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CN100424166C - 组织样品自动染色方法和装置 - Google Patents

组织样品自动染色方法和装置 Download PDF

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CN100424166C
CN100424166C CN 200380106521 CN200380106521A CN100424166C CN 100424166 C CN100424166 C CN 100424166C CN 200380106521 CN200380106521 CN 200380106521 CN 200380106521 A CN200380106521 A CN 200380106521A CN 100424166 C CN100424166 C CN 100424166C
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method
apparatus
auto
dyeing
tissue
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克里斯托弗·布坎南
戈登·法因格尔德
约翰·法武齐
道格·斯威特
马克·基
鲍勃·莱思罗普
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丹麦达科有限公司
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    • G01N1/30Staining; Impregnating Fixation; Dehydration; Multistep processes for preparing samples of tissue, cell or nucleic acid material and the like for analysis
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Abstract

本发明涉及一种组织样品染色装置(1)。所述装置(1)包括试剂区域(2)或试剂容器(3);至少一个染色区域或组织样品;可将试剂移到预定组织样品中的机器人头(22)或机器人部件(20),所述机器人部件(20)可以在试剂和染色区域的上方移动;可以管理染色过程的控制部件(85);用来检测相关特性的二维图像数据并将所捕获的图像数据馈送到控制部件(85)的2-D光学传感器。通过提供具有2-D光学传感器(86)的机器人部件(20),可提供具有多功能的公共图像处理器。通过采用2-D光学图像处理系统,装置的控制系统可容易地适合读取多种类型的数据表达形式,从而可以识别装置部分的实际图像,以便估计装置的状况。光学传感器用来自动识别装置中存在的载玻片和试剂容器,因此光学传感器可用于检查载玻片是否从载玻片位置错位或缺失等。

Description

组织样品自动染色方法和装置技术领域本发明涉及一种组织样品自动染色的装置和方法。本发明进一步涉及用于样品 处理以及样品处理的«收集、数据维护和数据检索的系统。本发明特别涉及的应 用领域包括免疫组织化学、原位杂交、荧光原位杂交、特异性染色和细胞学,以及 潜在的其它化学和生物学应用。背景技术免疫组织化学(mc)应用和其它化学和生物学分析(例如原位杂交、特异性 染色和细胞学)中的组织样品处理,要求一个或多个处理^W或规程作为一个或多 个样品分析的一部分。这些样品处理次序或规程是由要求分析的个体或组织(例如 医院的病理学家和组织学家)规定的,或者由待实施的特定分析指令(例如由组织 规定的标准方案)来规定。在样品分析的制备中,生物样品可以通过公知的样品获取技术来取得,并且可 以包括在一些应用中甚至是一个或多个分离的细胞的组织。组织样品可承载在样品 载体(例如载玻片、或者也许是显微镜载玻片)上。例如,免疫应用需要包括i者如脱蜡、靶回收和染色这些步骤的处理次序離见程。 以前,在一些应用中,这些步骤由人工来实施,因此潜在地导致这是一,时的规 程并且需要人员主动参与到样品处理中。尤其是关于^fe过程,多种组织载玻片的 自动染色设备是公知的,因为为了满M有利样品处理以及几乎不用人工烦琐操作 的需求,己会规样品处理的自动化作了一些尝试。本发明的各个方面尤其可应用于具有一个或多个处理步骤的样品处理中,所述 处理步骤是在一个样品、 一部分或全部样品上进行的,这些规程在一些情况下是由 呈现样品的各个载体来识别的。本发明的各个方面尤其可应用于免疫组织化学(IHC)技术、以及原位杂交(ISH)和荧光原位杂交(FISH),特别是包括样品染 色的技术。本发明的实施例进一步涉及样品处理的自动控制系统。这些实施例还涉及样品 处理的«收集、麵维护、数据检索,特别是处理规程和处理状态的信息分享, 例如各个样品或多批处理、样品诊断特性、以及多批处理的实时或适应能力。US5,839,091公开了一种组织自动染色的装置,其中将显微镜载玻片排列成许 多行,而将试剂瓶储存在B比邻此载玻片部分的部分中。机器人头按照控制禾旨从瓶 中拾取预定量的试剂,将这些量的试剂沉积在预定的载玻片上,并吹散载玻片上的 液体。此禾,在与染色^fi连接的计^^几上运行。M装置装载有许多载玻片,每 个载玻片及其位置都登记在计算机中,并选择染色次序。该程序还接收有关试剂及 雜试齐嘟分上的位置的数据。基于这些载玻片和试剂位置翻,该禾骄计算染色 运行,制机器人在染色装置中的运动。US6,352,861公开了一种转盘型自动染色装置,其中将载玻片布置在可旋转的 转盘式载玻片支持体上,将试剂同样布置在载玻片支持体上方的可旋转的转盘式试 剂支持体上。然后将特定载玻片旋转到输送区,将特定的试剂瓶也旋转到该位置, 分配试剂到载玻片上。载玻片和试剂ME有条形码,且^f共相关的条形码读取器来 分别识别载玻片和试剂。吹散区和识别区也配备在载玻片转盘的四周。载玻片条形 码识另幟玻片样品及其特定样品所需的特定免疫组织化学过程。定位试剂条形码读 取器,以扫描试剂瓶上的试剂条形码。来自载玻片条形码读取器和试剂条形码读取器的扫描信息被麟到计^m内,并分别与载玻片和试齐啭盘的索引位置相关。此信息用来旋转载玻片转盘和试剂转盘,以便为每M玻片的^^玻片处理步骤将 正确的试剂瓶定位在分配区中。,091中描述的自动^fe装置的缺陷是,载玻片部分和试剂部分的旨组织载玻 片和每^剂瓶的位置,必须分别人工输入到计算机中,因为控制禾聘不能检Sf寺 定载玻片和试剂瓶的部位。这样就带来一些风险:用错误的染色规程处理错位的载 玻片,并且使染色装置在使用中非常不灵活。虽然'861专利采用了载玻片和试剂的条形码识别,但是这种转盘型^S在运行 染色规程时赚时的,因为这涉及至树于规程中的齡步骤,要用全部试剂存货旋 转转盘,并用所有的载玻片旋转载玻片转盘。这些旋转是耗时的,并使得这种类型 的装置不适饭行大量的载玻片。而且,条形5驰能携带少量数据, 一般是简单的 识别码,这意n賴控制计對几必须配有有关识另鹏的相应数据。发明的公开内容本发明的一个目的是,提供一种开始提到的那种组织样品的自动处a^g,这 种,能够自动识别机器中存在的试剂和载玻片存货。另一个目的是,JI^对^S 相关特性的识别,以便在新装载的载玻片的皿过程启动之前,进行自动制备检査。在一个实施例中,这些目的魏过开始提到糊附體实现的,其中机器人部件(也许具有机器人头)配有光学传繊(或者也许是2-D光学传繊體),所述传感器用于检査相关恃性的二维图象数据并具有将所捕获的图象数,送到控制 装置的能力。本发明还提供了一种识别自动染色装置中的至少一,性的方法,戶,染色装置也i袍括至少一铺玻片阵列和试剂阵列,以及也用试剂实施载玻片她的机器 人部件(或者也许是机器人装置);戶,方法在一个实施例中包括以下步骤:在机器人装置的机器人头上配备光学传繊装置,将所述+几器人头上的光学传感器装置移动到预定位置,记录所述位置的相关图象数据,以及将戶腿图象数^t到控制系统,以便根据戶脱图象«操纵染舰程。而且,本发明涉及一种在自动染色装置中染色组织样品的方法,戶皿染色装置 也许包括至少一,玻片阵列和试剂阵列,以及按照组织样品的特异性^fe规程也用试剂实施载玻片染色的机器人部件(或者也许是机器人装置);所述方法在一个实 施例中包括以下步骤:在机器人装置的机器人头上配备光学传麟體,将戶,机器人头上的光学传«装置移动到预定位置,用所述光学传自^a记录戶;M位置的相关图象数据;将所述图象数^t到控制系统,以便根据戶腿图象«操纵染色过程;以及 也利用来自试剂容器的试剂给组织样品染色。在实施例中,自动M装置1 (是用至少一些自动操作染色的任何装置)可包括试剂容器3。 一个或多4i^剂容器3可位于自动染色装置1的试剂区域2。自动染 色装置还可包括在此处可位于载玻片上的组织样品74。其上具有组织样品的多, 玻片也可位于自动染色装置l的载玻片区域5。本发明在实施例中还可包括机器人 部件20、 一些类型的控制部件、甚至光学传感器(86),也许是图象捕获2-D光学 传繊。正如所容易理解的,控制部件85可以是计,、软件禾骄、或者仅仅辦 定的可编程的处理器功能。如上戶脱,本发明倉,光学探测二维图象。这可舰图像捕获2-D传繊来实 现,戶脱传感器在自动她装置l中可掛共部件的二维图象。通过提供具有2-D光 学传繊或装置的机器人部件(也许是机器人头),正如在一个实施例中,公共图象 处理装置能够具有多个功能。通过利用2-D光学图象处理系统,染色體的控制系统可容易地适^ii取多种数据表示形式,由此部件或者,置部分的实际图象一样,从而能够评估装置的状况。光学传自或光学传«,可用来自动识别装置中存 在的载玻片和试剂容器,由此光学传,或光学传«装置可用来检査载玻片是否 在某一载玻片位置错位或缺失等。光学传感器使按照本发明的染色装置具有迄今不可预见的灵活性并且能够使 染色装置中的识别功能自动化。通过也许在机器人头、甚至是机器人部件上采用 CCD-照相机等,可以不再需要用于針识别任务的各个识别装置。这意赠,对装 置的控制和维修容易进行。控制染色體的软件适合包驟置的多种特性和状况(包 括载玻片和试齐瞻息)的自动识别。通过利用识别鹏驢中相刘言息的方法和实 施按照本发明的染色过程的方法,自动^fe过程耗时更少且包括更多的定性检査, 而在载玻片的染色操作中不会怎么降低速度。在本发明的一个实施例中,试剂区域容纳多^剂容器,这些容器固定布置成 多行。同样,组织样品容纳在载玻片上,这些载玻片在染色过程中在至少一个染色 区域或在玻片部分固定布置成多行。这些区域的布局使得其代表机器人头的基本上 平坦的平台工作区,此工作区可以在X-轴和Y-轴上移动。在一,别tt^的实施例 中, 一行载玻片和/或试剂被移去或更换,而不会干扰染色过程。在另一个雌实施例中,染色装置包括至少两个被试剂区域分开的鹏区域, 即它们布置成使至少一些组织样品誕至少一些试剂容器。借此,可以显著限制机器人头为了到达所有载玻片而需要的运动,并借此增大^fe装置的容量,由此可减 少运行染色规程的时间或得到其它优点。进一步意识到,禾,这种载玻片和试剂部 分的布局还可达到更短的处理时间或其它优点,而无需可视系统例如光学传感器。在本发明的其它实施例中,光学传繊可以是照相机,或者也许包括CCD部 件。通过词汇"照相机",应该理解,可以采用任何图象捕获装置,而无论是薄膜、 板、存储器,还是任何类型的电子介质,而无论其麟的是光、可视电磁辐射,或 者甚至是诸如现在公知的不可视的电磁辐射。舰记录相关图象、相关图象«、 甚至记录数字图象«,禾,公知的已经可用的图象处理能力,可以快速的方式在 控制系统中完成该«的计^^几处理。而且,通过禾,该数字技术,育,用高^Df率记录相对复杂的图象,由此在机器人头连续穿过载玻片标记时,可实5M几个识别(例如一整行载玻片上的iH己)的快速记录,于是可避免每铺玻片识另啲终止 时间和开始时间。然而,通过本发明,意识到,根据图象解析的需要,还可采用其 它图象传繊例如固态传麟,或者也许是CMOS传麟。如上所述,光学传自适合记皿置中存在的各^剂容器或试剂瓶以及载玻 片。虽然其可给更大的区域、甚至齡设备成像,但是它可以构造成以电子、光学 或定位的方式^^t行成象。无论如何,作为成象能力的结果,无需装载到自动染 色装置内的载玻片或试剂容器或试剂瓶的预定位置,因为载玻片和试剂瓶一旦装载 到装置内,装置就适合自动识另噺的载玻片和试剂瓶。在一个实施例中,试剂容器和载玻片配有光学识别部件。例如,试剂容器可配 有试剂光学识别部件,载玻片可配有载玻片光学识别部件。这些光学识别部件可包 含有关试剂种类的机器可读的数据以及有关瓶内试剂的其它相关数据,载玻片识别 部件可含有有关组织样品的数据,例如病人的识别、染色规程等。光学识别部件可 包括重申信息、甚至冗余信息。这可包括重复、甚至部分重复的信息,并且甚至包 括可以是或者可以不是有关类似信息的不同译本的信息。光学识别部件或者替换型光学识别装置可以在或安装在试剂容器上或在载玻 片上,这样光学识别部件可以被光学传繊读取。Mil位于"之上(on)",预计任何 相关的方式都能够包括;由此应该理解,无需单独的固定或表面安装。同样,通过 在"上方(above)",应该理解,这不仅存在于诸如有关重力的定义中,而且还存在 于诸如大致垂直地在表面等上方的象形定义中。在一个实施例中,光学识别部件可以从上方由光学传自或替换型装置来读取。而且,光学识别装置可配置在标记上, 标己也许粘附地固定至鹏定载玻片或试剂瓶上。借此,断己、也许是粘附标记可呈 I见给载玻片和试剂瓶上方的^l器人头上的光学传自装置,从而容易进行光学识别 装置的读取。通过在固定至幟玻片上的印刷标记上配备光学识别装置,试剂瓶、各个标记可在现场分别制备,并且可以将相关数据输入到计算机内,而携带戶;M相关数据的相应^i己可在相关的1fi己印刷机JJS行印刷。在本发明的一个实施例中, 一种类型的光学识别部件是,诸如所谓的"Mbglyph™"型的二维高分辩率符号码。光学识别还可以是更通用的二维符号。 二维符号可以是以下数据的表示形式,包括(但不限于):组织样品相i^据、病人 识别数据、染色规程数据、试剂相关«、试剂种类«、试剂体积相关数据、试 剂有效期相关数据、以及类似数据。通过将相关信息编码成众多微小的各个图表元 素(一般是象0.02mm (1/100英寸)另卩么短的45、斗线的短线),可获得具有高对比 度编蹄言息标记的高分辩率,所述标记可以在印刷禾;Lh印刷,由高分辩率照相机读 取。可以用不同的颜色和各种材料来提供这种类型的2-D符号标记。或者是,光学识别装置或替换型光学识别部件可以是数据矩阵码、甚至一维条 形码,即具有垂直条图案的识另鹏,戶诚条的宽度和间隔识别所标记的项目。^f顿 能够读取2-D符号的光学传麟的优点是,装置能够读取任何种类的光学标识符, 因为仅需要对处理所捕获的也许是数字图象的软fH故些改动即可。在一个实施例中,光学识别部件标记可包括二维(2-D)符号区以及甚至至少 一个人可读取的文本区,每个如图5中所示意性表示的。借此,可由操作者对标记 进行额外的目视检査,以便斷正印刷^i己。在2-D图象捕获能力的更先进的用途中,图象处理能力或图象处理器部件适合 识别由光学传KI捕获的组织样品自身的纹理或轮廓,并且可以用所述的图象捕获 组织特性作为组织样品的个体标示。光学传«可以构造成能够识别组织样品的所 需特性,例如(但不限于)组织样品的纹理、轮廓、目视特性、甚至个体待征。当 然,多个不同的特征或特性都可按需来识别,以便检测、或许识别包括tti可属性、 特征等的特性。该实施例利用作废的载玻片标己作为自身的组织纹理,或者它的至 少一个预定部分(有或者没有放大)用作控制软件中的«表的标识。在本发明的一个«实施例中,光学传^是可移动的光学传,,其可沿染色及试剂部分上方的区域移动,所述光学传,适合确定载玻片在至少一个染色部 分的存在和位置。通过拥有响应或也许在机器人部件上移动的光学传感器,可容易 地实现这一点。 一旦将一组新的载玻片装载到装置内,此特性就使得按照本发明该 实施例的她装置自动确定载玻片的位置,以便计算处理步骤的最佳进度。光学传

ii^i至确定组织样品的大致部位和大致区域。而且,此能力还可向,Jim制 软件,警告载玻片是否正确定位,或者在装载载玻片的过程中是否出现其它不规则 定位。

在本发明的另一个实施例中,光学传感器适合定位预先选择的参比部位,以便 对控制机器人头运动的机器人控制系统或机器人部件进行自校正。照相机用来指出 校正系统所需的机器人臂的临界部位,从而使装置将机器人头定位到平台工作区内 所有要求的位置和部位。如果由于诸如维修等,装置已经移动或损害,那么此特性

就可使按照本发明的染色装置具有自动校正机器Aig动控制系统的能力,诸如,通

过检査滑轨是否正确装配在装置的接收部件内,和/或通过确定装置的预定参比部件 的位置,来确定载玻片是否被安s瞎轨道内(预计宽泛地包含任何局部捆绑集合)。

在本发明的另一个实施例中,光学传感器可以是照相机,用来记录|»纵的组 织样品的图象,该照相机可在所述组织样品经过一^规禾呈后记^t终组织样品的 图象。在组织样品接受用于记录所操纵的组织样品的图^后适合记^s终组织样

品图象的照相机。借此,可以im地以高分辨率记录已染色的组织样品的图面或数

字图象,以便随后检査或将该数字化图面发送到远程的检査场所。据此,在实施例 中,本发明可以储存有关组织样品染色过程的图象。这当然可包括染色或一些其它 操作之前和之后的图象。而且,本发明的此特性可以将要染色或已经染色的组织样

品图象存档,以便随后^i正组织样品分析或标示是否是所需的。这样,本发明可以 自动地使使用者的行为(例如上述那些)容易进行。为了弄懂多种可能性,自动容

易进行的行为是,躯样的行为,包括(但不限于):随后存取已染色的组织样品的组

织图象、远程存取已她的组织样品的图象、将已染色的组织样品的图象存档、随 后存取未染色的组织样品的组织图象、远程存取未^fe的组织样品的图象、将未染 色的组织样品的图象存档、以及其它行为。

在可以从一个或多铺玻片或试剂容器中自动识别信息的一些实施例中,配备 传麟。在一些实施例中,可以由适应性样品处理控制系棘麟方案信息。样品处理系统潜在地按照由具有样品的载玻片提供或由适应性样品处理控制系统麟的 方案信息,同时、依次或以任何其它临时方式处理一个或多1^玻片,或一批或多 批载玻片。通舰应性样品处理控制系统完成的控制和监测,在处理方案步骤中可 插入或除去成批样品或各个样品。

可以达到本发明的前述或其它目的的本发明的另一实施例包括: 一种样品处理

方法,该方^a括以下步骤:接近多个中的至少一个抽屉(drawer);使至少一个样 品载体止动组件具有至少一个样品载体;使至少一个抽屉具有至少一个样品载体止 动组件;以及适当处理样品载体。适当处理步骤可自动处理样品并且可以连续或批 处理载玻片,而且可以提供多个单独的载玻片处理,并且在一些实施例中可以提供 丰余的载玻片处理,以便^^虫处理每^玻片。

本发明的实施例还包括一种自动样品处理方法,该方^^括以下步骤:收集方 案信息;将方案信息传送给至少一个样品处理系统;适当处理样品;以及从适当处 理步骤中收集样品处理信息。而且,实施例可麟:维护方案信息、维护样品处理 信息、方案信息的信息共享以及样品处理信息。这些或其它方法步骤可,各个样 品或多批处理、样品诊断特性、以及多批处理的实时或适应性能力。

本发明的许多方面可应用于免疫组织化学(IHC)技术,以及样品的原位杂交 (ISH)和荧光原位杂交(FISH)特异性染色,还有微阵列,特别是包括样品的靶 挽回(targetretrieval)或染色的技术。

支持应该理解为是为本发明的以下方面和实施例而存在的:

一种自动M装置,包括:

至少一个i式剂容器; 至少一个样品;

适合影响所述试剂容器和0M样品的机器人部件; 控制部件,繊几器人部件响应该控制部件;以及

为了对0M自动^fe装置中的至少一个部件进行二维成像,而构造的图象捕获 2-D光学传繊。

一种识别自动^装置中的至少一个特性的方法,包括以下步骤:提供至少一个样品;

樹共至少一4H式剂容器;

iil共适合影响所述试剂容器和戶;M样品的机器人部件;

光学探测所述自动她驢中的至少一个部件的二维图象; 记录相关图象数据;以及

将戶,图象数据馈送到所述机器人部件响应的控制部件。

一种在自动染色装置中染色样品的方法,包括以下步骤:

提供至少一个样品; 提供至少,式剂容器;

提供适合影响所述试剂容器和所述样品的机器人部件;

提供响应所述机器人部件并适合探测所述自动染色装置中的至少一个部件的 二维图象的光学传感器;

记录相关图象数据;以及

将所述图象«,到所述机器人部件响应的控制部件。

一种自动染色装置,包括:

至少一4H式剂容器; 至少一个样品;

适合影响所述试剂容器和所述样品的机器人部件; 控制部件,戶,机器人部件响应该控制部件;以及

为了探测戶,自动染色装置中的至少一个部件而构造的多功能光学传,。

附图简述

以下参照附图来描述本发明,其中:

图1是按照本发明«实施例的染色装置的示意性透视图; 图2是图1所示染色装置中的工作区域的附视图;图3是按照本发明一些实施例的染色装置中的申几器人部f牛的细节图; 图4是具有光学识别装置的试剂瓶的附视图; 图5是其上具有光学识别标记的显微镜载玻片;

图6 ^t:iH己布局的一个实例;以及

图7-图10是载玻片上多种光学识别装置的实例。

本发明的,方式

图1和图2中表示出按照本发明的自动染色装置1。自动染色装置1包括围绕

试剂站或试剂区域2的矩形框架4,以及第一和第二载玻片区域5。试剂站或试剂区 域2包括试剂瓶或容器室,其中每个室内放置有试剂瓶或试剂容器3,许多分离的 轨道6放置在第一和第二区域5上,每个轨道6包^i午多并排安装在轨道6内的显 微镜载玻片7。多1H式剂容器、甚至载玻片以tti可所需的"酵(例如阵列)来放置。 在图示的实施例中,齡轨道可容纳8愧玻片,但是轨道可设计成能够容纳任何 适当数目的载玻片。由于,滩置有8个轨道,因此图示实施例可容纳64个载玻片 7,每个在载玻片的上面都固定有样品例如组织样品,因此试剂可从上方施加到每个 载玻片上的样品中。所处理的样品可以是任何材料,但是最可能是生物材料例如生 物样品或生物物种,也许是诸如组织样品例如组织或细胞物种、细胞、细胞集合或 组织样品,定义包括细胞系、蛋白质及合i^l太、组织、细胞前体、细胞制备品、血 液、体液、骨髓、细胞学物种、血液涂片、薄层制备品和微阵列。还应该理解,包 括载玻片基生物样品。

如上所述,本发明可包括在某种程度上影响试剂容器和组织样品的机器人部 件。这样,对试剂容器或组织样品实施的fti可类行为、由试剂容器或组织样品产生 的行为或只是来自试剂容器或组织样品的信息,都可通过机器人部件容易地进行。 机器人部件在实施例中,适合对施加有试剂等(包括作为结果或结合有)的载玻片 进行染色。机器人臂或机器人部件20还可将试剂从试剂容器转移到预定的组织样品 上。例如,用于沿X和Y (以及Z)方向(如箭头X和Y所示)移动探头10的机 器人部件20,被安置在染色装置的框架4上方。机器人臂可以纟鄉头10定位在所 有试剂瓶3以及所有载玻片7的上方,并且进一步操纵探头IO,以吸取任一瓶3中包含的部^H式剂,从而将那部^齐U传送并施加到任一载玻片7上,以旨每^; 玻片7上的样品有选择iikiS行染色和处理。控制部件M控制染色过程的全部、甚 至倒可部分,来管理染色过程。禾佣统的控制部件或等同型控制装置(例如具有 用于此目的的合适软件和输入数据的计算机(未示出)内的功能),该染色装置1 會,对需要不同染色或处理试齐诉口过程的样品进行^fe或处理。

如图1和3所示,探头10容纳在机器人头22中并由机器人部件20来操纵。 探头10上升到上部位置(在Z方向),在此处清楚地看到,瓶3在探头10的下面, 但是机器人可包括机器人头22中用于降低探头10的装置或部件,以便«头尖浸

到所选择的试剂瓶3的内容物中并吸取选定量的用于戶;?^择的染色或处理过程的试

剂。在一个实施例中,本发明包括在机器人部件上配备光学传麟86,或许还包括 通过机器人部件的动作将光学传麟移动至滪定位置。作为一个实例,机器人头22 配有光学传感器86、甚至是指向下方的CCD照相机25。光学传自位于机器人部 件上、或许更广泛地响应机器人部件。在光学传^l定位之后,就在配置光学传感 器的部位记录图象数据。

在一些实滩例中,机器人部件20、甚至机器人头22可包括各种元件,包括(但 不限于):可与汽缸39相连的推动工具38、可响应甚至与弹簧泵37相连的探头移 动部件36的探头10、以及光学传感器86 (如图3所示)。 在实施例中,光学传繊可检观湘斜寺性的二维图象«0它腿合在总体上 探测部件的二维图象。禾U用照相机确定载玻片和试剂瓶以及装置在工作区域内的其 它牛寺性的状^^言息,例如阅读配置在试剂容器上的代码,以确定系统内的试剂种类 和试剂部位。照相机还可确定组织样品载体的状态,例如特定玻片的部位、指示有 关呈现在载玻片上的组织样品或待实施的处理方案的信息的信息索弓l例如代码。照 相机可用于诊断目的。在一些实施例中,潜在地用计Ml扫描样品,以便进一, 行分析。本发明在实施例中可包括计算机图象生物分析部件、或许甚至是用计算机 对样品的图象«进行生物分析。

如上所述,本发明可包船己录各种相关图象数据。当然,可记录各种相关图象 数据。重要的是,这包船己录部件的校正参比点、或许甚至是装置上或装置内的机 器人部件的校正参比位置。正如所提到的,本发明还可记录载玻片识别图象数据和 试剂识另幅象数据。 一个实施例的显著方面是,可记雜定载玻片的光学识别部件、或iW又仅记录有关部件的信息。这样的信息当然可以包括有关组织样品的信息。同

样,包括有关试剂容器内含有的试剂的信息的光学^i只可记录在试剂容器上。它可

将二维符号记录在载玻片上、甚至试剂容器上。记录在载玻片上的二维符号所代表 的麵包括(但不限于):试齐湘关翻、试剂种类繊、试剂体积相关繊、试剂 有效期相关数据等。它还可提供连接部件,所捕获的图象数据通过连接部fM专送给 控制部件。它包括将图象«卞,到控制部件,以便机器人部件可以响应。在记录

相关图象«之后、或许作为数ig^到控制部件的结果,本发明可按照相关图象

«来操纵染色或其它过程。这样,本发明可按照组织特异性方案皿行载玻片的 染色。

本发明的染色装置1还包括探头清洗站8和试剂混合器9,机器人部件20 « 一步被设置成會,纟鄉头皿到清洗站8以及试剂混合器9。

如图4所示,试剂瓶3在安装有光学识别部件的表面上配有区域30。此光学标 识可以是携带有关瓶3的内容物的信息(例如试剂种类、制造«、有效期限等) 的粘附标记31。戶満码的信息是麵矩阵码形式、Moglyph码形式或2-D码的任何 其它类型,也可能主要是简单的l-D码即条形码。此外,f斜己31还配有人可读的 文本,以便诸如在将试剂瓶装载到染色装置内的过程中有助于操作者操纵试剂瓶。

图5表示出其上安装有Si己71的载玻片7。图6中表示出标记71的一个布局。 丰射己71可以是粘附的光学标识,是为特定载玻片制备的并在标己印刷机(未示出) 或倒可其它誠的印刷设备上进行印刷。甚至在特定瞎形,如果一批载玻片接受相 同的处理,贝iJ为这些载玻片Jlf共一组相同的标记。iH己71包括用于有关载玻片7 上组织样品的编码信息(例如病人«、 «和文件号码、染色方案和/或处理步骤) 的区域72。而且,^i己71配有一行或多行人可读的文本和减空白空间,以便制备 载玻片的实验室人员在载玻片标记上进行书写。

在图7-9中,表示出标记71的多种数据编码符号(如图所示的旨标记71, 或者仅用于iH己区域72 (参见图6)。

在图7中,表示出Mbglyph,型的2-D符号。这包括或许甚至是信息型地毪 型(carpet)符号。这种2-D符号是有益处的,因为它肯,携带大量的光学机器可读 信息。利用高分辨率照相机,这种类型的符号可以高,率来读取,并且大量信息 编码在其中。将此符号用不同方向、或许甚至不同颜色的微小斜线来印刷,并且能够用CCD照相机等容易地读取。

图8表示出用作Infoglyph符号替换形式的M矩阵码。数据矩阵同样用CCD 照相机来读取,但是可能不会象Infoglyph那職编码中携带那么多的«。然而, 如果载玻片和试剂瓶上需要的识别数据较少,则其就更容易印刷,因为它可具有不 高的分辨率,从而是一种简单经济有效的解决方案。另一种更简单的解决方案在图 9中示出,其中符号是老的条形码。在原理上这意歸,为了读取载玻片和试剂瓶 的信息仅需要一个条形码扫描器,但^1过使用2-D传感器,自校正和监测载玻片 的安装和在染色装置中的试齐啲可能性就可以增强。

在一个实施例中,载玻片上和试剂iLt的光学标示是同一类型。这可容易i舰 ^fe装置中的识别过禾St行图象处理。

一种识别各个载玻片的不同途径,或者是作为实施证实识别或储存证实信息的 新能力的一种方式,可记录组织样品74本身的轮廓和/或纹理,例如如图10所示。 通过采用照相机能够记录的图象的高分辨率,组织样品本身的独特性质可用作载玻 片的图表标示。而且,會^够记录已染色的组织样品的图象,从而产生组织样品的数 字表示形式。该数字图M过电子传送到用于立即检査的远程地方和减为随后检査 存档。这可使染色装置在使用上具有独特的灵活性,且可以引入新颖有益的组织样 品分析方法。 .

除了识别染色装置中的显微镜玻片和试剂)fCt外,2-D光学传«还能够用于 装置的自校正,诸如在,维修之后,如果装置已经拆卸或远送到另一个地方的话。 通过用照相机捕获图象来识别装置内部的临界部位,图象处理软件可以将所捕获的 图象与参比图^it行比较,以确定装置内的某些临界元件是否偏离创门的预定位置, 诸如滑轨或玻片是否稍稍偏离,如果偏离,就计t^几器Aii动控制系统的一组校正 数据,并将这组«用于校正装置。如果所需的校正皿某一尺寸,就向操作者自 动发出警告,从而确蝶置在载玻片处理过程中不发生故障。而且,此图象分析系 统还用于确定载玻片是存在于轨道上还是脱离轨道,以产生警告信号。

通过本发明,应该意识到,在不脱离如权利要求书限定的本发明范围的前提下, 可以对本发明一^M实施例的上述描述作出各种改变。正如所容易理解的,本发 明的基:«念可以各种方式来实施。它包括染色技术以及用于完成染色和其它功能 的多种系统、组件和设备。在该申请中,染色技术也是作为用所述的多种系统、组件和设备来完成的所示部分结果以及作为固有采用的步骤来公开的。它们应该被理 解为,采用预计和描述的设备的自然结果。此外,虽然公开了一些设备,但是应该 理解,这些不仅完成了一些方法,而且还能够用其它变换的方式来实施。重要的是, 对于上述所有内容,所有这些方面都应该理解为包括在本发明的公开文本中。

读者应该意识到,具体论述可能不会非常清楚地描^M有可能的实施例;许多 可以选择的例子都是示意的。它还不能充分解释本发明的总的性质,不能明白地表 ^Hf性或部件是如何实际代表更广泛功能或各种替换型或等同部件的。再者, 这些都明显包括在此公开文本中。当本发明使用一些术语重点来描述设备时,设备 的每个部件都明显行使一个功能。对于所述设备不4又包括装置权利要求,而且为了 实现本发明和每个部件实施的功能,还包括方法或工艺权禾腰求。无论是说明书还 就语都无獻蹄体公开文本的范围。

还应该理解,在不脱离本发明本意的前提下可以做出各种变化。这«化也都 明显包括在本说明书中。它们还落在本发明的范围内。包括图示的示范性实施例、 各种含蓄替换型实施例以及广泛的方法或工艺等的泛泛公开内容都包含在本公开文 本中,并且据此用以支持本专利申请或随后专利申请的附加权利要求。

而且,本发明及权利要求的每个部件还可用各种方式来实现。本公开文本应理 解为包?,个这样的变型,即任何装置实施例、方法或工艺实施例、或者仅仅是其 中任何部件的变型。尤其是,应该理解为,当本公开文本涉及本发明的部件时,每 个部件的词汇可以由等同的装置词汇或方法词汇来表达,即使仅仅功能或结果是一 样的。这样的等同、延伸、甚至更多派生词应该认为是包括在每个部件或行为的描 述中。当期望解释本发明所涉及的广泛范围时,这样的词汇是可替代的,其中需要 解释授予本发明的隐含宽泛范围。但是作为实例,应该理解,所有的行为都可表达 为实施该行为的方式或产生该行为的部件。同样,所公开的每,理部件应该理解 为包括物理部件所实施的行为的公开内容。关于最后这方面,作为一个实例,"传感 器"的公开应该理解为包括"探测"行为的公开,而无论是否是明显论述,反之, 如果有"探测"行为的有效公开,这样的公开就应该理解为包括"传感器"、甚至"探 测方式"的公开。还应该理解,在具体语言可直译为P艮定作用的权限中,作为美国 的一个实例,其中对部件"装置(means for)"的一些解释被限制窄了,而更宽泛的 等同语言(例如"部件"等)可用来避免窄的解释,并且应该理解为被本说明书所包含。这样的变化和等同词汇应该理解为明显包括在此描述中。

本专利申请中提到的任何专利、专利申请、公开出版物或其它参考文献在此处

都作为参考并A^文。此外,对于所用的每个词汇,应该理解,除3鹏本申请中 的使用与这些解释不符,否则通用的词典定义都应该理解为是针对每个词汇的,并 且诸如the Random House Webster's Unabridged Dictionary (第二版)中包含的所有定 义、等同词汇和同义词,在此都作为参考并A^:文。最后,任何本申请的以前案件 都附属在此并且作为参考并入本文。

这样,这些申请应该理解为对至少以下权利要求是支持的:i)正如本文所公开 和描述的,每个样品处理系统和子系统,ii)所公开和描述的相关方法,iii)每个这些 系统、组件、设备和方法的类似、等同、甚至是隐含的变型,iv)正如所公开和描述 的,完成所示每个功能的那些替换型设计,v)完成所示每个功能的那些替换型设计 和方法,vi)作为^^虫和3拉发明示出的每错征、元件和步骤,vii)由所公开的多种 系统或元件增强的应用,viii)由这样的系统或元件产生的最终产品,以及ix)基本上 作为此前描述的以及参照任何附带实例的方法和系统、组件、设备及装置,x)所公 开的每个部件的多种组合及变换,xi)正如附加在所表现的齡独立权禾腰求和概念 上的,每个潜在的从属权利要求,xii)如上戶腿的,借助于计^m实施的方法,xiii) 如上所述的,可编程的系统,xiv)如上所述的,用数据编码的计算机可读存储器, 戶,数据用于指导包括行使功能的装置或部件的计算机,xv)m^文所公开和描述的 那样构造的计算机,xvi)如本文所公开和描述的,单个或组合压规程和程序,xvii) 所公开和描述的相关的方法,xviii)这,个系统和方法的相似、等同、甚至是明显 的变型,xix)正如所公开和描述的,完成所^个功能的那些替换型设计,XX)完成 所示每个功能的那些替换型设计和方法,xxi)作为单独和独立发明示出的每个特 征、元件和步骤,xxii)以上每个发明的多种组合及变换。

另外,如果4顿或在i柳时,按照传统的权利要求解释,逝度词"包括"等的 使用,在本文是用来维持"开放式"权利要求的。这样,除非上下文有其它要求,

否则应该理解,词汇"包括(comprise)"或诸如"包括(comprises)"或"包括(comprising)" 等的变型,都意指暗示包括规定部件或步骤或部件或步骤的组合,但不排除任何其 它部件或步骤或部件或步骤的组合。这样的词汇用其最广泛的形式来解释,以便为 本申请提供最宽泛的法律许可的范围。所提出的任何权利要求必然作为本发明描述的一部分以参考文献的形式并A^ 发明,并且申请人清楚地保留用这些权禾腰求的所有或一部分组合内容作为额外说 明书描述的权利,以便支^tf何或全部权利要求或其任何部件或元件,申请人还清 楚地保留将这些权利要求的任何部分或全部组合内容或其任何部件航件从说明书 的描述中移到权禾腰求内的权利,或者反之亦然,以便规定本申请或其扭可随后连 续申请、分案申请或部分连续申请所寻求的保护主题,或者以便在itS宗或符合l封可 国家或条约的专利法、规则或规章的费用方面得到减少的好处,并且以参考文献的 形式并入的这些内容应该在本申请的齡待审过程中有效,包括其任何随后该案的 连续申请、分案申请或部分连续案的申请或任何再公告或基于其上的延伸申请。

Claims (32)

1. 一种自动染色装置(1),包括: 一个工作区,用于接收至少一个试剂容器(3)和至少一个样品; 适合在所述的工作区内活动的机器人部件(20);和 所述机器人部件响应的控制部件;其特征在于: 为了对所述自动染色装置(1)中的至少一个部件进行二维成像而配置的图像捕获二维光学传感器(86)。
2. 根据权利要求1所述的装置,其特征在于:戶皿的机器人部件(20)适用于吸取 一部分在试剂容器(3)中的试剂,转移该部佩剂并将其施加至脾品上,其中戶舰的试剂容器(3)和戶;M的样品被安s瞎戶;M的工作区内。
3. 根据权利要求1或2所述的装置,其特征在于:戶皿的光学传感器(86)用于装 置的自校正,即通ilffi获在装置中的部件的图像并将所捕获的图像与部件的参考图像比较以确定所捕获的图像中的部件是否偏离了它们在参考图像中的预定位置。
4. 根据权利要求1或2所述的装置,其特征在于,戶;M光学传自(86)适合定位 予M的用于自校正所述机器人部件的参比特征。
5. 根据权利要求1或2所述的装置,其特征在于,戶皿的光学传感器(86)被定位 在臓的机器人部件(20)上。
6. 根据权利要求i或2戶脱的装置,辦征在于,戶脱光学传繊适合在戶;f^样品经受染色方案之后记^终的样品图像。
7. 根据权利要求1或2所述的装置,其特征在于,0M至少一个部件包括从由以下 部分构成的组合中选择的要素:二维高^H率符号码、«矩阵码、条形码、粘附 銜己、二维符号区和人可读的文本区。
8. 根据权利要求1或2戶皿的装置,其特征在于,戶皿光学传自(86)被构造成 會辦识别从以下特征构成的组合中选择的特征:样品的纹理、样品的轮廓、样品的 可视特性、以及样品的个体识别特征。
9. 根据权利要求1或2戶脱的装置,其特征在于:戶腿的工作区包括一報剂部分 (2),其设置以容纳至少一^剂容器(3),和至少一个与戶;fi^试剂部分(2)相邻的载玻片部分(5),其中所述的载玻片部分(5)被设置^W纳包含在载玻片(7)上的至少一个样品。
10、 根据权利要求1或2戶脱的装置,其特征在于:戶腿至少一个部件包括光学识 别部件。
11、 根据权利要求10戶脱的装置,其特征在于:戶腿的光学识别部件具有重复信息。
12、 根据权利要求ll戶腿的装置,其特征在于,戶腿重复信息包括多重复信息。
13、 根据权利要求ii戶腿的装置,其特征在于,戶;f^n复信息包括冗余信息。
14、 根据权利要求io戶腿的装置,其特征在于,戶;M光学识别部件包括二维高彌率符号码。
15、 根据权利要求io戶皿的装置,»征在于,戶;M光学识别部件包括im矩阵码。
16、 根据权利要求io戶皿的装置,其特征在于,戶;M光学识别部件包括条形码。
17、 根据权利要求io所述的装置,其特征在于,还包括:计^i几图像生物分析部件。
18、 根据权利要求10戶脱的装置,其特征在于,戶腿光学传« (86)包括照相机。
19、 根据权利要求18 0M的装置,其特征在于,戶;MM相机包括CCD部件。
20、 根据权利要求io所述的装置,其特征在于,戶;f^样品是容纳在载玻片(7)上 的生物样品。
21、 根据权利要求10照悉的装置,其特征在于,还包括用于存储有关组织样品染色过程的图像的,。
22、 一种在自动染«置中染色样品的方法,包括以下步骤: 在工作区内提供至少一个样品;在工作区内,至少一1^剂容器;,适合在戶;Mx作区内g的机器人部件;衝娥制部件,戶脱机器人部件响应该控制部件;和衝共适合探测戶;M自动染色装置中的至少一个部件的二维图像的光学传感器。
23、 根据权利要求22戶腿的方法,其特征在于,还包船己录相关图像«的步骤。
24、 根据权利要求22或23所述的方法,其特征在于,还包括以下步骤:吸取一部分在试剂容器(3)内的试剂;转移该部假剂;将试剂施加在样品上;其中戶膽的 试剂容器(3)和所述的样品被设置在所述的工作区内。
25、 根据权利要求22或23所述的方法,其特征在于:还包括如下步骤:用所述的光学传感器(86)进行装置的自校正,ilil捕获在装置中的部件的图像并将所捕获的图像与部件的参考图微饭以确定所捕获的图像中的部件是否偏离了它们在参考 图像中的预定位置。
26、 根据权利要求22或23所述的方法,其特征在于,包括以下步骤:记录戶;M^ 置中的机器人部件的校正参比点;以及将戶«图像«输入到戶皿机器人部件响应 的控制部件。
27、 根据权利要求26所述的方法,其特征在于,所述的记录0M装置中的机器人部 件的校正参比点的步骤包括以下步骤:记录用于包括带有样品的载玻片的至少一个fiit的机器人部件校正参考位置。
28、 根据权利要求22或23戶腿的方法,包括以下步骤:用计#|鹏0^少一个 样品的图像«进行生物分析。
29、 根据权利要求22或23 0M的方法,其特征在于,所述J^共至少一个样品的步 骤包括采用载玻片的步骤。
30、 根据权利要求22或23所述的方法,其特征在于,戶;M皿光学传自的步骤, 包括采用照相机的步骤。
31、 根据权利要求22或23戶皿的方法,其特征在于,戶皿,光学传«的步骤, 包括采用CCD部件的步骤。
32、 根据权利要求22或23所述的方法,其特征在于,还包括储存有关组织样品染feii程的图像的步骤。
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