说明了各点的强度和直径。从图6A至6C中可见,点的均匀性得到改进,并且分辨率高达9.82。
因此,通过使用一种点样装置,当制作生物芯片或DNA微阵列时,可以形成具有相同形状的点,可以使温度对生物分子的影响减到最小,并且可以轻松操纵生物分子,其中,该装置包括生物分子溶液液滴形成单元30、第二微通道40、冷却单元50和点样单元60,其中,生物分子溶液液滴形成单元30横向连接到第一微通道10并通过向第一微通道10中流动的生物分子溶液5定期喷射气体形成具有预定尺寸的生物分子溶液液滴5;第二微通道40连接到第一微通道10并且具有比第一微通道10更大的直径;冷却单元50包围第二微通道40的至少一部分以冷冻通过第二微通道40的生物分子溶液5的液滴;点样单元60使生物分子溶液液滴71解冻,并将解冻的生物分子溶液液滴滴落到DNA微阵列3的表面。
虽然上面已经说明冷冻的生物分子溶液液滴71在点样单元60的第四微通道65中解冻,然而冷冻的生物分子溶液液滴71也可以在外面解冻。
而且,虽然上面已经说明安装了用于贮存冷冻的生物分子溶液液滴的冷冻生物分子溶液液滴贮液器70,然而当点样单元60连接到第二微通道40时,点样单元60的第三微通道61可以用作冷冻生物分子溶液液滴贮液器70,这消除了对冷冻生物分子溶液液滴贮液器70的需要。
如上所述,根据本发明,提供了一种在制作生物芯片或DNA微阵列时能够形成具有相同形状的点、使温度对生物分子的影响减到最小并且轻松操纵生物分子的点样装置以及使用该点样装置的点样方法。
而且,大量点样单元被规则地布置并且大量生物分子溶液液滴通过它们同时释放,以至制作生物芯片或DNA微阵列所需的时间可以显著减少。
虽然已经参考其典型实施例特别显示并说明了本发明,但是对于本领域的技术人员将可以理解,可以在不脱离所附权利要求书定义的本发明的精神和范围的条件下进行各种形式和细节上的变化。
Claims (13)
1.一种点样装置,用于在DNA微阵列表面上滴落和固定生物分子溶液,例如,核酸(如探针DNA、mRNA和肽核酸(PNA))和蛋白质以制作一种DNA微阵列,该点样装置包括:
管形的第一微通道;
给第一微通道提供生物分子溶液的供给单元;
生物分子溶液液滴形成单元,该单元横向连接到第一微通道,并通过定期向第一微通道中流动的生物分子溶液喷射气体而形成具有预定尺寸的生物分子溶液液滴;
第二微通道,该通道连接到第一微通道并且具有比第一微通道更大的直径;
冷却单元,该单元包围第二微通道的至少一部分以冷冻通过第二微通道的生物分子溶液液滴;和
点样单元,该单元将生物分子溶液液滴解冻并将已解冻的生物分子溶液液滴滴落到DNA微阵列的表面。
2.根据权利要求1所述的点样装置,其中点样单元包括:
第三微通道,所述第三微通道具有微阀用于打开和关闭冷冻的生物分子溶液液滴所通过的通道,并在零下温度贮存冷冻生物分子溶液液滴;
释放器,所述释放器连接到第三微通道并通过打开微阀将冷冻的生物分子溶液液滴从第三微通道释放;和
第四微通道,所述第四微通道连接到第三微通道并被加热器加热到预定的温度,使第三微通道释放的冷冻生物分子溶液液滴解冻。
3.根据权利要求2所述的点样装置,其中所述预定的温度是20至200℃,所述零下温度是-5至-30℃,并且隔热通道安装在第三微通道和第四微通道之间以防止热量从第四微通道传到第三微通道。
4.根据权利要求2所述的点样装置,其中释放器是安装在第三微通道上方的微激励器,并且大量点样单元规则布置。
5.根据权利要求1所述的点样装置,其中供给单元包括:
贮液器,所述贮液器连接到第一微通道并贮存生物分子溶液;和
第一微泵,第一微泵将贮存在贮液器中的生物分子溶液泵入到第一微通道中。
6.根据权利要求1所述的点样装置,其中气体是空气且生物分子溶液液滴形成单元包括:
贮存空气的储气器;和
第二微泵,所述第二微泵将贮存在储气器中的空气定期向第一微通道中流动的生物分子溶液喷射。
7.根据权利要求1所述的点样装置,其中生物分子溶液液滴的预定尺寸是直径2000μm到1nm。
8.根据权利要求1所述的点样装置,其中冷却单元还包括用于贮存冷冻生物分子溶液液滴的冷冻生物分子溶液液滴贮液器。
9.一种点样方法,用于在DNA微阵列表面上滴落和固定生物分子溶液,例如,核酸(如探针DNA、mRNA和肽核酸(PNA))和蛋白质以制作一种DNA微阵列,该点样方法包括:
(a)允许生物分子溶液流入管形的第一微通道;
(b)定期向第一微通道中流动的生物分子溶液喷射气体以形成具有预定尺寸的生物分子溶液液滴;
(c)冷冻通过第二微通道的生物分子溶液液滴并贮存冷冻的生物分子溶液液滴,其中第二微通道连接到第一微通道并且具有比第一微通道更大的直径;和
(d)将冷冻的生物分子溶液液滴解冻并将解冻的生物分子溶液液滴滴落到DNA微阵列的表面。
10.根据权利要求9所述的点样方法,其中在操作(c)中,冷冻的生物分子溶液液滴的贮存在保持在-5至-30℃的第三微通道中完成。
11.根据权利要求10所述的点样方法,其中在操作(d)中,冷冻的生物分子溶液液滴在通过由加热器保持在20至200℃并且连接到第三微通道的第四微通道时被解冻。
12.根据权利要求9所述的点样方法,其中在操作(b)中,气体是空气且液滴的预定尺寸是直径2000μm到1nm。
13.根据权利要求9所述的点样方法,其中在操作(d)中,冷冻的生物分子溶液液滴由大量规则布置的点样单元同时释放。
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KR20050064711A (ko) | 2005-06-29 |
US20050158755A1 (en) | 2005-07-21 |
US7416705B2 (en) | 2008-08-26 |
KR100647282B1 (ko) | 2006-11-17 |
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