CN101360447A - 通过光谱编码进行光学成像的方法和装置 - Google Patents

通过光谱编码进行光学成像的方法和装置 Download PDF

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CN101360447A
CN101360447A CNA2006800409801A CN200680040980A CN101360447A CN 101360447 A CN101360447 A CN 101360447A CN A2006800409801 A CNA2006800409801 A CN A2006800409801A CN 200680040980 A CN200680040980 A CN 200680040980A CN 101360447 A CN101360447 A CN 101360447A
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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

可以提供根据本发明的示例性实施方案的方法、设备和装置来获得与例如解剖结构的一部分的样本相关联的信息。可以使用第一数据和第二数据产生该信息，第一数据可以基于从样本上的位置获得的信号，第二数据可以通过组合从样本接收到的第二信号和第三基准信号来获得。还可以基于该信息产生样本的一部分的图像。例如，第一数据可以与光谱编码显微数据相关联，第二数据可以与光学相干断层扫描数据相关联。

Description

通过光谱编码进行光学成像的方法和装置
相关申请的交叉引用
本申请基于2005年9月29日提交的序列号为60/721,802的美国专利申请，并要求该美国专利申请的优先权，其全部内容通过引用包含于此。
技术领域
本发明涉及通过光谱编码对上皮器官和其它生物结构进行综合光学成像的设备和方法。
背景技术
例如X光计算断层扫描(“CT”，computed tomography)、磁共振成像(“MRI”，magnetic resonance imaging)和超声波的放射技术能够在器官级别进行人类病理的无创性显像。虽然这些模式能够识别大面积的病理，但是癌症的诊断可能需要对超出传统成像技术的分辨率的显微结构进行评价。因此，为了诊断可能需要活组织检查和组织病理学检查。因为癌前生长和早期癌症经常以微观规模出现，所以对识别和诊断提出了相当大的挑战。传统的对这些病理的筛选和监控依赖于对苏木精和曙红(“H&E”，Hematoxylin and Eosin)染色玻片的不可控的活组织检查和形态分析。虽然这种方法被视为显微诊断的现行标准，但是这种方法需要切下患者的组织并且需要相当长的处理时间来得到玻片。更重要的是，组织病理学固有地是一种点采样技术；常常只能切除病变组织非常小的一部分，并且经常病理学家仅可能检查不到1％的活组织检查样本。
从存活的人类患者的整个器官或者生物系统获得显微诊断可能更理想。然而，合适的成像技术的缺乏可能大大限制了筛选肿瘤前病况(例如组织变形)和异常结构的选择。另外，无法就地识别异常结构区域和癌区域导致例如前列腺、结肠、食道和膀胱等的随机活组织检查的筛选方法，这是非常不理想并且非常无选择性的。通过能够在显微标度对大的组织体积进行快速成像的诊断方式可以改进当前称为冰冻切片检查的许多诊断工作，例如肿瘤手术切缘的描绘。可以填补病理学和放射医学之间的这种空隙的技术将大大有利于患者管理和健康护理。
已经取得了技术进步来提高例如显微CT(micro-CT)、显微PET(micro-PET)和磁共振成像(“MRI”)显微术等无创性成像技术的分辨率。这些技术已经达到了接近20μm的分辨率，但是基本的物理限制可能仍然阻碍这些技术在患者中的应用。近来，对于不切除组织的病理学诊断，就地执行的显微光学活组织检查技术取得很大进步。由于反射共焦显微术(“RCM”，reflectance confocal microscopy)能够在没有组织接触的情况下测量显微结构并且不需要施用外部造影剂，因此尤其适合对患者的无创显微检查。RCM可以排除焦点未对准的光并且检测选择性地源于组织内的单个平面的反向散射光子。可以例如通过在平行于组织表面的平面上快速扫描聚焦的电磁辐射束来实现RCM，从而产生组织的横断面或者正面图像。可以在RCM中使用的大数值孔径(NA，numerical aperture)可以产生非常高的空间分辨率(1～2μm)，能够使亚细胞结构可视化。然而，高NA成像可能对光通过不均匀的组织传播时所产生的像差(aberration)特别敏感。此外，使用RCM的高分辨率成像一般限于大约100～400μm的深度。
已经广泛证明RCM是可行的用于皮肤组织的成像技术。内窥式共焦显微系统已很难得到发展，这至少部分是由于使扫描显微镜小型化时所遇到的实际技术挑战。将共焦显微术的原理直接应用于内窥镜检查的一个主要障碍是在小直径软探头的远端将聚焦的束快速光栅化的机制的设计。已经提出了多种方法来解决该问题，包括使用远端微机电系统(“MEMS”，micro-electromechanical system)束扫描设备和单模光纤束的近端扫描。此外，RCM仅可以提供仅在离散位置的显微图像——“点采样”技术。如目前所实现的，点采样是RCM固有的，这是因为其具有与活组织切片检查的视场相当或者小于活组织切片检查视场的有限视场，而且对于综合大场显微成像速率可能太慢。
使共焦显微术适用于内窥式应用的另一个挑战可能包括可以用来进行光学切片的高NA物镜的小型化。这种小型化可以通过设置渐变折射率透镜(gradient-index lens)系统、双轴物镜或者定制设计的微型物镜来实现。例如，可以使用耦合到微型物镜的光导纤维束体内获得宫颈上皮组织的详细图像，可以使用例如可以从Olympus Corp.和Pentax/Optiscan获得的商用仪器来获得基于荧光的结肠直肠损伤的图像。
尽管有了这些进步，但是还存在可以在大的区域上就地提供生物结构的显微分辨率的改进的成像技术的需要。
发明内容
本发明的目的之一是克服现有技术的系统和方法(包括上面描述的系统和方法)的某些不足和缺点，并且提供能够提供例如解剖结构、上皮器官或者其它身体组织的样本的综合显微光学成像的方法和设备的示例性实施方案。
例如，可以提供根据本发明的示例性实施方案的能够提供与样本相关联的信息的设备。该信息可以基于与样本区域相关联的第一数据以及与从样本和基准信号获得的第二信号相关联的第二数据。该区域的长度可以小于大约10微米。使用该信息可以产生该区域的二维或者三维图像。可选地，可以基本同时获得第一和第二数据，并且它们可以各自与样本上的共同的位置相关联。
可以以探头或者单个罩的形式提供设备。在本发明的示例性实施方案中，设备可以包括：定位装置，其被配置为基于第一和/或第二数据将探头或者罩相对于样本定位在特定位置处。例如光学部件的特定公共部件可以用于获得第一和第二数据。这些公共部件可以包括例如光或者其它辐射的源和/或检测器。
在本发明的示例性实施方案中，第一数据可以包括共焦显微信息，共焦显微信息包括例如反射共焦显微信息和/或光谱编码显微信息。第二数据可以包括光学相干断层扫描信息。具有多个波长和/或可以随着时间变化的波长的光源可以用于获得第二数据，第二数据还可以基于从样本和基准样本获得的信号之间的干涉。
在本发明的特定示例性实施方案中，设备可以被配置为基于第一和/或第二数据控制探头或者罩相对于样本的位置。
在本发明的又一示例性实施方案中，可以使用第一和第二数据产生分离的图像，这些图像可以基于与第一和第二数据相关联的样本上的位置而彼此相关联。
例如，根据本发明的示例性实施方案的设备可以包括：聚焦装置，其能够控制与共焦显微信息、光谱编码显微信息和/或光学相干断层扫描信息相关联的焦距和/或焦点位置。
结合所附权利要求，在阅读以下对本发明的实施方案的详细说明时，本发明的其它特征和优点将变得明显。
附图说明
从以下结合示出本发明的说明性实施方案的附图进行的详细说明，本发明的其它目的、特征和优点将变得明显，在附图中：
图1是示例性光谱编码共焦显微(SECM，spectrally encoded confocalmicroscopy)系统的示意图；
图2A是使用单模源和单模检测(SM-MM)配置在活体外从组织表面100μm获得的猪肠上皮的示例性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例性SECM图像；
图2C是猪肠上皮的SECM图像的放大视图；
图3A是以50μm的成像深度压迫肠壁之后在活体外获得的猪肠上皮的示例性SECM图像；
图3B是以100μm的成像深度压迫肠壁之后在活体外获得的猪肠上皮的示例性SECM图像；
图4是示例性SECM设备的示意图；
图5是USAF表的示例性SECM图像；
图6A是以1x的放大倍率显示的基于从镜头纸样本采集的数据的示例性SECM图像；
图6B是以4.5x的放大倍率显示的基于从镜头纸样本采集的数据的示例性SECM图像；
图6C是以16.7x的放大倍率显示的基于从镜头纸样本采集的数据的示例性SECM图像；
图6D是以50x的放大倍率显示的基于从镜头纸样本采集的数据的示例性SECM图像；
图6E是以125x的放大倍率显示的基于从镜头纸样本采集的数据的示例性SECM图像；
图7是在五个不同的焦点位置从镜头纸样本获得的一系列示例性SECM数据以及通过合成五个独立的图像的数据而产生的合成图像；
图8A是以1x的放大倍率显示的基于从猪肠组织切片采集的数据的示例性SECM图像；
图8B是以4x的放大倍率显示的基于从猪肠组织切片采集的数据的示例性SECM图像；
图8C是以20x的放大倍率显示的基于从猪肠组织切片采集的数据的示例性SECM图像；
图8D是以40x的放大倍率显示的基于从猪肠组织切片采集的数据的示例性SECM图像；
图9是能够对大的组织体积进行成像的示例性SECM系统的示意图；
图10是根据本发明的示例性实施方案的可以用来成像的示例性导管的远端的示意图；
图11是根据本发明的示例性实施方案的包括外部转动扫描设备的可以用来进行成像的示例性导管的远端的示意图；
图12A是弧形窗和发散柱面透镜的光学效果的示意图；
图12B是使用弧形窗进行像散像差(astigmatic aberration)校正的示意图；
图13A是可以用于通过在焦深(focal depth)范围内步进来获取所希望的深度范围的示例性技术的图示；
图13B是可以用于通过主动调节焦平面在特定深度对组织进行成像的示例性技术的图示；
图14A是双重双压电晶片压电弯曲(dual bimorph piezoelectricbender)的示意图；
图14B是使用弯曲致动器电机可以在透明外壳内移动的示例性设备的示意图；
图15是被配置为通过平移准直透镜来控制聚焦的示例性气囊导管设计的示意图；
图16是特定可变焦透镜的照片；
图17A是具有透明圆柱体形式的圆柱体形内壳体设计的示意图；
图17B是包括透明窗的圆柱体形内壳体设计的示意图；
图17C是在壳体壁上包括几个开口的圆柱体形内壳体设计的示意图；
图17D是在壳体和电机之间的连接部处包括开口的圆柱体形内壳体设计的示意图；
图18是示例性成像系统的部件之间的电连接和数据连接的示意图；
图19A是光束快速转动、同时沿轴向缓慢移位以提供空间成像图案的示例性探头扫描图案的图示；
图19B是光束快速转动、然后沿轴向重新定位的示例性探头扫描图案的图示；
图19C是光束沿轴向快速扫描、然后沿转动方向重新定位的示例性探头扫描图案的图示；
图19D是光束在覆盖圆形组织区域的同心圆路径上扫描的示例性探头扫描图案的图示；
图20A是包括位于壳体远端的引导线设备的快速交换气囊导管设计的示意图；
图20B是包括位于壳体的远端并且具有二次通道的形式的引导线设备的快速交换气囊导管设计的示意图；
图20C是包括位于壳体的近端并且具有二次通道的形式的引导线设备的快速交换气囊导管设计的示意图；
图21A是用于定位包括插入的引导线的配线气囊导管的示例性技术的第一步骤的示意图；
图21B是包括在引导线上放置气囊导管的用于定位配线气囊导管的示例性技术的第二步骤的示意图；
图21C是包括在气囊导管中放置光学设备的用于定位配线气囊导管的示例性技术的第三步骤的示意图；
图22A是包括被配置为将膨胀材料从远程位置递送到气囊中的单一通道的示例性气囊导管的示意图；
图22B是包括两个外壳的示例性气囊导管的示意图，其中可以在外壳之间提供膨胀材料；
图23A是具有配线框(cage)形式的中心对准设备的示意图，其中该设备包含在外壳之内；
图23B是具有配线框形式的中心对准设备的示意图，其中该设备部分从外壳中突出；
图23C是具有配线框形式的中心对准设备的示意图，其中该设备完全从外壳突出；
图24A是包括波分复用器和色散补偿器的示例性SECM/SD-OCT系统的示意图；
图24B是可以使用线性CCD阵列的SECM/SD-OCT系统提供的示例性光谱的示意图；
图25是示例性SECM/SD-OCT探头的示意图；
图26是包括用于SECM和SD-OCT设备两者的单个光纤的示例性SECM/SD-OCT探头的示意图；
图27是可以用于使用SD-OCT数据针对SECM图像调节焦点的技术的示例性流程图；
图28是示例性导管线缆的横截面的示意图；
图29是包括可以提供更紧凑的探头配置的光束偏转光学设备的示例性探头的示意图；
图30A是示出将探头递送到要成像的位置时的探头的紧凑配置的平移扫描技术的示意图；
图30B是示出探头的内壳体位于平移范围的远端极限的平移扫描技术的示意图；
图30C是示出探头的内壳体位于平移范围的近端极限的平移扫描技术的示意图；
图31是包括透明开口的外壳体的示意图；
图32是包括偏离中心的准直光学设备并且被配置为提供外部转动扫描的示例性紧凑探头的示意图；
图33A是包括前向可膨胀气囊和被配置为在与气囊的内壁相接触的同时进行扫描的探头的示意图；
图33B是与膨胀的气囊的内壁相接触的图33A所示探头的示意图；
图34A是包括可以被配置为在探头和膨胀时的外气囊的壁之间保持接触的外可膨胀气囊和内可膨胀气囊的示例性探头的示意图；
图34B是图34A所示的探头的示意图，其中膨胀的内气囊设置在探头周围并且被配置为在探头和膨胀的外气囊之间保持接触；
图35A是包括可以被配置为在探头和膨胀时的外气囊的壁之间保持接触的外可膨胀气囊和内可膨胀气囊的又一示例性探头的示意图；
图35B是图35A所示探头的示意图，其中膨胀的内气囊设置在探头和外气囊之间并且被配置为在探头和膨胀的外气囊之间保持接触；
图36A是被配置为在与可膨胀气囊的内壁相接触的同时沿着回程轴进行扫描的探头的仰视图的示意图；
图36B是图36A所示探头的侧视图的示意图；
图36C是图36A所示探头的侧视图的示意图，其中探头与膨胀的气囊的内壁相接触；以及
图36D是图36C所示的探头的主视图。
在全部附图中，除非另外说明，相同的附图标记和字符用于表示所说明的实施方案的类似的特征、元件、部件或者部分。此外，在参考附图详细描述本发明时，结合说明性实施方案来进行说明。旨在对所描述的实施方案进行变化和变形，而不脱离如所附权利要求所限定的本发明的真正的范围和精神。
具体实施方式
根据本发明的示例性实施方案，提供一种用于内窥式共焦显微术的方法和设备，其绕开探头内小型化、高速扫描机制的需要。光谱编码共焦显微术(“SECM”)是可以使用的波分复用(wavelength division multiplexed)共焦方法。SECM使用宽带宽光源，并且可以对光谱中的一维空间信息进行编码。
图1示出示例性SECM技术。可以用准直透镜110校准来自单模光纤100的输出，然后照亮色散光学元件(例如透射衍射光栅120)，单模光纤100可以位于探头的远端。然后，物镜130可以将每一个衍射的波长聚焦到样品内不同的空间位置，产生横向线聚焦140，其中线上的每一个点的特征在于不同的波长。在从例如可以是生物组织的样品反射之后，光信号可以由衍射元件120重新合成，并且被单模光纤100收集。单模光纤100的芯孔径可以提供能够排除焦点未对准的光的空间滤波机制。在探头外部(可选地在系统控制台内)可以测量返回的光的光谱，并将其转换为作为样品内横向偏移的函数的共焦反射率。可以快速地进行光谱解码。因此，可以通过相对慢的直线机械致动来完成通过沿垂直于线焦点的方向扫描束建立的图像。
SECM技术可以允许内窥式RCM的使用，并且使用高速线性CCD照相机能够以非常高的速率提供图像数据。市场上可获得的线性CCD阵列可以以大于六千万像素每秒的速率获得数据。当包含到SECM分光计中时，这些阵列可以以比一般的摄像速率快大约10倍、直到比一些内窥式RCM技术快100倍的速度产生共焦图像。典型的SECM系统的快速成像速率和光导纤维设计可以允许通过内窥式探头实现综合的大面积显微术。
使用光学相干断层扫描(“OCT”，optical coherence tomography)的技术和其各种变化可以用于进行综合构造筛选。在波长域而不是在时间域中获取OCT信号可以对成像速度提供呈数量级的改进，同时保持良好的图像质量。使用光谱域OCT(“SD-OCT”)技术，通过检测组织样本和基准之间的光谱分辨的干扰，可以在生物组织中进行高分辨率测距。因为SD-OCT系统可以利用与SECM系统相同的高速线性CCD，SD-OCT系统也能够以六千万像素/秒的速度捕获图像，这大约是传统的时域OCT(“TD-OCT”)系统的两个数量级倍。使用这种获取速率和分辨率，SD-OCT系统可以在临床环境中提供构造级别的大体积的显微术。
示例性SD-OCT系统和SECM系统提供的信息可以是互补的，使用两种技术的混合平台可以提供准确的诊断可能必需的组织的构造和细胞结构的信息。虽然完全不同的技术的组合一般需要大量工程并且可能产生性能折衷，但是SECM系统和SD-OCT系统可以共享关键部件，并且可以提供高性能的多模式系统而基本不增加各个系统的复杂性或者成本。
根据本发明的特定示例性实施方案的SECM系统可以使用波长扫描(wavelength-swept)1300nm源和单元件光电检测器来获得作为时间的函数的光谱编码信息。使用这种系统，可以在400μm的视场(“FOV”，field of view)上以具有高的横向分辨率(1.4lμm)和轴向分辨率(6μm)的直到大约30帧/秒的速率获取图像。用高速系统在活体外对新切除的猪十二指肠的段的图像进行成像，以说明SECM系统识别可以在特异性肠组织变形(“SIM”，specialized intestinal metaplasia)或者巴雷特食管(Barretts esophagus)的组织变形改变中发现亚细胞结构的能力。
图2A～2C示出使用两种成像模式以及相应的光纤配置：单模照明单模检测(“SM-SM”)和单模照明多模检测(“SM-MM”)，在活体外获得的猪肠上皮的示例性SECM图像。图2A中的SM-SM图像示出使用单模源和单模检测的位于距组织表面100μm的上皮结构。图2B所示的使用单模源和多模检测(SM-MM)以1∶4的芯：孔径比获得的同一组织区域的图像具有更光滑的外观，并且因为散斑噪声的减小更容易解释该图像。图2C是图2B所示的图像的放大视图，表示存在包含反射不足的芯(例如，固有层或者“lp”)的绒毛和更高散射的柱状上皮。图2C示出在柱状细胞的基部处可视的与细胞核一致的亮图像密度(用箭头示出)。
使用膨胀的气囊使用OCT技术在活体内成像的食管壁的厚度减小了例如大约两倍。图2A～2C所示的猪肠样本的厚度减小相同的量，并且很好地保留了使用SECM技术观察到的亚细胞特征。图3A和3B分别示出在50μm和100μm的深度获得的该变薄的样本的图像。
观察到商用800nm激光扫描共焦显微镜的穿透深度与使用1300nmSECM系统所获得的穿透深度相比减小了大约20％。该减小了的穿透率可能是增大了的更短波长的源的散射的结果。因此，使用840nm源的SECM系统可以提供充分的穿透率来识别例如肠上皮的亚细胞结构。
图4示意性地示出根据本发明的特定示例性实施方案的被配置为提供综合SECM图像的设备。该示例性设备可以被配置为从近似为食管远端的尺寸的长度为2.5cm、直径为2.0cm的圆柱状样本获得图像。中心波长在800nm并且带宽为45nm的光纤耦合2.0mW超发光二极管(QSSL-790-2，qPhotonics，Chesapeake，VA)可以被配置为照亮50/50单模光导纤维束分离器405。可以用准直器410校准通过分离器的一个部分传输的光，该光通过光纤412传输到聚焦设备415以及包括光栅420(1780lpmm，Holographix，LLC，Husdon，MA)和焦距f为4.5mm、通光孔径为5.0mm、NA为0.55的350230-B非球面透镜425(Thor Labs，Inc.，Newton，NJ)的光栅透镜对。这种配置能够在圆柱状样本的内表面上产生聚焦的光谱编码斑点430的500μm的纵向线性阵列或线。光栅透镜对可以通光壳体440附着到电机435(例如，从MicroMo Electronics，Inc.，Clearwater，FL获得的1516SR、15mm直径的电机)的轴上。当电机435转动时，光谱编码线可以在圆柱状样本的内圆周上进行扫描。例如使用计算机可控的线性模组(linear stage)445(例如从Melles Griot，Rochester，NY获得的Nanomotion II，2.5cm range)，在电机435转动过程中电机435、壳体440和光栅透镜对可以沿着圆柱状样本的纵轴平移。该过程产生对圆柱状样本的整个内表面的螺旋扫描。
从样本反射的光可以通光光学系统传输回单模光纤412中，光纤412将其提供给分光计450和例如包括2048像素并具有30kHz的线速率的线性CCD 455(例如从Basler Vision Technologies，Exton，PA获得的BaslerL104K)。计算机460可以用于存储、分析并显示分光计450和CCD 455提供的图像数据。可以将每次电机转动大约60000点(0.5Hz或者30rpm)数字化以提供大约1.0μm的圆周采样密度。电机的纵向速度近似为0.25mm/s，对圆柱状样本进行一次完整扫描所需的时间是大约100秒。
光栅透镜对上的准直光束的1/e2直径大约是4.0mm。其结果是，该示例性设备的有效NA近似为0.4，这对应于近似为1.2μm的理论斑点直径和近似为2.5μm的共焦参数。在没有光学像差的系统中，样本的理论光谱分辨率是0.8埃，其可以在光谱编码线430上产生多达大约630个可分辨的点。可以将检测臂中的分光计450设计为超过探头的预测光谱分辨率。
图5示出使用这种设备获得的1951 USAF分辨率图的SECM扫描。分辨出该图中以2.2μm分开的最小的条。测得使用通过焦点扫描的镜获得的横断线扩展函数的半峰全宽(“FWHM”，full-width-half-maximum)和轴向FWHM函数分别是2.1μm和5.5μm。观察到视场大约为500μm。这些测量值略微低于相应的理论值，这是由于光路中的像差。这些参数表示这里描述的示例性设备能够对在生物组织中使用共焦显微术提供充分的分辨率。
图6示出2.5cm的假样品的完整回程图像的示例性SECM图像数据。在生成所显示的这些图像之前，将极坐标转换为直角坐标。使用附着到2.1cm内径的特氟隆(Teflon)管的内表面的镜头纸制成该假样品。在图6A所示的低放大倍数图像中，可以观察到包括褶皱和孔隙的纸显微结构。可看到的圆形条纹可能是由于较低的谱功率和存在于光谱编码线的末端或者光谱编码线的末端附近的透镜像差所产生的。如图6B～6E所示，在以较高的放大倍数呈现的该数据集的区域中可以清楚地分辨出各个纤维和纤维的显微结构。
通过调节图4A中的聚焦设备415，在120μm的范围上在五个离散的焦深处获取该假样本的圆柱二维(“2D”)图像。然后，对图7所示的这五个图像710～750求和以建立合成图像，这证明几乎完全覆盖了假样本的表面。
使用例如这里描述的SECM设备对生物样本进行成像可能由于缺少光学扫描头的中心对准装置而变得复杂。为了对生成宽区域显微图像和数据提供进一步的改进，将猪肠样本放置在2.0cm直径的透明圆筒的顶部。图8A示出在1秒内获取的对该样本的360°扫描。很可能仅在圆柱扫描的一个区段中显示所成像的组织，这是因为没有将探头放置在中心，而且样本没有完全包裹圆筒。图8B～8D示出该组织样本的示例性放大区域的序列。图8B所示的图像是图8A中的虚线矩形给出轮廓的1.5cm区段的展开。类似地，图8C中的图像表示在图8B中给出轮廓的矩形的展开，图8D中的图像表示在图8C中给出轮廓的矩形的展开。图8B的图像中的组织的放大图像暗示有腺体结构。图8C～8D中的放大图像显示与如图2和3所示的使用1300nm SECM系统观察到的绒毛和核特征类似的绒毛和核特征。图8A中的SECM扫描的其它区域显示包括来自透明圆筒的镜面反射和完全的信号遗失的人为现象，这两者可能都是由聚焦的SECM束的不正确定位所引起的。
对患者执行综合共焦显微术可能遇到各种技术挑战。这些挑战包括例如提高成像速率、使探头的光学部件和机械部件小型化、引入中心对准机制以及实现用于动态地改变焦平面的技术。
与上面描述的示例性系统相比，SECM系统的图像获取速度可以提高例如2～4倍。可以通过提供某些变形来实现这种改进。例如，更高功率的半导体光源(例如Superlum Diode，T-840HP：25mW，840nm，100nm光谱带宽)可以提供例如大约1000个光谱可分辨的点。这种光功率的增大可以提高灵敏度，并且更大的带宽可以加宽视场，从而使得可以以大约快两倍的速度扫描SECM束。此外，使用例如OC-3-850(Optics forResearch，Caldwell，NJ)的光学循环器可以提高传送到探头以及从探头收集的光的效率。使用例如具有2048像素和60kHz读出速率的AVIIVAM4-2048(Atmel Corporation)的更快、更灵敏的线性CCD可以在用于生成图像数据的整个波长范围上提供数据获取速度的两倍增加以及改善的光谱响应。使用例如能够以大约120MB/s的速率将数据从照相机传送到用于进行存储的硬驱动阵列的Camera Link接口也可以改善性能。
可以被理解为是指最小可检测反射率的灵敏度是可以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，可以在直到大约300μm的深度从皮肤反射大约为10-4到10-7的入射光部分。基于在这里描述的根据本发明的特定示例性实施方案的示例性系统中使用的物镜的NA以及对皮肤比非角质化上皮粘膜更大地削弱光的观察，这里描述的示例性SECM探头物镜可以收集从组织内深处反射的大约3×10-4至3×10-7的照明光。可以将25mW的光源分离为例如大约1000个独立的光束。估计最大双程插入损耗(double pass insertion loss)是大约10dB(其包括来自探头的6dB损耗和来自光导纤维和分光计的4dB损耗)。因此，基于估计的这些参数，对于每一个线合成过程，阵列中的每一个像素可能被大于50到50,000个的光子/像素照亮。
使用多模检测技术，可以获得10倍的信号增益，从而对这种配置产生近似为每次扫描500到500000个光子/像素。如果信号在以近似为240个光子出现的暗电流波动以上，则例如Atmel A VIIVA M4照相机上的每一个像素可以可靠地检测光。如果该设备在这些波长处具有近似为50％的量子效率，则可以以近似为每次扫描480光子/像素产生最小可检测信号。基于这些近似，Atmel照相机有充分的灵敏度以允许在更深的组织深度进行SECM成像。通过使用多模光纤进行收集或者通过增大源功率，可以实现对预测的最小反射率的量子噪声限制检测(quantumnoise-limited dectection)。
图9示出根据本发明的特定示例性实施方案的能够对上皮器官进行大面积显微成像的设备的示意图。可以是宽带光源或者波长扫描光源的光源900可以提供通过循环器910或者可选地通过光纤分离器传输的光。然后，通过扫描机构920将光传输到成像导管930。可以在导管外部或者在导管内部进行扫描。在特定优选示例性实施方案中，可以在导管外部进行回程扫描，而在导管内部进行转动扫描。如果使用宽带光时，可以用例如是分光计的检测器940检测所收集的反射光。如果使用波长扫描光源时，检测器940也可以是例如单检测器。计算机950可以对检测器940提供的数据进行处理、显示和/或保存，计算机950还可以被配置为对扫描过程进行控制和同步。
筛选大的内腔器官优选利用：将导管的远端部分放置在内腔内的中心，以相对于组织提供一致的聚焦距离和/或深度；以及在几厘米的长度上快速获取圆周图像。可以通过在中心对准装置内包含圆周扫描成像探头来满足这些标准。如果位于中心对准装置的中部或者中心对准装置的中部附近的成像光学设备可以提供几个附加优点，例如包括：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，这可以大大减小可能出现的人为运动现象。
图10示出根据本发明的特定示例性实施方案的SECM导管的远端的示意图。可以通过光纤100提供光，可以用光纤卡盘1005固定光纤1000，然后使用准直透镜1010校准光。然后，该光通过可变聚焦机构1015和柱面透镜1020，可变聚焦机构1015和柱面透镜1020可以被配置为预先补偿光路以针对像散效应进行校正。然后，通过衍射光栅1025衍射光，衍射光栅1025可以被配置为将光的中心波长衍射衍射例如90度，然后成像透镜1030将光聚焦在光谱编码线1035上。
可以通过增大与光纤1000相关联的针孔孔径的直径使用多模检测来减小斑点人为现象。这种技术可以提供提高了的信号产量以及斑点人为现象的减少，而空间分辨率仅略微降低。双包层(double clad)光纤可以用于实现用于进行光谱编码的这种技术，其中单模芯可以照亮组织，多模内包层可以检测反射光。
成像透镜1030优选具有相对大的工作距离，例如可以是大约2～7mm，并且保持大约0.25到0.5的大的NA。另外，成像透镜1030可以薄，优选不超过大约5mm厚。可以使用例如非球面或者消色差透镜的传统透镜作为成像透镜。
内壳体1040可以围绕各个光学部件和电机1045中的一部分或者全部，并且允许在外壳体1060内纵向定位这些部件。内壳体1040可以包括具有良好的光学传输特性和低波前失真的部分，以允许进行高质量的成像，同时仍保持结构刚度(rigidity)以保持电机轴1050在探头的中心。可以用来形成作为内壳体1040的一部分或者全部的透明窗的材料例如可以包括例如玻璃或者塑料材料，例如Pebax和高密度聚乙烯(HDPE，high-density polyethylene)。
外壳体1060可以围绕内壳体1040，并且可以被配置为使用中心对准机构1065保持在相对于成像组织1080的固定位置。外壳体1060的壁上的开口可以允许回程线缆1065移动内壳体1040。通过将内壳体1040附着到计算机可控的平移器(例如可以由Newport Corp.，Irvine，CA提供的平移器)同时相对于要成像的组织1080将外壳体1060保持在固定位置，可以进行线性扫描。可以使用这种回程技术例如来获得纵向食管OCT图像。外壳体1060的全部或者一部分可以是透明的，以允许通过其传输光。外壳体1060的透明部分的光学特性可以类似于内光学窗1055的光学特性。
可以在转动壳体1070中容纳柱面透镜1020、衍射光栅1025和成像透镜1030，转动壳体1070可以附连到电机轴1050。可以使用传统的电机1045，其具有大约1.5mm或者更小的直径。使用编码器可以改善图像质量和配准(registration)，也可以将电机1045的直径增大到大约6～10mm。例如，可以由(MicroMo Electronics，Inc.(Clearwater，FL)提供这种电机。可以使电机配线的尺寸最小化以限制对设备的视场的阻挡。可以通过使用电机1045经由电机轴1050在内壳体1040内使转动壳体1070转动来进行圆周扫描。
图11示意性地示出根据本发明的特定示例性实施方案的导管，该导管被配置为由导管远端外部提供内壳体1040相对于外壳体1060的转动。可以通过光学转动接合部1100传输转动运动，光可以耦合到转动光学光纤1110中。转动接合部还可以经由一个或多个电线1120保持电接触，并且经由可被配置为控制回程和聚焦机构的可转动回程线缆1030保持机械接触。在图11所示的示例性设备配置中，内壳体1140不包围电机，因此内壳体1140可以更小并且更轻。
柱面透镜可以用于针对可能由气囊或者另一个中心对准装置的壁和/或由内和/或外壳体的透明窗或者透明部分建立的散光效应进行校正。弧形玻璃可能包括与发散柱面透镜的散光形式类似的散光。例如，图12A所示的两个弧形透明壁引起的散光在光学上与朝该图的右侧所示的发散柱面透镜类似。通过图12A所示的物体中的任意一个的中心虚线的光具有比通过上或者下虚线的光短的路径，这导致引起的散光。例如，通过在光路中放置与引起散光的窗类似的弧形窗，可以获得对这种光学失真有效且准确的校正，如图12B所示。校正弧形窗的曲率轴应当垂直于弧形壳体窗的轴以对散光提供光学校正。
在本发明的另一个示例性实施方案中，可以提供一种能够对器官进行综合成像而在获取图像数据期间不需要用户介入的内窥式SECM系统。该系统能够补偿由于例如心跳、呼吸和/或蠕动运动而产生的运动。中心对准机构的使用可以大大减少由要成像的组织的运动所引起的人为现象。例如，成像设备和要成像的组织之间的距离的变化可能在一次综合扫描过程中变化大约±250μm。相对于圆形扫描速度，这种距离变化可能以慢的时间标度(例如在几秒上)发生，但是这种距离变化相对于在成像设备的纵向回程期间扫描要成像的组织区域的长度所需的时间是很显著的。
可以使用根据本发明的特定示例性实施方案的示例性技术来减小或者消除采样期间组织运动的影响。图13A所示的这种技术可以包括用于在更宽范围的焦深上获得图像数据的过程。如果理想的总成像深度例如是200μm并且距成像设备的组织距离的变化例如是±250μm，则可以在大约700μm的焦点范围上获取图像数据。该过程可以保证在整个所希望的组织体积上获得图像数据。虽然在成像时体积图像(volumetric image)的许多部分可能不包含组织，但是很可能从感兴趣的组织体积的大多数区域获得至少一个良好的图像。
图13B示出在成像期间用于补偿组织的运动的第二示例性技术。这种技术可以包括确定成像透镜和要成像的组织的表面之间的距离的过程。可以跟踪该距离，并且可以自适应地控制透镜的聚焦，以在整个获取感兴趣的组织体积的图像数据期间提供相对于组织表面的已知焦距。自适应聚焦可以减少所需要的焦点扫描的数量，因此，还可以减少获得对感兴趣的组织体积的全面覆盖所需的时间。可以使用例如干涉测量(interferometric)信号、飞行时间(time-of-flight)信号、电磁辐射强度等等来控制光束的聚焦。
上述针对要成像的组织的运动的示例性技术可以利用用于调节成像设备的焦距的机制。有几种示例性技术可以用来调节要成像的组织体积内的焦深。例如，可以相对于外壳体移动包括聚焦透镜的成像设备的内壳体。为了获得这种运动，例如可以将图14A所示的多层的双压电晶片压电致动器1410(例如D220-A4-103YB，Piezo Systems，Inc.，Cambridge，MA)在两端附连到金属薄片1420，这可以提供陶瓷材料的抗弯力(buckling)。如图14A所示，可以背靠背地放置这些致动器，这可以有效地使其自由运动范围加倍。如图14B所示，可以在外壳1440与包括电机和电机周围的焦点光学部件的组件1450之间布置四个这种致动器1430。利用这些致动器1430，可以通过相对于外壳体1440可控地偏移组件1450在所需要的范围上改变焦距。这种技术可能需要在探头内存在高压、可能横贯并妨碍视场的附件电配线和/或使包含成像设备的探头的总直径增大例如几毫米。
图15示出可以用于调节成像设备的焦距的可选示例性技术。可以设置围绕线缆1530的线缆壳体1510。线缆1530可以在一端附连到准直透镜1540，准直透镜1540可以被配置为相对于壳体1550沿纵向方向可移动。准直透镜1540可以相对于壳体1550和其它光学部件移动以改变焦距。例如，可以使用如图15所示的线缆1530在成像导管外部对这种平移进行控制。可选地，可以由设置在导管内部的电机或者压电电机控制准直透镜1540的运动。还可以通过相对于准直透镜1540移动可以提供用于对组织进行成像的光的光纤1520来改变焦距。可选地，光纤1520和准直透镜1540可以相对于彼此移动以改变焦距。
通过使光纤1520和准直透镜1540之间的间隔改变大约M2Δz的距离而使焦距移动距离Δz，其中M是成像设备的放大因数。例如，示例性成像设备可以具有近似为3的放大因数。为了获得大约±450μm的焦距的变化，需要光纤1520和准直透镜1540之间的距离移动大约±4.0mm，这是使用上述用于改变焦距的技术中的任意一种可以获得的距离。
可以用于改变焦距的另一种示例性技术是利用电子可调可变透镜。例如，可以使用图16所示的在市场上可获得的可以在手机照相机中使用的透镜1600(Varioptic AMS-1000，Lyon，France)来改变根据本发明的示例性实施方案的成像设备的焦距。该透镜1600利用电湿(electrowetting)原理，可以提供大约-200mm到40mm之间的可变焦距，并且具有仅受衍射效应限制的光学品质。该示例性透镜1600的电流有效的通光孔径(CA，clear aperture)是3.0mm，总外径(OD，outer diameter)是10mm。可以生产具有4.0mm CA和6.0mm OD的类似的透镜。该示例性透镜1600的全程响应时间(full-range response time)大约是150ms，这足够快以用来跟踪光学部件和组织表面之间的距离并相应地调节焦距。可以生产具有大约10ms的响应时间的这种类型的透镜。使用例如以上描述的可变透镜的可变透镜，可以在准直器和SECM光栅之间提供例如可以变化大约±300μm或者更大的焦距。
可以对根据本发明的特定示例性实施方案的内壳体提供各种配置。例如，如图17A所示，可以使用由透明材料1700形成的壳体。可选地，如图17B所示，可以提供包括透明窗1710的壳体。还可以提供在两个壁之间包括例如如图17C所示的开口1720的壳体，或者包括例如如图17D所示的附连到壳体的与电机1730相邻的开口的壳体。
在图18中提供可以与图9所示的示例性系统一起使用的控制和数据记录设备的示例性示意图。图18所示的设备可以被配置为在获取成像数据1800的同时记录束位置，这可以对成像数据1800提供更准确的空间配准。如图18所示，可以由数据获取和控制单元1810获取成像数据1800。导管扫描器设备可以扫描束，例如使用转动电机1820提供束的角运动，并且使用回程电机1830纵向移动束。可以由转动电机控制器1840控制转动电机1820，并且由回程电机控制器1850控制回程电机1830。可以使用闭环操作执行这些控制技术中的每一种。数据获取和控制单元1810可以指示电机控制器单元1840、1850提供指定的电机速度和/或位置。可以向电机控制器单元1840、1850二者和数据获取和控制单元1810提供电机1820、1830产生的编码器信号。以这种方式，当获取一行成像数据1800时，可以记录与每一个电机1820、1830相关联的编码器信号，从而允许将准确的束位置与数据1800的每一行相关联。
图19示出可以在根据本发明的示例性实施方案的成像导管中使用的各种扫描优先级。图19A示出作为第一优先级执行转动扫描、作为第二优先级执行轴向(回程)扫描的示例性扫描技术。这种技术可以提供具有螺旋状几何形状的一组数据。在另一种扫描技术中，可以以小的增量执行轴向扫描，旋转一周之后增加一个轴向增量，如图19B所示。可选地，可以作为第一优先级执行轴向(回程)扫描，而作为第二优先级执行转动扫描，其可以产生图19C所示的扫描图案。沿着第一扫描优先级的方向可以获得更好的成像质量。因此，扫描优先级的选择取决于希望横断(转动)图像还是轴向图像。可以以几种方式进行可能具有不同的对称性的其它器官或者组织的成像。例如，图19D示出可以用于对特定器官进行成像的圆形成像图案。
在本发明的又一个示例性实施方案中，例如图10所示的气囊导管的气囊导体可以被配置为允许使用引导线执行快速交换放置过程。在快速交换放置过程中，可以首先将引导线放置在要成像的器官中，然后使导管向下穿过引导线。在许多应用中，该过程可以允许更容易并且更准确地放置导管。各种配置可以用于使用快速交换过程引导导管。例如，图20A示出通过外壳体2040的远端中的孔2010的示例性引导线2000。在图20B所示的第二示例性配置中，引导线2000通过附连到外壳体2040的远端的管2020。可选地，引导线2000可以被配置为通过可以附连到外壳体2040的近端的管2020，如图20C所示。
图21A～21C示出利用导管的中央内腔中的引导线放置导管的示例性过程。首先，如图21A所示，可以将引导线2100放置在器官2150内。接下来，如图21B所示，在引导线2100上穿过导管的外壳体2110以及气囊2120。最后，如图21C所示，可以包含光学设备的内壳体2130向下穿过导管中央内腔，然后可以进行使用光学设备的成像过程。
图22示出气囊导管的两个示例性配置。在图22A中，可以使用包括加压空气或者气体源的装置2200以使气囊2210膨胀。可以设置管或者其它小的通道2230，其连接到包围导管的气囊2210并且允许将加压空气或者气体传送到气囊2210。使用压力计2220监视膨胀的气囊2210内的压力。该压力可以用于优化气囊的膨胀并且通过监视可能与膨胀的气囊2210接触的周围器官内的压力来评价导管的放置。可选地，沿着导管的外壳可以设置通道2240，这可以允许将加压空气或者气体输送到气囊2210，如图22B所示。可以使用能够响应于压力的变化改变直径的气囊，从而可以通过相对于成像透镜改变气囊直径并因此移动周围组织以允许将加压空气或者气体传送到气囊2210来控制焦深。
图23A～23C示出根据本发明的另一个示例性实施方案的可以使用的示例性导管设计。该导管设计可以被配置为使用一个或多个可扩展绞索(wire strand)2300将成像装置的内部光学核心放置到内腔器官内的中央。导管可以包括附加外壳2310和位于设置在外壳体2320周围的外壳2310内的一组可扩展绞索2300，如图23A所示。在放置导管之后，可以将绞索2300推过外壳2310从其末端突出，如图23B所示。可选地，可以使外壳2310从外壳体2320缩回。在外壳体2320周围露出足够长度的绞索2300以允许绞索2300扩展周围器官或者组织，如图23C所示，并且将壳体2320放置在中央。在执行了成像过程之后，可以将绞索2300拉回到外壳2310中，然后可以去除导管。
示例性OCT和RCM技术可以排除或者忽略从要成像的组织样本接收到的多散射光，从而检测可能包含结构信息的单后向散射光子。然而，这些技术中每一种可以以不同的方式排除多散射光。
例如，RCM技术可以利用要成像的组织从精确聚焦的入射光束反射的光的共焦选择。可以通过在平行于组织表面的平面上快速扫描聚焦的光束来实现RCM技术，这可以提供组织的横断面图像或者正面图像。可以与传统的RCM技术一起使用的大的数值孔径(NA)可以产生非常高的空间分辨率(例如大约1～2μm)，这使得可以使亚细胞结构可视化。然而，使用高NA的成像过程可能对光通过不同类的组织传播时所产生的像差特别敏感。此外，使用RCM技术的高分辨率成像一般限于大约100～400μm的深度。
OCT技术可以针对光学切片使用相干选通(gating)原理，而不依赖于高NA透镜的使用。因此，可以使用具有相对大的共焦参数的成像透镜来实现OCT技术。这可以提供更大的到要成像的组织中的穿透深度(例如大约1～3mm)和横截面图像格式。可以以一般在大约10～30μm级别的减小的横断面分辨率为代价来获得这些优点。
因此，根据上述区别，示例性OCT和RCM技术可以提供可能互补的不同的成像信息。例如，RCM技术可以提供亚细胞的细节，而OCT技术可以提供例如构造形态(architectural morphology)。对于组织病理学诊断，来自这两种尺寸体系的成像信息可能是关键的，在许多情况下，如果不可能使用两者，则难以进行准确的诊断。虽然传统上这些完全不同的成像技术的组合可以使用可能产生性能折衷的大量工程努力，但是SECM技术和SD-OCT技术可以共享特定部件。因此，可以提供使用这两种成像技术的高性能的多形态系统，相对于单独使用任一种技术的系统基本不包括复杂性或者成本的提高。
图24A示出根据本发明的示例性实施方案的能够实现SECM技术和SD-OCT技术两者的示例性系统的概略图。在该示例性系统中，宽带光源的带宽的一部分可以用来获得SECM图像数据，可以使用该带宽数据的另一部分来例如获得SD-OCT数据。例如，光源2400可以用来提供带宽大于例如大约100nm的电磁能量。可以用作光源2400的装置包括例如二极管泵浦超速激光器(diode-pumped ultrafast laser)(例如可以从IntegralOCT，Femtolasers Produktions GmbH，Vienna，Germany获得的激光器)或者超发光二极管阵列(其可以从例如Superlum，Russia获得)。
可以使用波分复用器(WDM，wavelength division multiplexer)2410从可以用于SECM数据的光谱的一部分中分离可以用于SD-OCT数据的光源光谱的一部分(例如波长在大约810～900nm之间的光)，并且将其发送到导管2420和基准臂2445。可以向分光计2450提供从导管2420通过SECM光纤2430和SD-OCT光纤2440返回的光。可以配置分光计2450，使得图24B所示的示例性CCD阵列2460的元件中的大约一半可以检测与SECM数据相关联的信号，该CCD元件中的大约一半可以检测与SD-OCT数据相关联的信号。例如，通过从波长空间到k空间对SD-OCT数据进行插值之后进行傅立叶(Fourier)变换，可以将SD-OCT数据转换为轴向结构数据。例如，如果分光计2450具有大约0.1nm的分辨率，则总的SD-OCT测距深度可能大于大约2.0mm。使用SD-OCT技术的轴向图像分辨率可以是大约5μm。
图25示出示例性SECM/SD-OCT探头的示意性概略图。该探头与例如图15所示的探头类似，其还包括被配置为提供SD-OCT束路径的设备。为了获得SD-OCT束，可以将OCT光纤2500与SECM光纤2510一起插入到内壳体中。OCT光纤2500可以被配置为照亮小透镜2520。可以选择SD-OCT束的共焦参数和斑点大小以在深度范围内实现横截面成像。共焦参数和斑点大小的示例值分别可以是例如大约1.1mm和25μm。可以将SD-OCT透镜2520的NA选择为例如大约0.02，可以将SD-OCT束的准直束直径选择为例如大约200μm。可以将分色镜2530放置在SECM光栅之前以反射SD-OCT光束2540并透射SECM光束2550。图25所示的分色镜2530以相对于SD-OCT光束2540大约45度的角度布置。通过在镜2530上使用合适的涂层可以增大该角度，这可以允许SD-OCT束2540与SECM束2550重叠，用于两个图像更准确的空间配准。如图12B所示，可以通过使用柱状元件预先补偿散光来校正例如可能由弧形窗或者气囊产生SD-OCT束2540的光学像差。
图26示出可以用于SECM成像和SD-OCT成像两者的导管探头的又一个示例性实施方案。代替通过如图25所示的两个分离的光纤2500、2510，可以通过单个光纤2600提供宽带光。可以使用分色镜2610将用于形成SD-OCT束2640的一部分光反射出SECM束2650的光路。可以用孔径2620和/或通过使用透镜2630对SD-OCT束2640进行聚焦来减小SD-OCT束2640的直径。甚至在SD-OCT深度分辨率在大约20～100μm之间的情况下，SD-OCT设备也可以用于使用SECM技术来定位要成像的组织的表面。这即使在SD-OCT束2640的带宽不足以获得高品质的SD-OCT图像的情况下也可以实现。
从示例性SD-OCT图像获得的数据可以用于调节SECM束的焦平面。图27示出说明这种技术的示例性流程图。例如，可以从深度扫描获得SD-OCT图像数据(步骤2700)，随后进行处理(步骤2710)。可以作为SD-OCT图像分析并显示该图像数据(步骤2720)。该图像数据还可以用于例如使用边缘检测算法确定组织表面的位置(步骤2730)。在确定了组织的表面位置之后，可以使用可变聚焦机构来调节SECM设备的焦平面的位置(步骤2740)。可以快速地(例如小于大约100ms)执行这种聚焦控制技术，这可以允许实时跟踪组织表面并对组织表面进行聚焦。可以利用相对于SECM束形成的角度对组织边缘的位置进行校准。
图28示出可以与本发明的特定示例性实施方案一起使用的示例性导管线缆2800的横截面。线缆2800例如可以包括回程线缆2810、被配置为对电机提供电力的多个配线2820、聚焦控制线缆2830、被配置为向可膨胀气囊或者隔膜提供气体或者其它流体的通道2840、SECM光纤2850和/或SD-OCT光纤2860。
图29示出示例性SECM探头2900的示意图。探头2900包括两个棱镜2910，棱镜2910可以被配置为在光束2920通过光栅2930和成像透镜2940之前偏转光束2920。该示例性配置可以在探头2900内为物镜2940提供更多空间，这可以产生更高的NA和/或探头2900的尺寸减小。
使用图30A～30C所示的示例性探头配置3000可以获得探头长度的进一步减小。探头3000可以包括内壳体3010，在将探头3000递送到成像位置时，可以将内壳体3010设置在外壳体3020内，如图30A所示。在将探头3000放置在要成像的组织或者器官内的中央之后，内壳体3010可以滑过外壳体3020以提供延伸的回程范围，如图30B和30C所示。例如，在内壳体3010的中央附近设置成像透镜3020可以在图30B和30C所示的极端扫描位置提供提高的位置稳定性。
图31示出示例性外壳体3100。外壳体3100可以由例如不锈钢或者塑料的刚性材料制成。外壳体3100可以包括一个或多个缝隙3110，缝隙3110可以允许光通过以生成图像数据而不引入光学像差。可选地，缝隙3110可以包括透明窗。
图32示出根据本发明的特定示例性实施方案的示例性探头。探头3200可以提供部件的紧凑配置和小的总探头尺寸。例如，柱状内壳体3210可以被配置为在柱状外壳体3220内自由转动和移动，这允许偏离内壳体3210的中心轴地放置准直透镜3230和光纤3240。可以在外部进行对要成像的组织的区域的扫描，其中可以使用回程线缆3250控制内壳体3210的运动。
在本发明的特定示例性实施方案中，可以在成像透镜和要成像的组织表面之间的空间中提供例如水或者折射率匹配油的液体。提供该液体例如可以改善例如NA的光学参数和/或减小用于获得图像数据的光束的背反射。
图33A和33B示出可以提供高NA以获得图像数据的示例性探头配置3300。例如可以将内壳体3310设置在外壳体3320中，外壳体3320还可以包括未膨胀的气囊3330。可以使未膨胀的气囊3330膨胀，使得未膨胀的气囊3330可以向外壳体3320前方扩展。然后，内壳体3310可以在外壳体3310外部、膨胀的气囊3340内展开。如图33A所示，在内壳体3310和外壳体3320之间的压缩配置中可以设置弹性设备3350。弹性设备3350可以被配置为当内壳体3310展开时依靠膨胀的气囊3340的内侧壁定位内壳体3310，如图33B所示。内壳体3310可以被配置为使用回程线缆3360扫描在膨胀的气囊3340外部的气囊区域组织区域。线缆3360能够控制内壳体3310在膨胀的气囊3340内的转动和纵向平移(例如回程)二者。间隔物3370可以用于改善成像光学设备和膨胀的气囊3340的壁或者相邻的组织表面之间的接触。
图34A和34B示出根据本发明的特定示例性实施方案的能够保持内探头壳体3410贴靠外气囊3420的内侧壁的又一示例性探头配置3400。例如，可以设置在图34A中显示为未膨胀的外气囊3420和内气囊3430使得它们包围内壳体3410。如图34B所示，每一个气囊均可以膨胀。在该示例性配置中，内壳体3410可以附连到内气囊3430的一面。可以通过相对于外气囊3420与内气囊3430一起移动内壳体3410来进行外气囊3420内的转动和平移扫描。
图35A和35B示出根据本发明的特定示例性实施方案的能够保持内探头壳体3510贴靠外气囊3520的内侧壁的再一示例性探头配置3500。在图35A中显示为未膨胀的外气囊3520可以在要成像的器官或者组织区域内膨胀。可以在内壳体3510和外气囊3520之间设置在图35A中显示为未膨胀的内气囊3530。如图35B所示，内气囊3530可以膨胀，内气囊3530提供的压力可以用于保持内壳体3510和外气囊3520的内侧壁之间的接触，如图35B所示。可以在没有外壳体的情况下使用分别在图34和35中示出的示例性探头配置3400和3500。可以将未膨胀的气囊3420、3430、3520、3530包裹在外罩(enclosure)内部，外罩可以用于将探头3400、3500递送到所希望的位置。可选地，该外罩可以由例如可分解材料形成。
图36A～36D示出能够提供垂直于器官或者气囊柱体的轴的光谱编码线3610的SECM探头3600的示例性配置。图36A提供该探头配置的仰视图，图36B示出相应的侧视图。与图33B所示出的类似，图36C示出探头壳体3640在膨胀的气囊3650内展开的又一侧视图。在该示例性配置中，纵向(回程)方向可以是主扫描方向，从而探头壳体3640以相对快的速率沿该纵向方向移动。可以以与纵向速度相比相对慢的速率进行围绕纵向轴的转动方向的扫描。探头3600可以设置有例如在图33～35中的任意一个中示出的定位设备的定位设备。探头壳体3640可以包括镜3620，镜3620可以被配置为朝适当定位的光栅偏转光束，以提供如图36A和36D所示的所配置的光谱编码线3610。
探头内SD-OCT和SECM成像设备的组合可以提供使用不同的图像格式以不同的标度获得结构信息的有用设备。因为两种技术的分辨率是不同的，所以可以同时获取针对两种成像技术获得的数据。然而，这两种技术的有用扫描速率可能彼此不兼容。例如，可以使用例如大约1Hz的转动速率和大约1mm/s的纵向回程速度提供典型的SECM扫描速率。用于获得SD-OCT图像数据的典型扫描速率可以是例如转动方向上的大约50～100Hz以及例如纵向方向上的大约0.2～0.5mm/s。
一种用于获得针对两种技术适当采样的综合图像数据的技术是在获取SECM数据集之后，适当采样，进行附加的综合SD-OCT扫描。这种技术可能将针对组织区域的数据获取时间增大例如大约1～2分钟。可以在每一次扫描中将针对转动电机和线性平移电机两者获得编码器信号数字化。定量地相关的SD-OCT图像针对气囊位置的偏移校正编码器信号，以确定每一次扫描的角移位和转动移位。这种技术可以提供大约500μm内的SD-OCT和SECM数据集的准确的空间配准。
在本发明的又一示例性实施方案中，例如设置在探头中的成像设备可以以简化的成像模式工作(例如“侦察(scout)”成像)以判断是否在要成像的器官或者组织区域内正确定位了可以用于递送探头的导管。在确认正确的导管放置之后，可以获得一组综合的图像数据。
在本发明的再一示例性实施方案中，可以使用除了空气之外的例如水。重水(D2O)、油等等光学透明的材料使放置在导管中央的气囊膨胀。还可以使用润滑剂来协助导管的插入。在本发明的特定示例性实施方案中，可以在获得图像数据之前应用粘液去除剂(mucousal removal agent)以减少存在于要成像的器官中的粘液的量，该粘液的存在可能降低图像质量。
前面仅仅说明了本发明的原理。根据这里的启示，所描述的实施方案的各种变形和变化对于本领域技术人员将变得明显。事实上，可以与任意OCT系统、OFDI系统、SD-OCT系统或者其它成像系统，例如在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第11/266,779号以及在2004年7月9日提交的美国专利申请第10/501,276号中描述的系统，一起使用根据本发明的示例性实施方案的设备、系统和方法，这些专利申请的全部内容通过引用包含于此。因此，应当理解，本领域技术人员能够提出大量系统、设备和方法，虽然这里没有明确示出或者描述，但是这些系统、设备和方法实施本发明的原理，因此在本发明的精神和范围之内。另外，虽然上面没有明确地通过引用包含现有技术知识，其全部内容明确地通过引用包含于此。上面引用的所有出版物的全部内容通过引用包含于此。

Claims (21)

1.一种设备，包括：
至少一个第一装置，其被配置为提供与从至少一个样本的至少一个区域接收到的第一信号相关联的第一数据，其中所述区域具有不大于大约10微米的线性尺寸；
至少一个第二装置，其被配置为提供与从至少一个样本接收到的第二信号和从基准接收到的第三信号相关联的第二数据；以及
至少一个第三装置，其被配置为基于第一和第二数据产生其它数据。
2.根据权利要求1所述的设备，其中至少一个第三装置还被配置为基于其它数据产生至少一个二维图像或者三维图像。
3.根据权利要求1所述的设备，其中基本同时获得第一和第二数据。
4.根据权利要求1所述的设备，其中第一和第二数据与至少一个样本上的大约同一位置相关联。
5.根据权利要求1所述的设备，其中第一和第二装置设置在探头或者单个罩中的至少一个中。
6.根据权利要求5所述的设备，还包括：定位装置，其被配置为基于第一数据或者第二数据中的至少一个将探头或者单个罩中的至少一个定位在相对于样本的特定位置处。
7.根据权利要求1所述的设备，其中第一和第二装置包括至少一个公共部件。
8.根据权利要求7所述的设备，其中至少一个公共部件设置在源装置或者检测器装置中的至少一个中。
9.根据权利要求1所述的设备，其中至少一个第一装置被配置为获得共焦显微信息。
10.根据权利要求9所述的设备，其中共焦显微信息是反射共焦显微信息。
11.根据权利要求1所述的设备，其中至少一个第一装置被配置为获得光谱编码显微信息。
12.根据权利要求1所述的设备，其中至少一个第二装置被配置为获得光学相干断层扫描信息。
13.根据权利要求1所述的设备，其中至少一个第二装置被配置为获得与具有多个波长的源装置提供的信号相关联的光学相干断层扫描信息，所述设备还包括：多个检测器，其被配置为基于波长检测第二和第三信号之间的光谱干涉。
14.根据权利要求1所述的设备，其中至少一个第二装置被配置为获得与波长随着时间变化的源装置提供的信号相关联的光学相干断层扫描信息。
15.根据权利要求1所述的设备，还包括：
至少一个第四装置，其被配置为基于第一数据或者第二数据中的至少一个控制第一装置或者第二装置中的至少一个。
16.根据权利要求1所述的设备，还包括：
至少一个第五装置，其被配置为基于第一和第二数据产生图像。
17.根据权利要求1所述的设备，还包括：
至少一个第六装置，其被配置为基于第一数据产生至少一个第一图像以及基于第二数据产生至少一个第二图像，其中第一和第二图像基于第一和第二数据彼此相关联。
18.根据权利要求1所述的设备，还包括：聚焦装置，其被配置为基于第一数据或者第二数据中的至少一个控制与至少一个第一装置或者至少一个第二装置中的至少一个相关联的焦距或者焦点位置中的至少一个。
19.根据权利要求1所述的设备，其中第一数据与至少一个区域内的至少一个第一位置相关联，第二数据与至少一个样本的至少一个第二位置相关联。
20.根据权利要求1所述的设备，其中至少一个样本是解剖结构。
21.一种用于获得与至少一个样本相关联的特定数据的方法，包括：
获得与从至少一个样本的至少一个区域接收到的第一信号相关联的第一数据，其中所述区域具有不大于大约10微米的线性尺寸；
获得与从至少一个样本接收到的第二信号和从基准接收到的第三信号相关联的第二数据；以及
基于第一和第二数据产生特定数据。
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