CN101365375A - 用于经由谱编码进行光学成像的方法和设备 - Google Patents

用于经由谱编码进行光学成像的方法和设备 Download PDF

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CN101365375A
CN101365375A CNA2006800405035A CN200680040503A CN101365375A CN 101365375 A CN101365375 A CN 101365375A CN A2006800405035 A CNA2006800405035 A CN A2006800405035A CN 200680040503 A CN200680040503 A CN 200680040503A CN 101365375 A CN101365375 A CN 101365375A
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electromagnetic radiation
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吉列尔莫·J·蒂尔尼
德维尔·叶林
布雷特·尤金·鲍马
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Abstract

提供了根据本发明的示范性实施例的方法、设备和装置，用于生成解剖结构的至少一个部分的图像。例如，该部分具有大于大约1mm2的面积，并且该图像具有在大约10μm之下的横向分辨率。例如，光在这样的部分之上进行扫描，以便生成与该部分相关的第一信息，其中所述光可以被提供通过衍射装置以生成谱分散线。提供了根据本发明的进一步的示范性实施例的方法、设备和装置，用于在解剖结构之内定位辐射束或光束，该定位基于通过使用相同或不同射束来扫描该结构的一部分而生成的信号。

Description

用于经由谱编码进行光学成像的方法和设备
相关申请的交叉引用
本申请基于并要求2005年9月29日提交的序列号为60/721,802的美国专利申请的权益，其整体内容通过引用结合于此。
技术领域
本发明涉及用于经由谱编码对上皮器官和其它生物结构进行全面光学成像的装置和方法。
背景技术
放射技术如X射线计算机断层扫描(“CT”)、磁共振成像(“MRI”)和超声波使得器官水平的人体病变的非侵入可视化成为可能。尽管这些医疗器械可能能够识别大尺度的病变，但是癌症的诊断需要微观结构的评估，这超出了传统成像技术的分辨率。因此，诊断可能需要活组织检查和病理组织学检查。因为癌症前期的生长和早期癌症常常以微观尺度出现，所以它们为识别和诊断提供显著的挑战。这些病变的传统筛选和监视依赖于苏木精和伊红(“H&E”)染色玻片的无制导的活组织检查和形态分析。尽管这种方法可以被认为是用于微观诊断的当前标准，但是它需要从患者去除组织并且需要显著的处理时间以生成玻片。更重要地，组织病理学固有地为点采样技术；常常只有非常小的一部分的患病组织能够被切除，并且病理学家常常可能检查小于1％的活组织检查样品。
可以优选的是，从活人患者的整个器官或生物系统中获得微观诊断。然而，合适成像技术的缺乏极大地限制了用于筛选肿瘤前的状况(例如转化)和发育异常的选项。另外，无能力现场识别发育异常和恶性肿瘤的区域已导致诸如像前列腺、结肠、食道和膀胱等等的随机活组织检查的筛选过程，这是高度不希望的和杂乱无章的。当前涉及冷冻切片实验室的许多诊断任务如外科肿瘤边界的描绘可以通过诊断医疗器械来改进，该诊断医疗器械能够以微观尺度迅速成像大的组织体积。能够填补病理学和放射学之间的这个空白的技术将会对患者管理和卫生保健具有重大利益。
已进行了技术进步以增加非侵入成像技术诸如像微CT、微PET和磁共振成像(“MRI”)显微术的分辨率。通过这些技术已实现了接近20μm的分辨率，但是基本的物理限制仍然阻止它们应用于患者。对于非切除的组织病理学诊断，现场进行的微观光学活组织检查技术近来已取得进展。反射共焦显微术(“RCM”)可以特别好地适合于对患者的非侵入显微镜检查，因为它能够测量微观结构而没有组织接触，并且不需要管理外在造影剂。RCM能够抑制离焦光，并且检测选择性地起源于组织内单平面的背散射的光子。例如通过在平行于组织表面的平面内迅速扫描电磁辐射的聚焦束，能够实施RCM，获得组织的横断或表面图像。可以用在RCM中的大数值孔径(NA)能够获得非常高的空间分辨率(1-2μm)，使得亚细胞结构的可视化成为可能。然而，高NA成像对随着光传播通过不均匀的组织而出现的像差特别敏感。而且，使用RCM的高分辨率成像典型地被限制到大约100-400μm的深度。
RCM已被广泛地展示为用于表皮组织的可行成像技术。内窥镜共焦显微系统的开发已变得更加困难，这至少部分地归因于涉及使扫描显微镜小型化的重要技术挑战。将共焦显微镜检查的概念直接应用于内窥镜检查的一个主要障碍是机构的操纵，该机构用于在小直径软质探针的远端快速扫描聚焦束。已提议了多种方法来应对这个问题，包括远端微机电系统(“MEMS”)束扫描装置的使用和单模光纤束的近端扫描。而且，RCM可以提供仅在离散位置处的微观图像——“点采样”技术。如当前实施的那样，点采样是RCM所固有的，因为它具有有限的视场，其可以与切除活组织检查的视场相当或比它小，并且对于全面的大视场显微镜检查，成像速率太慢。
使共焦显微镜检查适用于内窥镜应用的另一个挑战包括可以用于光学切片的高NA物镜的小型化。通过提供例如梯度指数透镜系统、双轴物镜或定制设计的小型化物镜，可以实现这样的小型化。例如，使用耦合到小型化物镜的光纤束，可以在体内获得子宫颈上皮的形态的详细图像，并且使用商用仪器如可以从例如Olympus Corp.(奥林巴斯公司)和Pentax/Optiscan获得的商用仪器，可以得到结直肠病变的基于荧光的图像。
尽管有这些进展，仍然需要改进的成像技术，该成像技术能够在大的区域之上现场提供生物结构的微观分辨率。
发明内容
本发明的目的之一是要克服现有技术系统和方法的某些缺陷和缺点(包括上面在此描述的那些)，并且提供方法和设备的示范性实施例，所述方法和设备能够提供对解剖结构诸如像上皮器官或其它身体组织的全面微观光学成像。
例如，根据本发明的示范性实施例的设备可以采用探针或组件的形式，其可以是可置换的。所述探针或组件例如可以包括：一个或多个光波导管，其能够将电磁辐射转送到所述探针或组件并形成光束；一个或多个聚焦装置，其提供在远端，可以被配置成聚焦所述光束；以及扫描装置，其配置成跨越所述解剖结构的一部分扫描所述光束。所述电磁辐射可以包括多个波长，并且所述波长可以随时间变化。所述探针还可以包括：一个或多个衍射装置，其可以配置成衍射或谱分散所述光束；一个或多个校正装置，其可以配置成校正光学像差；机械装置，其能够使所述探针或组件在被成像的所述解剖结构之内置于中心或定位；和/或引导线装置，其能够使所述探针或组件平移和/或旋转。所述波导管例如可以是光纤或光纤束或其它波导管。所述探针或组件可以进一步包括谱编码装置和/或校正光学装置诸如像弯曲的透明表面，其能够用于校正光束路径中的像差如像散。
在本发明的某些示范性实施例中，所述探针或组件能够配置成扫描所述解剖结构的区域，该区域能够具有大于大约1mm2的面积，并且其中所述区域可以包括表面、体积或所述解剖结构的表面之下的位置。所述探针或组件可以配置成获得数据，该数据能够用于以近似10μm之下的分辨率生成区域的图像。
在本发明的进一步的示范性实施例中，能够提供探针或组件，该探针或组件能够相对于所述解剖结构定位和/或聚焦所述光束。所述定位和/或聚焦例如能够基于干涉测量信号、飞行时间信号或电磁辐射的强度。所述探针或组件能够包括共焦光学装置。
在本发明的更进一步的示范性实施例中，所述探针或组件能够包括：定位装置，其能够确定所述探针或组件相对于所述解剖结构之内位置的位置；以及可选定位装置，其能够基于所述位置控制所述探针的移动和/或定位。
在本发明的其它示范性实施例中，能够提供用于获得对解剖结构进行全面微观光学成像的方法，该方法能够包括：使用电磁辐射诸如像光束，扫描大于大约1mm2的要被成像的所述解剖结构的区域；基于所述辐射接收信号；以及基于所述信号生成图像，其中所述图像能够具有大约10μm之下的横向分辨率。
在本发明的更进一步的示范性实施例中，提供了用于在解剖结构之内定位或指引的电磁辐射的方法，该方法能够包括：使用电磁束扫描所述解剖结构的至少一部分；以及使用可以基于所述电磁辐射的信号来控制所述辐射的位置和/或聚焦。还能够提供方法，以基于从在解剖结构的区域之上扫描电磁辐射获得的信号，来控制解剖结构之内的共焦束的位置或聚焦。
结合所附的权利要求书，当阅读以下对本发明实施例的详细描述时，本发明的其它特征和优点将会变得明显。
附图说明
结合示出了本发明的示意性实施例的附图，从以下详细描述中，本发明的进一步的目的、特征和优点将会变得明显，其中：
图1是示范性谱编码共焦显微(SECM)系统的示意性图示；
图2A是使用单模源和单模检测(SM-MM)配置离组织表面100μm在体外获得的猪肠上皮的示范性SECM图像；
图2B是使用单模源和多模检测(SM-MM)配置获得的猪肠上皮的另一个示范性SECM图像；
图2C是猪肠上皮的SECM图像的放大图；
图3A是在以50μm的成像深度压缩肠壁之后在体外获得的猪肠上皮的示范性SECM图像；
图3B是在以100μm的成像深度压缩肠壁之后在体外获得的猪肠上皮的示范性SECM图像；
图4是示范性SECM设备的示意性图示；
图5是USAF图表的示范性SECM图像；
图6A是以1x的放大率显示的基于取自镜头纸样品的数据的示范性SECM图像；
图6B是以4.5x的放大率显示的基于取自镜头纸样品的数据的示范性SECM图像；
图6C是以16.7x的放大率显示的基于取自镜头纸样品的数据的示范性SECM图像；
图6D是以50x的放大率显示的基于取自镜头纸样品的数据的示范性SECM图像；
图6E是以125x的放大率显示的基于取自镜头纸样品的数据的示范性SECM图像；
图7是在5个不同焦点位置从镜头纸样品获得的一系列示范性SECM数据以及通过组合5个各自图像中的数据生成的组合图像；
图8A是以1x的放大率显示的基于取自猪肠组织片段的数据的示范性SECM图像；
图8B是以4x的放大率显示的基于取自猪肠组织片段的数据的示范性SECM图像；
图8C是以20x的放大率显示的基于取自猪肠组织片段的数据的示范性SECM图像；
图8D是以40x的放大率显示的基于取自猪肠组织片段的数据的示范性SECM图像；
图9是能够对大组织体积进行成像的示范性SECM系统的示意性图示；
图10是根据本发明的示范性实施例的可以用于成像的示范性导管的远端的示意性图示；
图11是包括外部旋转扫描装置的根据本发明的示范性实施例的可以用于成像的示范性导管的示意性图示；
图12A是弯曲窗口和负圆柱透镜的光学效果的示意性图示；
图12B是使用弯曲窗口的像散像差校正的示意性图示；
图13A是可以用于通过单步调试聚焦深度的范围而获取预期深度范围的示范性技术的图示；
图13B是可以用于通过主动调整焦平面而在特定的深度对组织进行成像的示范性技术的图示；
图14A是双重双压电晶片压电弯片(dual bimorph piezoelectricbender)的示意性图示；
图14B是使用弯曲执行器可以在透明外护套之内移动马达的示范性装置的示意性图示；
图15是配置成通过平移准直透镜来控制聚焦的示范性气囊导管设计的示意性图示；
图16是特定可变焦透镜的照片；
图17A是具有透明圆柱形式的圆柱形内套设计的示意性图示；
图17B是包括透明窗口的圆柱形内套设计的示意性图示；
图17C是在套壁中包括几个开口的圆柱形内套设计的示意性图示；
图17D是在套和马达之间的连接中包括开口的圆柱形内套设计的示意性图示；
图18是示范性成像系统的部件之间的电连接和数据连接的示意性图示；
图19A是示范性探针扫描模式的图示，在该模式下，迅速旋转射束并同时在轴向上缓慢地移动射束以提供螺旋成像模式；
图19B是示范性探针扫描模式的图示，在该模式下，迅速旋转射束然后沿轴向重新定位射束；
图19C是示范性探针扫描模式的图示，在该模式下，在轴向上快速扫描射束，然后在旋转方向上重新定位射束；
图19D是示范性探针扫描模式的图示，在该模式下，在圆形组织区域之上的同心圆形路径之上扫描射束；
图20A是包括位于套远端末端的引导线装置的快速交换气囊导管设计的示意性图示；
图20B是包括位于套远端末端并且具有次级通道形式的引导线装置的快速交换气囊导管设计的示意性图示；
图20C是包括位于套近端末端并且具有次级通道形式的引导线装置的快速交换气囊导管设计的示意性图示；
图21A是用于定位线气囊导管的示范性技术中的第一步骤的示意性图示，其包括引导线的插入；
图21B是用于定位线气囊导管的示范性技术中的第二步骤的示意性图示，其包括在引导线之上放置气囊导管；
图21C是用于定位线气囊导管的示范性技术中的第三步骤的示意性图示，其包括在气囊导管中放置光学装置；
图22A是示范性气囊导管的示意性图示，该气囊导管包括配置成从远程位置向气囊传递膨胀材料的单个通道；
图22B是示范性气囊导管的示意性图示，该气囊导管包括两个护套，其中能够在护套之间提供膨胀材料；
图23A是具有线笼(wire cage)形式的定心装置的示意性图示，其中该装置包含在外护套之内；
图23B是具有线笼形式的定心装置的示意性图示，其中该装置部分地从外护套伸出；
图23C是具有线笼形式的定心装置的示意性图示，其中该装置完全从外护套伸出；
图24A是包括波分复用器和色散补偿器的示范性SECM/SD-OCT系统的示意性图示；
图24B是可以通过使用线性CCD阵列的SECM/SD-OCT系统提供的示范性谱的示意性图示；
图25是示范性SECM/SD-OCT探针的示意性图示；
图26是包括既用于SECM装置又用于SD-OCT装置的单个光纤的示范性SECM/SD-OCT探针的示意性图示；
图27是可以用于使用SD-OCT数据来为SECM图像调整聚焦的技术的示范性流程图；
图28是示范性导管线缆的横截面的示意性图示；
图29是包括可以提供更紧凑探针配置的射束偏转光学装置的示范性探针的示意性图示；
图30A是平移扫描技术的示意性图示，示出了在向要被成像的场所传递探针期间的探针的紧凑配置；
图30B是平移扫描技术的示意性图示，示出了位于平移范围的远端极限的探针的内套；
图30C是平移扫描技术的示意性图示，示出了位于平移范围的近端极限的探针的内套；
图31是包括透明开口的外套的示意性图示；
图32是包括偏心准直光学装置并且配置成提供外部旋转扫描的示范性紧凑探针的示意性图示；
图33A是探针的示意性图示，其包括前向可膨胀气囊和内套，配置成在扫描的同时与气囊的内壁相接触；
图33B是与膨胀气囊的内壁相接触的图33A中示出的探针的示意性图示；
图34A是示范性探针的示意性图示，其包括外可膨胀气囊和内可膨胀气囊，可以配置成当膨胀时维持探针和外气囊壁之间的接触；
图34B是图34A中示出的探针的示意性图示，其中膨胀的内气囊提供在探针周围，并且配置成维持探针和膨胀的外气囊壁之间的接触；
图35A是进一步的示范性探针的示意性图示，其包括外可膨胀气囊和内可膨胀气囊，可以配置成当膨胀时维持探针和外气囊壁之间的接触；
图35B是图35A中示出的探针的示意性图示，其中膨胀的内气囊提供在探针和外气囊之间，并且配置成维持探针和膨胀的外气囊壁之间的接触；
图36A是探针的底视图的示范性图示，该探针配置成在沿着回拉轴扫描的同时与可膨胀气囊的内壁相接触；
图36B是图36A中示出的探针的侧视图的示意性图示；
图36C是图36A中示出的探针的侧视图的示意性图示，其中该探针与膨胀的气囊的内壁相接触；以及
图36D是图36C中示出的探针的正视图。
贯穿附图，除非另外声明，否则相同的标号和字符用于指示图示实施例的相同特征、元件、部件或部分。此外，虽然现在将参考附图详细地描述本发明，但是这将结合示意性实施例进行。能够对描述的实施例进行改变和修改，而不认为脱离了如所附权利要求所限定的本发明的真实范围和精神。
具体实施方式
根据本发明的示范性实施例，提供了用于内窥镜共焦显微术的方法和设备，其避开了对探针之内的小型高速扫描机构的需要。谱编码共焦显微术(“SECM”)是可以使用的波分复用共焦方法。SECM利用了宽带宽光源，并且能够对光谱中的一维空间信息进行编码。
在图1中示出了示范性SECM技术。来自可以位于探针远端的单模光纤100的输出能够被准直透镜110校准，然后照射色散光学元件(诸如透射衍射光栅120)。物镜130然后能够将每个衍射波长聚焦到样品之内的不同空间位置，导致横断线状焦点140，其中线上的每个点用不同的波长表征。在从可以例如是生物组织的样品反射之后，光信号可以被衍射元件120重新组合并由单模光纤100收集。单模光纤100的核心孔径可以提供空间滤波机制，其能够滤去散焦光。在探针外部(并且任选地在系统控制台之内)，返回的光的光谱可以被测量并被转换成作为样品之内横向位移的函数的共焦反射。能够快速执行谱解码。这样一来，通过相对缓慢和直接的机械动作，就能够完成通过在正交于线状焦点的方向上扫描射束而产生的图像。
SECM技术可以允许使用内窥镜RCM，并且能够通过使用高速线性CCD摄像机以极高速率提供图像数据。商业上可用的线性CCD阵列能够以大于大约每秒60兆像素的速率获得数据。当结合到SECM分光计中时，这些阵列能够以大约10倍于典型视频速率并且一直到100倍于某些内窥镜RCM技术的速度产生共焦图像。典型SECM系统的快速成像速率和光纤设计允许通过内窥镜探针的全面的大面积显微镜检查。
使用光学相干断层扫描(“OCT”)的技术及其变体可以用于全面的构造筛选。获取波长域中的而不是时域中的OCT信号，能够提供成像速度的数量级改善，同时维持良好的图像质量。使用谱域OCT(“SD-OCT”)技术，通过检测组织样品和基准之间的谱分辨干涉，能够在生物组织中实施高分辨率测距。因为SD-OCT系统能够使用与SECM系统相同的高速线性CCD，所以它们也能够以每秒60兆像素捕捉图像，这近似于两个数量级的传统时域OCT(“TD-OCT”)系统的速率。使用这种获取速率和分辨率，SD-OCT系统能够在临床环境中以构造水平提供全面的体积显微镜检查。
示范性SD-OCT和SECM系统提供的信息可以是互补的，并且使用这两种技术的混合平台能够提供可能对于准确诊断所必需的有关组织的构造和细胞结构的信息。尽管不同技术的结合典型地需要大范围的工程并且可能损害性能，但是SECM和SD-OCT系统能够共享关键的部件，并且能够提供高性能多模态的系统，而不会显著增加单个系统的复杂性或成本。
根据本发明的某些示范性实施例的SECM系统能够使用波长扫描1300nm的源和单元件光检测器来获得作为时间函数的谱编码信息。使用这个系统，能够以在400μm视场(“FOV”)之上具有高横向(1.4μm)和轴向(6μm)分辨率的高达约30帧/秒的速率获取图像。用高速系统在体外成像新近切除的猪十二指肠片段的图像，以展示SECM系统识别亚细胞结构的能力，该亚细胞结构例如可以在专化肠上皮化生(“SIM”)或Barretts食道的化生变化中发现。
图2A-2C描绘了在体外获得的猪肠上皮的示范性SECM图像，其使用了两种成像模式和相应的光纤配置：具有单模检测的单模照射(“SM-SM”)以及具有多模检测的单模照射(“SM-MM”)。图2A中的SM-SM图像示出了使用单模源和单模检测的距离组织表面100μm的上皮结构。使用具有1:4的核心-孔径比的单模源和多模检测(SM-MM)获得的示出在图2B中的相同组织区域的图像，因为斑点噪声减少而可以具有更加平滑的外观并且可以更加容易地解释。图2C是图2B中示出的图像的放大图，其指示了包含不良反射的核心(例如固有层或“lp”)和较高散射的柱状上皮的绒毛的存在。在图2C中示出了在柱状细胞的底部可见的明亮图像密度，其与核一致(用箭头指示)。
使用膨胀气囊，能够将使用OCT技术在体内成像的食道壁的厚度减少例如大约二分之一。图2A-2C中示出的猪肠样品被减少相同的量，并且使用SECM技术观察到的亚细胞特征被很好地保存。图3A和3B分别示出了在50μm和100μm的深度获得的该变薄样品的图像。
商用800nm激光扫描共焦显微镜的穿透深度被观察到与用1300nmSECM系统获得的穿透深度相比减少了大约20％。减少的穿透可能是较短波长源的散射增加的结果。这样一来，使用840nm源的SECM系统就可以提供足够的穿透，以识别例如肠上皮的亚细胞结构。
在图4中示意性地图示了被配置成提供全面SECM图像的根据本发明的某些示范性实施例的设备。这个示范性设备被配置成从圆柱形样品获得图像，该圆柱形样品具有2.5cm的长度和2.0cm的直径，这近似为远端食道的尺度。具有以800nm为中心的波长和45nm的带宽的光纤耦合的2.0mW超辐射二极管200(QSSL-790-2，qPhotonics，Chesapeake，VA)，被配置成照射50/50单模光纤分束器405。被传输通过分束器的一个端口的光被准直仪410校准，并且被传输通过光纤412到达聚焦设备415并到达光栅透镜对，该光栅透镜对包括：光栅420(1780 lpmm，Holographix，LLC，Hudson，MA)；以及350230-B非球面透镜425(Thor Labs，Inc.，Newton，NJ)，其具有4.5mm的焦距f、5.0mm的通光孔径和0.55的NA。这种布置能够在圆柱形样品的内表面上产生聚焦的谱编码的斑点430的500μm纵向线性阵列或线。光栅透镜对通过套440附着到马达435(例如从MicroMo Electronics，Inc.，Clearwater，FL获得的1516SR、15mm直径马达)的轴。随着马达435旋转，能够跨越圆柱形样品的内圆周扫描谱编码线。使用计算机控制的线性级445(诸如像从Melles Griot，Rochester，NY获得的Nanomotion II，2.5cm范围)，在马达435的旋转期间沿着圆柱形样品的纵轴平移马达435、壳体440和光栅透镜对。这个过程产生了圆柱形样品的整个内表面的螺旋扫描。
从样品反射的光被传输返回通过光学系统进入单模光纤412，并且被光纤412提供给分光计450和线性CCD455，该线性CCD455能够包括例如2048个像素并且具有30kHz的线速率(诸如像从Basler VisionTechnologies，Exton，PA获得的Basler L104K)。计算机460能够用于存储、分析和显示分光计450和CCD 455提供的图像数据。每周马达旋转大约有60,000点(以0.5Hz或30rpm)可以被数字化，以提供近似1.0μm的圆周采样密度。马达的纵向速度能够近似为0.25mm/s，并且圆柱形样品的一个完整扫描所需的时间可以大约为100秒。
光栅透镜对上的准直束的1/e2直径能够大约为4.0mm。结果，这个示范性设备的有效NA能够近似为0.4，这对应于近似1.2μm的理论斑点直径和近似2.5μm的共焦参数。在没有光学像差的系统中，样品上的理论谱分辨率可以为
Figure A200680040503D0017180901QIETU
其能够跨越谱编码线430得到高达近似630个可分辨点。检测臂中的分光计450能够被设计成超过探针的预测谱分辨率。
在图5中示出了使用这种设备获得的1951 USAF分辨率图表的SECM扫描。被分开2.2μm的这个图中的最小条被分辨。使用扫描通过焦点的镜获得的横断线扩展函数半高宽(“FWHM”)和轴向FWHM函数分别被测量为2.1μm和5.5μm。观察到视场大约为500μm。这些测量结果略微低于相应的理论值，这可能归因于光路中的像差。这些参数表明，在此描述的示范性设备能够提供足够的分辨率以用于生物组织中的共焦显微镜检查。
在图6中示出了用于2.5cm体模样品的完全回拉图像的示范性SECM图像数据。在生成这些显示的图像之前，将极坐标转换成直角坐标。使用附着到2.1cm内径的特氟隆(Teflon)管的内表面的镜头纸来制作体模样品。在图6A示出的低放大率图像中，能够观察到纸的包括褶皱和空隙的宏观结构。可见的圆周条纹可能起因于存在于谱编码线的末端处或其附近的较低的谱功率和透镜像差。如图6B-6E所示，在以较高的放大率提供的这个数据集的区域中，能够清楚地分辨各个纤维和纤维微观结构。
通过调整图4A中的聚焦设备415，在120μm的范围的5个离散聚焦深度处获取体模样品的圆柱形二维(“2D”)图像。图7中示出的这5个图像710-750然后被求和以产生综合图像760，其展示了体模样品表面的几乎完整的覆盖。
由于缺少用于光学扫描头的定心设备，使用如在此描述的SECM设备来成像生物样品能够被复杂化。为了提供进一步的改进以便生成宽视场显微图像和数据，在2.0cm直径的透明圆柱之上放置猪肠的样品。在图8A中示出了1秒内获取的这个样品的360°扫描。成像的组织可能仅在圆柱形扫描的一个区段中出现，因为探针未被置于中心，并且样品没有完全缠绕在圆柱周围。图8B-8D示出了这个组织样品的一系列放大区域。图8B中示出的图像是图8A中的打点矩形框出的1.5cm区段的扩展。类似地，图8C中的图像表示了图8B中框出的矩形的扩展，而图8D中的图像则表示了图8C中框出的矩形的扩展。图8B中的组织的放大图像暗示了腺结构。图8C-8D中的放大图像展示了绒毛和核特征，它们类似于如图2和3所示的使用1300nm SECM系统观察到的绒毛和核特征。图8A中的SECM扫描的其它区域示出了伪像(artifact)，包括来自透明圆柱的镜反射和全信号丢失，这两者都可能起因于聚焦SECM束的不适当定位。
对患者实施全面共焦显微镜检查提出了多种技术挑战。这样的挑战可能包括例如增加成像速率、使探针光学部件和机械部件小型化、结合定心机构以及实施用于动态改变焦平面的技术。
与在上文描述的示范性系统相比，能够将SECM系统的图像获取速度改进为该示范性系统的例如大约2-4倍。通过提供某些修改能够实现这样的改进。例如，更高功率半导体光源(诸如像超辐射二极管T-840HP：25mW，840nm，100nm谱带宽)能够提供例如近似1000个谱可分辨点。光功率的这种增加能够改进灵敏度，并且较大的带宽可以拓宽视场，使得可以以近似两倍的速度扫描SECM束。而且，使用光环行器诸如像OC-3-850(Optics for Research，Caldwell，NJ)能够增加被传递到探针和从探针收集的光的效率。使用更快更灵敏的线性CCD诸如像具有2048个像素和60kHz读出速率的AVIIVA M4-2048(Atmel Corporation)能够提供两倍的数据获取速度和用于生成图像数据的波长范围的改进的谱响应。还可以通过使用例如Camera Link(摄像机链接)接口来改进性能，所述Camera Link接口能够以近似120MB/s的速率从摄像机向用于存储的硬盘驱动器阵列传送数据。
被理解为指的是最小可检测反射率的灵敏度是影响共焦图像质量和穿透深度的系统参数。当使用近红外RCM技术时，能够从一直到近似300μm的深度处的皮肤反射入射光的一小部分，其可能近似为10-4到10-7。基于在此描述的根据本发明的某些示范性实施例的示范性系统中使用的物镜的NA以及皮肤比非角质化上皮黏膜更加显著地可以使光衰减的观察，在此描述的示范性SECM探针物镜可以收集近似3×10-4到3×10-7的从组织之内深处反射的照射光。25mW光源可以被分成例如近似1000个独立的射束。最大双程插入损耗被估计为近似10dB(其包括来自探针的6dB损耗以及来自光纤和分光计的4dB损耗)。基于这些估计的参数，对于每线集成周期，从而可以用近似50到50,000个光子/像素来照射阵列中的每个像素。
使用多模检测技术，可以实现10倍的信号增益，使得对于这样的配置每次扫描有近似500到500,000光子/像素。如果信号在以近似240个光子发生的暗电流波动之上，则例如Atmel AVIIVA M4摄像机上的单个像素能够可靠地检测光。如果这个装置在这些波长处具有近似50％量子效率，则能够以每次扫描近似480光子/像素产生最小可检测信号。基于这些近似，Atmel摄像机可以具有足够的灵敏度以允许较深的组织深度处的SECM成像。通过使用多模光纤来收集或者通过增加源功率，能够实现对预测的最小反射率进行的量子噪声限制检测。
在图9中示出了根据本发明的某些示范性实施例的能够进行上皮器官的大面积微观成像的设备的示意图。可以是宽带源或波长扫描源的光源900能够提供光，所述光可以被传送通过环行器910，或者可替选地通过光纤分束器。然后能够通过扫描机构920将光传送到成像导管930。能够在导管外部或导管之内进行扫描。在某些优选示范性实施例中，可以在导管外部进行回拉扫描，并且可以在导管内部进行旋转扫描。然后可以用检测器940检测收集的反射光，如果使用宽带光，则所述检测器940例如可以是分光计。如果使用波长扫描源，则检测器940例如还可以是单个检测器。检测器940提供的数据可以由计算机950处理、显示和/或保存，该计算机950还可以配置成对扫描过程进行控制和同步。
拍摄大的内腔器官可以优选地利用将导管的远端部分置于内腔之内的中心的方式，以提供相对于组织的一致聚焦距离和/或深度，以及几个厘米的长度之上的周围图像的快速获取。通过在定心装置之内结合圆周扫描成像探针，能够满足这些标准。提供位于定心装置中间或其附近的成像光学装置能够提供几个额外优点，包括例如消除表面高度波动，这可以简化聚焦要求，以及将成像系统物理耦合到患者，这能够大大减少可能发生的运动伪像。
在图10中示出了根据本发明的某些示范性实施例的SECM导管的远端的示意图。光能够被提供通过光纤1000，该光纤1000可以由光纤夹盘1005固定，然后使用准直透镜1010校准。这个光然后可以穿过可变焦机构1015和圆柱形透镜1020，其能够配置成预补偿光路以校正像散效应。然后可以通过衍射光栅1025对光进行衍射，该衍射光栅1025能够配置成将光的中心波长衍射例如近似90度，然后由成像透镜1030将光聚焦到谱编码线1035上。
通过增加与光纤1000相关联的针孔孔径的直径，使用多模检测可以减少斑点伪像。这种技术能够提供增加的信号传输量和减少的斑点伪像，伴随的仅仅是空间分辨率的略微下降。双包层光纤可以用于实施用于谱编码的这种技术，其中单模核心能够照射组织，而多模内包层则能够检测反射光。
成像透镜1030可以优选地具有例如能够近似为2-7mm的相对大的工作距离，并且维持近似0.25到0.5的大NA。另外，成像透镜1030能够很薄，优选地不超过大约5mm厚。传统透镜如非球面或消色差透镜可以用作成像透镜。
内套1040可以包围各种光学部件和马达1045中的一些或全部，并且可以允许这些部件在外套1060之内的纵向定位。内套1040能够包括如下的部分，该部分具有良好的光透射特性和低波前失真以允许高质量成像，同时仍然维持结构刚性以维持在探针之内被置于中心的马达轴1050。可以用于形成作为内套1040的一部分或全部的透明窗口的材料例如可以包括玻璃或塑料材料，诸如像Pebax和高密度聚乙烯(HDPE)。
外套1060能够包围内套1040，并且能够配置成使用定心机构1065来相对于成像组织1080保持在固定位置。外套1060壁中的开口能够允许拉回线缆1065移动内套1040。通过以下能够实施线性扫描：将内套1040附着到计算机控制的平移器(诸如可以例如由Newport Corp.，Irvine，CA提供的平移器)，同时相对于被成像的组织1080将外套1060维持在固定的位置。这样的拉回技术例如可以用于获得纵向食道OCT图像。所有或部分的外套1060可以是透明的，以允许光从中透过。外套1060的透明部分的光学特性能够类似于内部光学窗口1055的光学特性。
圆柱形透镜1020、衍射光栅1025和成像透镜1030可以容纳在旋转壳体1070中，该旋转壳体1070可以附着到马达轴1050。可以使用传统的马达1045，其能够具有小至约1.5mm以下的直径。使用编码器可以改进图像质量和配准，并且还可以将马达1045的直径增加到近似6-10mm。这样的马达例如能够由MicroMo Electronics，Inc.(Clearwater，FL)提供。能够将马达线的尺度最小化以限制设备的视场障碍。通过使用马达1045经由马达轴1050来旋转内套1040之内的旋转壳体1070，可以进行圆周扫描。
在图11中示意性图示了根据本发明的某些示范性实施例的导管，其配置成从导管远端外部的位置相对于外套1060提供内套1040的旋转。旋转运动能够被传输通过光学旋转结点1100，并且光可以被耦合到旋转光纤1110中。旋转结点还可以经由一个或多个电线1120维持电接触，并且经由可旋转拉回线缆1030维持机械接触，该可旋转拉回线缆1030能够配置成控制拉回和聚焦机构。在图11示出的示范性设备配置中，内套1140没有包围马达，这样一来它就能够更小并且更轻。
圆柱形透镜可以用于校正像散效应，所述像散效应能够通过气囊壁或别的定心设备产生，和/或通过内套和/或外套的透明窗口或透明片段产生。弯曲的玻璃能够以类似于负圆柱形透镜的方式引起像散。例如，图12A中示出的两个弯曲透明壁引起的像散在光学上类似于朝向这个附图的右侧示出的负圆柱形透镜。穿过图12A中示出的物体中的任何一个的中心虚线的光可以具有比穿过上虚线或下虚线的光更短的路径，这导致引起的像散。如图12B所示，例如通过在光路中放置与引起像散的窗口类似的弯曲窗口，能够实现这种光学失真的有效且准确的校正。校正用弯曲窗口的弯曲轴应当垂直于弯曲套窗口的轴，以提供像散的光学校正。
在本发明的另一个示范性实施例中，能够提供内窥镜SECM系统，其能够对器官进行全面成像，而不用用户在获取图像数据期间进行干预。该系统能够虑及例如由心跳、呼吸和/或蠕动运动引起的移动。定心机构的利用能够大大减少由被成像的组织的运动造成的伪像。例如，成像装置和被成像的组织之间的距离变化在一个全面扫描期间例如能够变化多达近似±250μm。这个距离变化相对于圆周扫描速度能够以慢的时间规模(例如几秒钟)发生，但是相对于在成像装置的纵向拉回期间扫描被成像的组织区域的长度所需的时间，它可能是显著的。
根据本发明的某些示范性实施例，能够使用示范性技术来减少或消除采样期间的组织运动的影响。图13A中图示的这种技术能够包括用于获得聚焦深度的较宽范围之上的图像数据。如果希望的总成像深度例如为200μm，并且组织离开成像装置的距离的变化例如为±250μm，那么能够在大约700μm的聚焦范围获取图像数据。这个过程能够确保贯穿希望的组织体积获得图像数据。尽管成像时的体积图像的许多部分可能不包含组织，但是很可能会从所关心的组织体积的大多数区域中获得至少一个好的图像。
在图13B中图示了可以用于补偿成像期间组织运动的第二示范性技术。这个技术能够包括用于确定成像透镜和被成像的组织表面之间的距离的过程。能够跟踪这个距离，并且能够适应性控制透镜的焦点，以贯穿所关心的组织体积中的图像数据的获取来相对于组织表面提供已知的焦距。适应性聚焦能够减少需要的聚焦扫描的次数，并从而还可以减少获得所关心的组织体积的全面覆盖所需的时间。例如使用干涉测量信号、飞行时间信号、电磁辐射的强度等等能够控制射束的聚焦。
用于应对被成像组织的运动的上述示范性技术能够利用用于调整成像装置的焦距的机构。存在几种示范性技术可以用于调整被成像的组织体积之内的聚焦深度。例如，包括聚焦透镜的成像装置的内套能够相对于外套被移动。为了实现这个移动，例如图14A中示出的多层双压电晶片压电执行器1410(例如D220-A4-103YB，Piezo Systems，Inc.，Cambridge，MA)能够在两端附着到例如金属板1420，这可以提供陶瓷材料的弯曲。这些执行器能够背对背地放置，如图14A所示，这能够有效地加倍它们自由运动的范围。4个这样的执行器1430能够布置在外护套1440和组件1450之间，该组件1450能够包括马达和包围马达的聚焦光学部件，如图14B所示。这些执行器1430能够用于通过可控地相对于外套1440移动组件1450来在需要的范围改变聚焦位置。这种技术能够需要在探针之内存在高电压、可能横穿和中断视场的额外电线、和/或将包含成像装置的探针的总体直径增加例如几毫米。
在图15中示出了可以用于调整成像装置的焦距的替换示范性技术。能够提供包围线缆1530的线缆套1510。线缆1530能够在一端附着到准直透镜1540，该准直透镜1540可以配置成相对于套1550在纵向方向上可移动。准直透镜1540能够相对于套1550和其它光学部件移动以改变焦距。如图15所示，例如在成像导管外部使用线缆1530能够控制这种平移。可替选地，例如通过能够在导管内部提供的电马达或压电马达，能够控制准直透镜1540的运动。通过相对于准直透镜1540移动光纤1520，所述光纤1520能够提供用于对组织进行成像的光，也能够改变焦距。可替选地，光纤1520和准直透镜1540两者可以相对于彼此移动以改变焦距。
通过将光纤1520和准直透镜1540之间的间隔改变近似M2Δz的距离，能够将焦距转移距离Δz，其中M为成像设备的放大倍数。例如，示范性成像设备能够具有近似为3的放大倍数。为了获得近似±450μm的焦距变化，光纤1520和准直透镜1540之间的距离会需要移动近似±4.0mm，这是使用用于改变焦距的上述技术中的任何一种都能够实现的距离。
用于改变焦距的进一步的示范性技术是利用电子可调谐的可变透镜。例如，可以用在蜂窝电话照相机中的图16中示出的商业上可用的透镜1600(Varioptic AMS-1000 Lyon，France)可以用于改变根据本发明的示范性实施例的成像设备中的焦距。这个透镜1600使用电润湿(electrowetting)原理，并且能够提供大约-200mm和40mm之间的可变焦距，具有可以仅由衍射效应限制的光学质量。这个示范性透镜1600的当前有效通光孔径(CA)为3.0mm，并且总外径(OD)为10mm。可以生产具有4.0mm CA和6.0mm OD的类似透镜。这个示范性透镜1600的全范围响应时间大约为150ms，这能够快得足以用于跟踪光学部件和组织表面之间的距离并相应地调整焦距。可以生产具有大约10ms的响应时间的这种类型的透镜。在准直仪和SECM光栅之间使用如上所述的可变透镜例如可以提供能改变大约±300μm以上的焦距。
能够为根据本发明的某些示范性实施例的内套提供各种配置。例如，如图17A所示，能够使用由透明材料形成的套1700。可替选地，能够提供包括透明窗口1710的套，如图17B所示。还可以提供如下的套，所述套包括两个壁之间的开口1720，如图17C所示，或者包括相邻于可以附着到套的马达1730的开口，如图17D所示。
在图18中提供了能够与图9中示出的示范性系统一起使用的控制和数据记录装置的示范性示意图。图18中示出的装置能够配置成记录射束位置同时获取成像数据1800，这能够提供成像数据1800的更加精确的空间配准。如图18所示，通过数据获取和控制单元1810能够获取成像数据1800。导管扫描仪装置可以扫描射束，例如使用旋转马达1820来提供射束的角运动，以及使用拉回马达1830来纵向移动射束。旋转马达1820能够由旋转马达控制器1840控制，并且拉回马达1830能够由拉回马达控制器1850控制。这些控制技术中的每一个可以使用闭环操作来进行。数据获取和控制单元1810能够指引马达控制器单元1840、1850以提供指定的马达速度和/或位置。马达1820、1830生成的编码器信号能够被提供给马达控制器单元1840、1850与数据获取和控制单元1810。用这种方式，当获取成像数据1800的线时，能够记录与每个马达1820、1830相关联的编码器信号，从而允许精确的射束位置与数据1800的每个线相关联。
在图19中示出了可以在根据本发明的示范性实施例的成像导管中使用的各种扫描优先级。例如，在图19A中示出了如下的示范性扫描技术，其中，作为第一优先级进行旋转扫描，并且作为第二优先级进行轴向(拉回)扫描。这种技术能够提供具有螺旋形几何形状的一组数据。在进一步的扫描技术中，能够以小增量进行轴向扫描，其中每个轴向增量跟随全旋转，如图19B所示。可替选地，能够作为第一优先级进行轴向(拉回)扫描，并且能够作为第二优先级进行旋转扫描，这可以生成图19C中示出的扫描图案。沿着第一扫描优先级的方向能够实现更高的成像质量。这样一来，扫描优先级的选择就可以取决于是横向(旋转)图像还是轴向图像为优选。能够以几种方式进行可以具有不同对称的其它器官或组织的成像。例如，在图19D中示出了可以用于对某些器官进行成像的圆形扫描图案。
在本发明的进一步的示范性实施例中，如图10所示的气囊导管能够配置成使用引导线允许快速交换放置过程。在快速交换放置过程中，引导线能够首先被放置到要被成像的器官中，然后导管能够沿着引导线向下穿线。这个过程能够允许导管在许多应用中更容易更精确地放置。各种配置可以用于使用快速交换过程来引导导管。例如，图20A示出了示范性引导线2000，该引导线2000穿过外套2040的远端中的孔2010。在图20B示出的第二示范性配置中，引导线2000穿过附着到外套2040远端的管2020。可替选地，引导线2000能够配置成穿过可以附着到外套2040近端的管2020，如图20C所示。
在图21A-C中图示了可以用于定位导管的示范性过程，其使用了导管的中心内腔中的引导线。首先，能够将引导线2100放置在器官2150之内，如图21A所示。下一步，导管的外套2110与气囊2120一起能够在引导线2100之上穿线，如图21B所示。最后，可以包含光学部件的内套2130能够沿着导管中心内腔向下穿线，如图21C所示，并且能够进行使用光学装置的成像过程。
在图22中示出了气囊导管的两个示范性配置。在图22A中，可以包括压缩空气或气体的源的装置2200能够用于使气囊2210膨胀。能够提供管或其它小通道2230，其连接到包围导管的气囊2210，并且允许将压缩空气或气体传送到气囊2210。使用压力计2220能够监视被膨胀的气囊2210之内的压力。这个压力能够用于使气囊膨胀最优化，并且通过监视可以与膨胀气囊2210接触的周围器官之内的压力来估计导管的放置。可替选地，能够沿着导管的外护套提供通道2240，其能够允许将压缩空气或气体传送到气囊2210，如图22B所示。可以使用能够响应压力变化而改变其直径的气囊，其中通过以下能够控制聚焦深度：使得压缩空气或气体传送到气囊2210以改变气囊直径并从而相对于成像透镜移动周围组织。
在图23A-23C中示出了根据本发明的另一个示范性实施例的可以使用的示范性导管设计。这个导管设计能够配置成使用一个或多个可扩展的绞合线2300，以使成像装置的内光芯在内腔器官之内置于中心。导管可以包括额外的护套2310和位于护套2310之内的一组可扩展的绞合线2300，所述护套2310可以提供在外套2320周围，如图23A所示。在放置导管之后，能够将绞合线2300推挤通过护套2310以从其末端伸出，如图23B所示。可替选地，能够将护套2310从外套2320缩回。足够长的绞合线2300能够暴露在外套2320周围，以允许绞合线2300扩展周围的器官或组织，如图23C所示，并且使套2320置于中心。在执行成像过程之后，可以将绞合线2300拉回到护套2310中，并且能够去除导管。
示范性OCT和RCM技术能够滤去或忽略从被成像的组织样品中接收的多重散射光，并从而检测可能包含结构信息的单独背散射的光子。然而，这些技术中的每一种都能够以不同的方式滤去多重散射光。
例如，RCM技术可以使用从紧密聚焦的入射束中共焦选择由被成像的组织反射的光。RCM技术能够通过以下实施：在平行于组织表面的平面内快速扫描聚焦束，这可以提供组织的横断或表面图像。能够与传统RCM技术一起使用的大数值孔径(NA)可以得到非常高的空间分辨率(例如近似1-2μm)，这能够允许亚细胞结构的可视化。然而，使用高NA的成像过程能够对随着光传播通过不均匀的组织而出现的像差特别敏感。因此，使用RCM的高分辨率成像可以被限制到大约100-400μm的深度。
OCT技术能够使用用于光学分割的相干光栅原理，并且可以不依赖于高NA透镜的使用。这样一来就可以使用具有相对大的共焦参数的成像透镜来执行OCT技术。这能够提供进入到被成像的组织中的较大穿透深度(例如近似1-3mm)和横截面图像格式。这些优点可以以减少的横向分辨率为代价而得到，所述减少的横向分辨率能够典型地相当于大约10-30μm。
这样一来，考虑到上述区别，示范性OCT和RCM技术就能够提供不同的成像信息，其可以是互补的。例如，RCM技术能够提供亚细胞细节，而OCT技术则例如能够提供结构形态。来自这两个尺寸体系的成像信息对于组织病理学诊断可以是决定性的，并且在许多情况下，不使用这两者而进行准确的诊断如果不是不可能，那也可能是困难的。尽管这些完全不同的成像技术的结合可能传统上利用广大的工程计划，这能够损害性能，但是SECM和SD-OCT技术能够共享某些部件。因此，能够提供利用这两种成像技术的高性能多模态的系统，它并没有包括相对于可以单独使用任一技术的系统的复杂性或成本的显著增加。
在图24A中示出了根据本发明的示范性实施例的能够执行SECM技术和SD-OCT技术两者的示范性系统的概述。在这个示范性系统中，宽带光源带宽的一部分能够用于获得SECM图像数据，而带宽数据的进一步的部分则例如能够用于获得SD-OCT数据。例如，光源2400能够用于提供具有例如大于大约100nm的带宽的电磁能。可以用作光源2400的装置例如能够包括二极管泵浦超快激光器(诸如可从例如IntegralOCT，Femtolasers Produktions GmbH，Vienna，Germany得到的那种)或超辐射二极管阵列(这例如可以从Superlum，Russia获得)。
可以用于SD-OCT数据的光源谱的一部分(例如具有大约810-900nm之间的波长的光)，能够通过使用波分复用器(WDM)2410而与可以用于SECM数据的谱的一部分分开，并被传送到导管2420和基准臂2445。从导管2420通过SECM光纤2430和SD-OCT光纤2440返回的光能够被提供给分光计2450。分光计2450可以配置成图24B中示出的示范性CCD阵列2460中的元件的近似半数能够检测与SECM数据相关联的信号，并且CCD元件的近似半数能够检测与SD-OCT数据相关联的信号。例如通过在从波长空间到k空间内插SD-OCT数据之后进行傅立叶变换，能够将SD-OCT数据转换成轴向结构数据。例如，如果分光计2450具有近似0.1nm的分辨率，则总的SD-OCT测距深度可以大于大约2.0mm。使用SD-OCT技术的轴向图像分辨率可以近似为5μm。
在图25中示出了示范性SECM/SD-OCT探针的示意性概述。这个探针类似于如图15所示的探针，并且进一步包括配置成提供SD-OCT射束路径的装置。为了获得SD-OCT射束，OCT光纤2500能够与SECM光纤2510一起插入到内套中。OCT光纤2500能够配置成照射小透镜2520。能够选择用于SD-OCT射束的共焦参数和斑点尺寸，以实现深度范围的横截面成像。共焦参数斑点尺寸的示范性值例如能够分别近似为1.1mm和25μm。SD-OCT透镜2520的NA例如能够被选择为近似0.02，并且SD-OCT射束的准直射束直径例如能够被选择为近似200μm。分色镜2530能够放置在SECM光栅之前，以反射SD-OCT光束2540并透射SECM光束2550。以相对于SD-OCT光束2540近似45度的角度布置图25中示出的分色镜2530。通过在镜2530上使用合适的涂层，能够增加这个角度，这能够允许SD-OCT射束2540交迭SECM射束2550，用于两个图像的更加精确的空间配准。能够通过使用圆柱形元件来校正例如可以由弯曲窗口或气囊产生的SD-OCT射束2540的光学像差，以预补偿如图12B所示的像散。
在图26中示出了可以用于SECM成像和SD-OCT成像两者的导管探针的进一步的示范性实施例。宽带光可以被提供通过单个光纤2600而不是如图25所示的两个分开的光纤2500、2510。使用分色镜2610可以将可以用于形成SD-OCT射束2640的光的一部分反射到SECM射束2650的光路以外。通过孔径2620，和/或通过使用透镜2630来聚焦SD-OCT射束2640，可以减少SD-OCT射束2640的直径。SD-OCT装置还可以用于通过使用SECM技术来定位被成像的组织的表面，甚至其中SD-OCT深度分辨率在大约20-100μm之间。即使SD-OCT射束2640的带宽不足以获得高质量SD-OCT图像，这也能够被执行。
从示范性SD-OCT图像获得的数据能够用于调整SECM射束的焦平面。在图27中示出了图示这种技术的示范性流程图。例如，SD-OCT图像数据可以从深度扫描中获得(步骤2700)并随后被处理(步骤2710)。图像数据可以被分析并显示为SD-OCT图像(步骤2720)。这个图像数据还可以用于例如通过使用边缘检测算法来确定组织表面的位置(步骤2730)。一旦组织的表面位置已被确定，就能够使用可变焦机构来调整SECM装置的焦平面的位置(步骤2740)。能够快速执行这种聚焦控制技术(例如在小于大约100ms内)，这可以允许实时跟踪和聚焦组织表面。使用相对于SECM射束形成的角度，能够校准组织边缘的位置。
在图28中示出了可以与本发明的某些示范性实施例一起使用的示范性导管线缆2800的横截面。线缆2800例如可以包括拉回线缆2810、配置成向马达供应电力的多个线2820、聚焦控制线缆2830、配置成向可膨胀气囊或膜提供气体或其它流体的通道2840、SECM光纤2850和/或SD-OCT光纤2860。
在图29中示出了示范性SECM探针2900的示意性图示。探针2900包括两个棱镜2910，其可以配置成在射束2920穿过光栅2930和成像透镜2940之前使射束2920偏转。这种示范性配置能够为物镜2940在探针2900之内提供更多空间，这能够导致探针2900的更高NA和/或尺寸减少。
使用图30A-30C中示出的示范性探针配置3000，能够实现探针长度的进一步减少。探针3000能够包括内套3010，该内套3010可以在探针3000被传递到成像位置时提供在外套3020之内，如图30A所示。在探针3000被放置并在要被成像的组织或器官之内被置于中心之后，内套3010能够滑动通过外套3020以提供伸出的拉回范围，如图30B和30C所示。例如，在内套3010的中心附近提供成像透镜3020能够在图30B和30C中示出的极端扫描位置处提供增加的位置稳定性。
在图31中示出了示范性外套3100。外套3100能够由刚性材料诸如像不锈钢或塑料制成。它可以包括一个或多个间隙3110，其能够允许光从中穿过以生成图像数据而不会引入光学像差。可选地，间隙3110可以包括透明窗口。
图32示出了根据本发明的某些示范性实施例的示范性探针。探针3200可以提供部件的紧凑配置和小的总体探针尺寸。例如，圆柱形内套3210能够配置成在圆柱形外套3220之内自由地旋转和移动，允许准直透镜3230和光纤3240离开内套3210的中心轴放置。能够在外部进行要被成像的组织的区域的扫描，其中能够使用拉回线缆3250来控制内套3210的运动。
在本发明的某些示范性实施例中，能够在成像透镜和要被成像的组织表面之间的空间中提供液体诸如像水或指标匹配的油。提供这样的液体例如能够改善光学参数如NA和/或减少用于获得图像数据的光束的背反射。
在图33A和33B中示出了能够提供用于获得图像数据的高NA的示范性探针配置3300。例如，内套3310能够提供在外套3320中，外套3320还可以包括未膨胀的气囊3330。未膨胀的气囊3330可以被膨胀，使得它能够从外套3320向前扩展。内套3310然后可以展开在外套3310之外和膨胀气囊3340之内。弹性装置3350能够以压缩配置的方式提供在内套3310和外套3320之间，如图33A所示。弹性装置3350能够配置成当内套3310被展开时对着膨胀气囊3340的内壁安置内套3310，如图33B所示。内套3310能够配置成使用拉回线缆3360来扫描膨胀气囊3340气囊区域外部的组织的区域。线缆3360能够控制内套3310在膨胀气囊3340之内的旋转和纵向平移(例如拉回)。隔离物3370可以用于改善成像光学装置和膨胀气囊3340的壁或相邻组织表面之间的接触。
在图34A和34B中示出了根据本发明的某些示范性实施例的进一步的示范性探针配置3400，其能够对着外气囊3420的内壁维持探针内套3410。例如，能够提供在图34A中示出为未膨胀的外气囊3420和内气囊3430，使得它们包围内套3410。每个气囊可以被膨胀，如图34B所示。在这个示范性配置中，内套3410可以附着到内气囊3430的一个面。通过相对于外气囊3420移动内套3410连同内气囊3430，可以进行内气囊3420之内的旋转和平移扫描。
在图35A和35B中示出了根据本发明的某些示范性实施例的更进一步的示范性探针配置3500，其能够对着外气囊3520的内壁维持探针内套3510。在图35A中示出为未膨胀的外气囊3520可以在要被成像的组织的器官或区域之内被膨胀。在图35A中示出为未膨胀的内气囊3530可以提供在内套3510和外气囊3520之间。内气囊3530可以被膨胀，如图35B所示，并且内气囊3530提供的压力能够用于维持内套3510和外气囊3520的内壁之间的接触，如图35B所示。分别在图34和35中示出的示范性探针配置3400和3500可以被使用而没有外套。可以在能够用于将探针3400、3500传递到预期位置的外部罩的内部包装未膨胀气囊3420、3430、3520和3530。这样的外部罩能够可选地例如由可分解材料形成。
在图36A-36D中示出了SECM探针3600的示范性配置，其能够提供与器官或气囊圆柱的轴垂直的谱编码线3610。在图36A中提供了这个探针配置的底视图，并且在图36B中示出了相应的侧视图。图36C示出了进一步的侧视图，其中探针套3640在膨胀气囊3650之内被展开，与图33B中示出的类似。在这个示范性配置中，纵向(例如拉回)方向能够是主要扫描方向，使得探针套3640以相对快的速率在这个纵向方向上移动。与纵向速度相比，能够以相对慢的速率进行围绕纵轴的旋转方向上的扫描。探针3600能够提供有定位装置，如图33-35中的任何一个所示。探针套3640能够包括镜3620，其可以配置成使光束朝向适当定位的光栅偏转，以提供如图36A和36D所示配置的谱编码线3610。
探针之内SD-OCT和SECM成像装置的组合能够提供有用的设备，用于获得使用不同图像格式的不同标度的结构信息。因为两种成像技术的分辨率是不同的，因此能够同时获取为这两种成像技术获得的数据。然而，用于这两种技术的有用扫描率可能彼此不兼容。例如，使用例如大约1Hz的转速和例如近似1mm/s的纵向拉回速度，能够提供典型的SECM扫描率。用于获得SD-OCT图像数据的典型扫描率能够是在旋转方向上例如近似为50-100Hz，并且在纵向方向上例如近似为0.2-0.5mm/s。
为两种技术恰当采样的可以用于获得全面图像数据的一种技术是在获取SECM数据集之后，适当采样，实施另外的全面SD-OCT扫描。这种技术可以将用于组织区域的数据获取时间增加例如近似1-2分钟。为旋转和线性平移马达获得的编码器信号能够贯穿每次扫描被数字化。通过使SD-OCT图像定量地相关以便为每次扫描确定角度和旋转偏移，能够为气囊位置的转移对编码器信号进行校正。这种技术能够提供大约500μm之内的SD-OCT和SECM数据集的准确空间配准。
在本发明的进一步的示范性实施例中，可以以简略的成像模式(例如“探察成像”)操作例如提供在探针中的成像装置，以确定可以用于传递探针的导管是否恰当地安置在要被成像的器官或组织区域之内。在恰当的导管放置被确认之后，能够获得全面的一组图像数据。
在本发明的更进一步的示范性实施例中，可以使用除了空气之外的光学透明的材料诸如像水、重水(D2O)、油等等使气囊定心导管膨胀。润滑剂也可以用于辅助导管的插入。在本发明的某些示范性实施例中，可以在获得图像数据之前施加黏液去除剂以减少要被成像的器官中存在的黏液量，那里存在的这种黏液会降低图像质量。
前述仅仅表明了本发明的原理。考虑到在此的教导，对所描述的实施例的各种修改和变更对本领域技术人员而言将会是明显的。事实上，根据本发明的示范性实施例的装置、系统和方法，可以与任何OCT系统、OFDI系统、SD-OCT系统或其它成像系统一起使用，并且例如与2004年9月8日提交的国际专利申请PCT/US2004/029148、2005年11月2日提交的美国专利申请No.11/266,779和2004年7月9日提交的美国专利申请No.10/501,276中描述的那些一起使用，这些专利申请的整体内容通过引用结合于此。这样一来，将会意识到的是，本领域技术人员将会设计众多的系统、装置和方法，它们尽管没有在此明确地示出或描述，但却体现了本发明的原理，并从而处在本发明的精神和范围之内。另外，就上面尚未明确地将现有技术知识通过引用结合于此而言，明确地以其整体结合于此。上面引用在此的所有公布都以其整体通过引用结合于此。

Claims (43)

1.一种设备，包括：
至少一个第一装置，其配置成将电磁辐射转送到解剖结构，并且使用所述电磁辐射连续地扫描所述解剖结构的至少一个部分的整个区域，以生成至少一个特定信号，其中所述整个区域具有大于1mm2的面积；以及
至少一个第二装置，其配置成接收所述特定信号，并且基于所述特定信号生成至少一个图像，该图像具有在10μm之下的横向分辨率。
2.根据权利要求1所述的设备，其中，所述整个区域为所述结构的体积。
3.根据权利要求1所述的设备，其中，所述至少一个图像是邻接的，其中没有显著的间隙。
4.根据权利要求1所述的设备，其中，在所述解剖结构的表面上提供所述至少一个部分。
5.根据权利要求1所述的设备，其中，在所述解剖结构的表面之下提供所述至少一个部分。
6.根据权利要求1所述的设备，其中，所述电磁辐射包括多个波长。
7.根据权利要求1所述的设备，其中，所述电磁辐射包括随时间变化的一个或多个波长。
8.根据权利要求1所述的设备，其中，所述至少一个第一装置或所述至少一个第二装置中的至少一个包括显微镜装置，并且其中所述显微镜装置为多光子显微镜装置或共焦显微镜装置中的至少一个。
9.根据权利要求8所述的设备，其中，所述显微镜装置包括谱编码装置。
10.根据权利要求1所述的设备，其中，所述至少一个解剖结构为内部器官。
11.根据权利要求1所述的设备，其中，如下中的至少一个被执行：所述至少一个第一装置经由光纤装置转送所述电磁辐射，或所述至少一个第二装置经由光纤装置接收所述特定信号。
12.根据权利要求11所述的设备，其中，所述光纤装置包括多个电磁辐射引导装置。
13.根据权利要求1所述的设备，其中，所述特定信号与从所述解剖结构接收的电磁辐射的强度的至少一部分相关联。
14.根据权利要求1所述的设备，其中，在探针中提供所述至少一个第一装置。
15.根据权利要求1所述的设备，其中，所述第一装置包括至少一个光学部件，其配置成补偿至少一个光学像差。
16.根据权利要求15所述的设备，其中，所述至少一个光学部件包括弯曲表面。
17.根据权利要求16所述的设备，其中，所述至少一个光学像差为像散。
18.根据权利要求1所述的设备，进一步包括定位装置，其配置成将所述至少一个第一装置或所述至少一个第二装置中的至少一个定位在相对于所述解剖结构的特定位置处。
19.根据权利要求1所述的设备，其中，所述至少一个第一装置进一步配置成将所述电磁辐射的焦点定位在所述解剖结构之内的多个深度处。
20.根据权利要求1所述的设备，进一步包括至少一个第三装置，其配置成：
生成进一步的信号；
基于所述进一步的信号，确定与所述解剖结构相关联的特定片段的至少一个位置；以及
基于所述进一步的信号，控制所述至少一个电磁辐射的焦点向所述解剖结构之内的进一步的位置的移动或定位中的至少一个。
21.根据权利要求20所述的设备，其中，所述进一步的信号为所述特定信号。
22.根据权利要求21所述的设备，其中，所述进一步的信号为干涉测量信号、飞行时间信号或电磁辐射的强度中的至少一个。
23.根据权利要求20所述的设备，其中，所述进一步的信号与所述解剖结构的区域之内的至少一个位置和所述至少一个第一装置的至少一个部件之间的至少一个距离相关联。
24.一种设备，包括：
至少一个第一装置，其配置成将至少一个电磁辐射转送到解剖结构，并且使用所述至少一个电磁辐射扫描所述解剖结构的至少一个部分，以生成至少一个信号；
至少一个第二共焦装置；以及
至少一个第三装置，其配置成将所述至少一个第二共焦装置的焦点的位置作为所述至少一个信号的函数自动地控制到所述解剖结构之内的预定位置。
25.根据权利要求24所述的设备，其中，所述至少一个信号为干涉测量信号、与所述至少一个电磁辐射相关联的飞行时间信号或所述至少一个电磁辐射的强度中的至少一个。
26.根据权利要求24所述的设备，进一步包括：
至少一个第三装置，其配置成接收所述至少一个信号和来自基准的进一步的信号，以生成所述干涉测量信号；以及
至少一个第四装置，其能够生成所述至少一个电磁辐射，其中所述电磁辐射包括多个波长。
27.根据权利要求24所述的设备，其中，所述至少一个第一装置为共焦显微镜装置或多光子显微镜装置中的至少一个。
28.根据权利要求24所述的设备，其中，所述至少一个第一装置包括谱编码装置。
29.根据权利要求24所述的设备，其中，所述至少一个解剖结构为内部器官。
30.根据权利要求24所述的设备，其中，如下中的至少一个被执行：i)所述至少一个第一装置经由光纤装置转送所述电磁辐射，或ii)所述至少一个第二装置经由光纤装置接收所述特定信号。
31.根据权利要求30所述的设备，其中，所述光纤装置包括多个电磁辐射引导装置。
32.根据权利要求24所述的设备，其中，所述至少一个电磁辐射包括多个波长。
33.根据权利要求24所述的设备，其中，所述至少一个电磁辐射包括随时间变化的一个或多个波长。
34.一种设备，包括：
至少一个第一装置，其配置成将至少一个电磁辐射转送到解剖结构，并且使用所述电磁辐射扫描所述解剖结构的至少一个部分以生成数据；以及
至少一个第二装置，其配置成：
a)基于对所述解剖结构的特定片段的至少一个位置的确定来生成信号；以及
b)作为所述信号的函数，相对于所述解剖结构之内的所述至少一个位置，控制所述至少一个电磁辐射的焦点的移动或定位中的至少一个。
35.根据权利要求34所述的设备，其中，在所述解剖结构的表面上提供所述特定片段。
36.根据权利要求34所述的设备，其中，基本上同时地执行操作a)和b)。
37.根据权利要求34所述的设备，其中，所述至少一个第二装置配置成将所述至少一个电磁辐射的焦点定位在所述解剖结构之内的多个深度处。
38.根据权利要求34所述的设备，其中，所述至少一个第二装置控制所述焦点在所述解剖结构之内的深度。
39.根据权利要求34所述的设备，其中，基于干涉测量信号确定所述至少一个位置。
40.根据权利要求39所述的设备，其中，所述干涉测量信号至少部分地基于所述数据。
41.一种用于对解剖结构的区域进行成像的方法，包括：
将至少一个电磁辐射转送到解剖结构；
使用所述电磁辐射连续地扫描所述解剖结构的至少一个部分的整个区域，其中所述整个区域具有大于1mm2的面积；
基于所述电磁辐射获得至少一个特定信号；以及
基于所述特定信号生成至少一个图像，其中所述图像具有在10μm之下的横向分辨率。
42.一种用于在解剖结构之内定位电磁辐射的方法，包括：
将至少一个电磁辐射转送到解剖结构；
使用所述至少一个电磁辐射扫描所述解剖结构的至少一个部分；
基于所述电磁辐射获得至少一个特定信号；以及
基于所述至少一个特定信号将所述至少一个电磁辐射的焦点的位置控制到所述解剖结构之内的预定位置。
43.一种用于在解剖结构之内定位电磁辐射的方法，包括：
将至少一个电磁辐射转送到解剖结构；
使用所述至少一个电磁辐射扫描所述解剖结构的至少一个部分；
基于所述至少一个电磁辐射获得数据；
基于对所述解剖结构的特定片段的至少一个位置的确定来生成信号；以及
基于所述信号，相对于所述至少一个位置，控制所述至少一个电磁辐射的焦点的移动或定位中的至少一个。
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