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Publication numberCN101304683 B
Publication typeGrant
Application numberCN 200680040695
PCT numberPCT/US2006/038277
Publication date12 Dec 2012
Filing date29 Sep 2006
Priority date29 Sep 2005
Also published asCA2624109A1, CN101304682A, CN101304682B, CN101304683A, CN101360447A, CN101360447B, CN101365375A, CN101365375B, CN103479331A, EP1928305A1, EP1928306A1, EP1937137A1, EP1940286A1, EP2275026A1, EP2279691A1, US7843572, US7847949, US7872759, US8149418, US8289522, US8384907, US8760663, US8928889, US9304121, US9513276, US20070081236, US20070121196, US20070229801, US20070233396, US20110058178, US20110144504, US20110149296, US20130100455, US20130148106, US20130176571, US20150049339, WO2007038787A1, WO2007041376A1, WO2007041382A1, WO2007041412A1
Publication number200680040695.X, CN 101304683 B, CN 101304683B, CN 200680040695, CN-B-101304683, CN101304683 B, CN101304683B, CN200680040695, CN200680040695.X, PCT/2006/38277, PCT/US/2006/038277, PCT/US/2006/38277, PCT/US/6/038277, PCT/US/6/38277, PCT/US2006/038277, PCT/US2006/38277, PCT/US2006038277, PCT/US200638277, PCT/US6/038277, PCT/US6/38277, PCT/US6038277, PCT/US638277
Inventors吉列尔莫J蒂尔尼, 德维尔叶林, 本杰明J瓦科奇, 梅利莎苏特, 布雷特尤金鲍马
Applicant通用医疗公司
Export CitationBiBTeX, EndNote, RefMan
External Links: SIPO, Espacenet
Method and apparatus for method for viewing and analyzing of one or more biological samples with progressively increasing resolutions
CN 101304683 B
Abstract  translated from Chinese
提供了根据本发明的示范性实施例的方法、设备和装置,用于分析和/或图示解剖结构的至少一个部分。 It provides methods, devices and device according to an exemplary embodiment of the present invention, at least one part for analysis and / or illustrated anatomy. 例如,将光转送到这样的部分,以便生成与该部分相关的第一信息。 For example, the light transferred to this part, in order to generate the information associated with the first portion. 例如,将光提供到受检对象上或受检对象之内。 For example, to provide light to the subject of an object or objects within the subject. 接收第一信息,并且可以基于第一信息选择该部分的至少一个截面,以便生成第二信息。 Receiving first information, based on the first information and may select the at least one portion of cross section, in order to generate the second message. 可以作为第二信息的函数而渐进修改该部分的显示的放大率。 As a function of the second information and gradual modification of the portion of the display magnification.
Claims(22)  translated from Chinese
1. 一种用于分析和/或图示解剖结构的至少ー个部分的方法,包括: 将光转送到所述至少ー个部分以便生成与所述至少ー个部分相关的第一信息,其中,位于包含所述解剖结构的受检对象之内的生成装置将所述光提供到所述受检对象上或所述受检对象之内,所述生成装置生成所述第一信息,所述第一信息与图像相关联; 接收所述第一信息,并且基于所述第一信息选择所述至少ー个部分的至少ー个截面,以便生成第二信息;以及渐进地修改作为所述第二信息的函数的所述至少ー个部分的显示的放大率。 1. A method for analyzing and / or illustrated anatomy ー least part, comprising: the light is transferred to a portion of said at least ー ー to generate at least one of said first portion associated information, wherein generating unit with a subject that contains the anatomical structure within the light provided to the subject within the object or objects of the subject, said generating means generates said first information, said The first is associated with the image information; receiving the first information, based on the first information and selecting at least one of said at least Romeo and a sectional part so as to generate second information; and the second as a progressively modifying The function of the information ー least a portion of the display magnification.
2.根据权利要求I所述的方法,其中,所述修改步骤包括修改所述至少ー个部分的位置的显示。 2. The method of claim I, wherein said modifying step includes modifying said display at least a portion ー positions.
3.根据权利要求I所述的方法,其中,所述修改步骤包括修改所述至少ー个部分在所述解剖结构之内的深度的显示。 3. The method of claim I, wherein said modifying step includes modifying at least a part of the display ー depth within the anatomical structure of the.
4.根据权利要求I所述的方法,其中,所述第二信息与所述至少ー个部分之内提供的区域相关联。 4. The method of claim I, wherein said second information and said inner portion of the at least ー provide associated area.
5.根据权利要求I所述的方法,其中,通过用户选择所述区域来获得所述第二信息。 5. The method of claim I, wherein the second information is obtained by the user to select the area.
6.根据权利要求I所述的方法,其中,所述选择步骤通过处理装置自动执行而不用从用户输入。 6. The method of claim I, wherein said selecting step automatically performed by the processing means without input from the user.
7.根据权利要求I所述的方法,进ー步包括确定所述至少ー个部分之内的异常性区域,并且其中处理装置执行所述选择步骤和修改步骤,以便显示所述异常性的至少ー个截面。 7. The method of claim I, further comprising determining the feed ー ー least a portion of the abnormal region, and wherein the processing means executing said selection step and the modifying step, so as to display the abnormality of at leastー a section.
8.根据权利要求I所述的方法,进ー步包括使用处理装置确定所述至少ー个部分之内的异常性区域,以便生成第三信息,并且其中所述选择步骤作为所述第三信息的画数而被用户执行。 8. The method according to claim I, further comprising the use of feed ー processing means determines the abnormality ー least partially within a region, so as to generate third information, and wherein said step of selecting as said third information The painting was executed a few users.
9.根据权利要求I所述的方法,进ー步包括使用处理装置确定所述至少ー个部分之内的异常性区域,以便生成第三信息,并且其中所述选择步骤作为所述第三信息的函数而被所述处理装置执行。 9. The method according to claim I, further comprising the use of feed ー processing means determines said at least ー abnormal region within the portion, so as to generate third information, and wherein said step of selecting as said third information The function of the processing executed by the device.
10.根据权利要求I所述的方法,其中,所述第一信息与所述至少ー个部分的ニ维表示相关联。 10. The method of claim I, wherein said first information and said at least a portion ー ni associated dimensional representation.
11.根据权利要求I所述的方法,其中,所述第一信息与所述至少ー个部分的三维表示相关联。 11. The method of claim I, wherein said first information and said at least one three-dimensional portion ー associated representation.
12.根据权利要求I所述的方法,其中,所述第一信息与具有多于三维的所述至少ー个部分的表示相关联。 12. The method according to claim I, wherein said first information and said at least ー having more than three-dimensional representation of the associated parts.
13.根据权利要求I所述的方法,其中,所述至少ー个部分具有大于Imm2的面积。 13. The method according to claim I, wherein at least a portion of said ー greater than Imm2 area.
14.根据权利要求I所述的方法,其中,所述至少ー个部分具有大于IOmm2的面积。 14. The method according to claim I, wherein at least a portion of said ー greater than IOmm2 area.
15.根据权利要求I所述的方法,其中,所述至少ー个部分的显示的截面具有小于Icm2的面积。 15. The method of claim I, wherein said at least one section portion ー display having an area of less than Icm2.
16.根据权利要求I所述的方法,其中,所述至少ー个部分的显示的截面具有小于Imm2的面积。 16. The method of claim I, wherein said at least one section portion ー display having an area of less than Imm2.
17.根据权利要求I所述的方法,其中,所述至少ー个部分的显示的截面具有小于100V- m2的面积。 17. The method of claim I, wherein said at least one section portion ー display has an area of less than 100V- m2.
18.根据权利要求I所述的方法,其中,所述第一信息与以下中的至少ー个相关联: 共焦显微镜检查过程; 谱编码共焦显微镜检查过程; 光学相干断层扫描过程;以及光学频域干渉量度过程。 18. The method according to claim I, wherein said first information following at least one associated ー: Confocal microscopy process; spectrum encoded confocal microscopy procedure; optical coherence tomography procedure; and an optical frequency domain measurement process re- quired dry.
19.根据权利要求I所述的方法,进ー步包括在所述解剖结构之内提供装置,以便将所述光提供给所述至少ー个部分。 19. The method according to claim I, further comprising providing means into ー within the anatomical structures, so as to provide the light to at least ー parts.
20.根据权利要求I所述的方法,其中,所述至少ー个部分是血管。 20. The method of claim I, wherein the at least one part ー vessel.
21. 一种用于分析和/或图示解剖结构的至少ー个部分的设备,包括: 至少ー个第一装置,其位于包含所述解剖结构的受检对象之内并且配置成将光转送到所述至少ー个部分上或所述受检对象之内,以便生成与所述至少ー个部分相关的第一信息,所述第一信息与图像相关联; 至少ー个第二装置,其配置成接收所述第一信息,并且基于所述第一信息选择所述至少ー个部分的至少ー个截面,以便生成第二信息;以及至少ー个第三装置,其配置成渐进地修改作为所述第二信息的函数的所述至少ー个部分的显示的放大率。 21. A method for analyzing and / or illustrated anatomy ー least part of the apparatus, comprising: at least a first ー means, positioned within the object containing the subject's anatomical structure, and configured to transmit light to the ー at least in the upper part of the subject or the object of so as to generate at least a portion of the ー first information related to the first information associated with the image; at least ー a second means configured to receive the first information, based on the first information and selecting at least ー ー least a part of the cross section, in order to generate the second information; and at least one third means ー configured to progressively modified as The second function of the at least one portion of the information display ー magnification.
22.根据权利要求21所述的设备,其中,所述至少ー个部分是血管。 22. The apparatus of claim 21, wherein said at least one part ー vessel.
Description  translated from Chinese

以渐进増加的分辨率观察和分析ー个或多个生物样品的方法和用于该方法的设备 Resolution and analysis methods to observe one or more biological samples ー progressive to increase in the method and apparatus for

[0001] 相关申请的交叉引用 Cross [0001] REFERENCE TO RELATED APPLICATIONS

[0002] 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。 [0002] This application is based upon and claims the serial number of September 29, 2005 filed as equity 60 / 721,802 U.S. patent application, the entire contents of which are incorporated herein by reference.

技术领域 Technical Field

[0003] 本发明涉及用于以渐进增加的分辨率观察和分析ー个或多个生物样品和解剖结构的方法和装置。 [0003] The present invention relates to a gradual increase in the resolution of observation and analysis ー one or more of the methods and apparatus for biological samples and anatomic structures.

背景技术 Background

[0004] 放射技术如X射线计算机断层扫描(“CT”)、磁共振成像(“MRI”)和超声波能够使得器官水平的人体病变的非侵入可视化成为可能。 [0004] Radiation techniques such as X-ray computed tomography ("CT"), magnetic resonance imaging ("MRI") and Ultrasound enables the body organ level of non-invasive visualization of lesion becomes possible. 尽管这些医疗器械可能能够识别大尺度的病变,但是癌症的诊断能够需要微观结构的评估,这超出了传统成像技术的分辨率。 While these medical devices may be able to identify a large scale of disease, but the diagnosis of cancer can be required to assess the microstructure, which is beyond the resolution of conventional imaging techniques. 因此,诊断可能需要活组织检查和病理组织学检查。 Therefore, the diagnosis may require biopsy and histopathological examination. 因为癌症前期的生长和早期癌症常常以微观尺度出现,所以它们能够为识别和诊断提供显著的挑战。 Because the growth of precancerous and early cancers often appear microscopic scale, so they can provide a significant challenge for the identification and diagnosis. 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。 These lesions traditional screening and monitoring depend on hematoxylin and eosin ("H & E") stained slides unguided biopsy and morphological analysis. 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。 While this approach can be considered the current standard for microscopic diagnosis, but it is necessary to remove tissue from the patient and requires significant processing time to generate the slide. 更重要地,组织病理学固有地为点采样技木;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I %的活组织检查样品。 More importantly, as inherently pathological point sampling technology of wood; often only a very small portion of the diseased tissue can be removed, and the pathologist is often possible to inspect less than I% of biopsy samples.

[0005] 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。 [0005] It may be preferred to obtain microscopic diagnosis of the patient's whole organs from living or biological systems. 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。 However, the lack of suitable imaging technique for greatly limited situation (e.g., conversion) and options dysplastic tumors before screening. 另夕卜,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。 Xi Bu another scene to identify dysplasia and malignancy of regional incapacity screening process has resulted in such as prostate, colon, esophagus and bladder, and so random biopsies, which is highly undesirable and disorganized. 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。 Many current diagnostic tasks involved with frozen section laboratory as depicted surgical tumor boundaries can be improved by diagnostic medical devices, diagnostic medical devices which can be micro-scale rapid imaging large tissue volume. 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。 The technology can fill the gap between pathology and radiology will have significant benefits for patient management and health care.

[0006] 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”)显微的分辨率。 [0006] The technological advances have been made to increase the non-invasive imaging techniques, such as micro-CT, micro-PET and magnetic resonance imaging ("MRI") microscopic resolution. 通过这些技术已实现了接近20 的分辨率,但是基本的物理限制仍然阻止它们应用于患者。 These techniques have achieved close to 20 of the resolution, but the basic physical constraints still prevent them applied to the patient. 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。 For histopathological diagnosis of non-removal of microscopic optical biopsy technology has been the scene of recent progress. 反射共焦显微(“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剤。 Reflectance confocal microscopy ("RCM") may be particularly well suited to non-invasive patient microscopic examination, because it can be measured without contact with the tissues microstructure, and does not require external management contrast Ji. 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。 RCM is possible to suppress defocused light, and detecting selectively originated in the organization of a single plane of backscattered photons. 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。 For example, by a plane parallel to the surface of the tissue in the rapid scanning of a focused beam of electromagnetic radiation, to implement RCM, to obtain cross-sectional images, or surface tissue. 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(ljym),使得亚细胞结构的可视化成为可能。 RCM can be used in the large numerical aperture (NA) can be obtained in a very high spatial resolution (ljym), such that visualization of subcellular structures possible. 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。 However, the high NA imaging aberrations as the light propagates through inhomogeneous tissue appears particularly sensitive. 而且,使用RCM的高分辨率成像典型地被限制到大约100-400 um的深度。 Moreover, the use of high-resolution imaging RCM is typically limited to a depth of about 100-400 um. [0007] RCM已被广泛地展示为用于表皮组织的可行成像技木。 [0007] RCM has been widely demonstrated as a viable imaging techniques for wood epidermal tissue. 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。 Develop endoscopic confocal microscopy system has become more difficult, at least in part attributed to involve the scanning microscope miniaturization important technical challenges. 将共焦显微镜检查的概念直接应用于内窥镜检查的ー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。ー major obstacle to the concept of confocal microscopy is directly applied to endoscopy of the operating mechanism, the mechanism for the distal end of the small-diameter flexible probe fast scanning focused beam. 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。 Various methods have been proposed to address this issue, including the distal end of the micro-electromechanical systems ("MEMS") proximal to use and single-mode optical fiber bundle beam scanning device scans. 而且,RCM可以提供仅在离散位置处的微观图像——“点采样”技木。 Moreover, RCM may only provide micro image at discrete locations - "point sampling" technology of wood. 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。 As currently implemented as point sampling is inherent in RCM, because it has a limited field of view, which may be the field of resection or biopsy rather than its small and large field of view for a comprehensive microscopy, imaging speed too slow.

[0008] 使共焦显微镜检查适用于内窥镜应用的另ー个挑战包括可以用于光学切片的高NA物镜的小型化。 [0008] so confocal microscopy suitable for endoscopic applications include another challenge ー can be used for optical sectioning of high NA objective lens of miniaturization. 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。 For example, by providing a gradient index lens system, miniaturization of the objective lens or objective lens biaxially custom design, we can achieve such miniaturization. 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。 For example, using coupled into the fiber bundle miniaturized lens, you can get a detailed image of the cervical epithelium in vivo morphology, and commercial instruments using commercially available from, for example, such as Olympus Corp. (Olympus) and Pentax / Optiscan instrument, you can get colorectal lesion based on fluorescence images.

[0009] 尽管有这些进展,仍然需要提供方法和装置,该方法和装置能够解析(例如从大的表面面积乃至可能整个器官获得的以细胞水平、结构水平或两者提供的)数据,以便它可以以及时、准确的方式被适当地解释。 [0009] Despite these advances, still a need to provide a method and apparatus, the method and apparatus can resolve (e.g., from a large surface area and the entire organ may be available to the cellular level, the structure provided by the level, or both) of data, so that it When possible and accurate manner is properly interpreted. 事实上,这种数据的量很大并且难以同时观察这样的数据,因而这样的方法和装置将会对于其观察和分析有益。 In fact, a large amount of data, and this is difficult to simultaneously observe such data, and thus such a method and apparatus which will be advantageous for observation and analysis.

发明内容 DISCLOSURE

[0010] 本发明的目的之ー是要克服现有技术系统的某些缺陷和缺点(包括上面在此描述的那些),并且提供用于以渐进增加的分辨率观察和分析ー个或多个生物样品和解剖结构的方法和装置的示范性实施例。 [0010] ー object of the present invention is to overcome some of the drawbacks and disadvantages of prior art systems (including those described herein above), and provides for a gradual increase of the resolution observation and analysis ー or more An exemplary method and apparatus for biological samples and anatomic structures embodiments. 这样的示范性方法和装置能够和数据的目视检查一起使用,或者通过数据的自动处理过程使用,以引导最有可能包含异常和/或不健康组织的区域的可视化。 Such exemplary method and apparatus capable of and used in conjunction with visual inspection of the data, or through the use of automated processing of data to guide the most likely to contain abnormalities and / or unhealthy tissue area visualization.

[0011] 因此,提供了根据本发明的示范性实施例的方法、设备和装置,它们可以分析和/或图示解剖结构的至少ー个部分。 [0011] Thus, a method, apparatus and system according to an exemplary embodiment of the present invention, they can be analyzed and / or at least a partial illustration ー anatomy. 例如,在这样的示范性实施例中,将光转送到这样的部分,以便生成与该部分相关的第一信息。 For example, in such an exemplary embodiment, the light transferred to this part, in order to generate first information associated with the portion. 例如,将光提供到受检对象上或受检对象之内。 For example, to provide light to the subject of an object or objects within the subject. 接收第一信息,并且可以基于第一信息选择该部分的至少ー个截面,以便生成第二信息。 Receiving first information, and may be based on the first information selection section ー least one section in order to generate the second information. 可以作为第二信息的函数而渐进修改该部分的显示的放大率。 As a function of the second information and gradual modification of the portion of the display magnification.

[0012] 在本发明的进ー步的示范性实施例中,(例如在解剖结构之内)能够修改所述至少ー个部分的位置和/或深度的显示。 [0012] In an exemplary step into ー embodiment of the present invention, (for example, within the anatomical structures) capable of modifying the ー least a portion of the position and / or display depth. 第二信息能够与在这样的部分之内提供的区域相关联,和/或可以通过用户选择该区域来获得。 The second information can with area within such a part of the offer of associated and / or by the user to select the region to obtain. 该选择能够通过处理装置自动进行而不用从用户输入。 This selection can be performed automatically without input from the user through the treatment plant. 可以确定所述至少ー个部分之内的异常性区域,并且处理装置可以进行选择和修改,以便显示异常性的至少ー个截面。 It can determine the abnormal ー least partially within the region, and the processing unit can be selected and modified to show abnormal sexual ー at least one section. 使用处理装置能够确定该部分之内的异常性区域以便生成第三信息,并且该选择能够作为第三信息的函数而被用户和/或处理装置执行。 Using the processing device to determine the abnormal region within the portion so as to generate third information, and the selection can be as a function of the third information is a user and / or processing apparatus.

[0013] 根据本发明的再一个示范性实施例,第一信息能够与该部分的ニ维、三维、四维或更多维表示相关联。 [0013] According to a further exemplary embodiment of the present invention, the first portion of the information can ni-dimensional, three, four or more associated dimensional representation. 进ー步,该部分可以具有大于Imm2和/或IOmm2的面积。ー step into this section may have more than Imm2 and / or IOmm2 area. 该部分的显示的截面可以具有小于Icm2Umm2和/或100 y m2的面积。 Section of the portion of the display may have less than Icm2Umm2 and / or 100 y m2 area. 第一信息能够与共焦显微镜检查过程、谱编码共焦显微镜检查过程、光学相干断层扫描过程和/或光学频域干渉量度过程相关联。 The first information can confocal microscopy process, spectral encoded confocal microscopy process, optical coherence tomography process and / or optical frequency domain measurement process associated with dry re- quired. 装置位于解剖结构之内,以便将光提供给该部分。 Means located within the anatomical structures in order to provide light to the part.

[0014] 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。 Book [0014] rights conjunction with the appended claims, when reading the following detailed description of embodiments of the present invention, other features and advantages of the invention will become apparent.

附图说明 Brief Description

[0015] 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,本发明的进ー步的目的、特征和优点将会变得明显,其中: [0015] combination shows a schematic drawing of an embodiment of the present invention, from the following detailed description, step into ー objects, features and advantages of the invention will become apparent, including:

[0016] 图I是示范性谱编码共焦显微镜检查(SECM)系统的示意性图示; [0016] FIG. I is an exemplary schematic illustration of the spectrum encoded confocal microscopy (SECM) systems;

[0017] 图2A是使用单模源和单模检测(SM-MM)配置离组织表面100 U m在体外获得的猪肠上皮的示范性SECM图像; [0018] 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ー个示范性SECM图像; [0017] FIG. 2A is a single-mode and single-mode source detection (SM-MM) configuration from the tissue surface 100 U m obtained in vitro epithelial pig intestines exemplary SECM image; [0018] FIG. 2B is a single-mode source and Multimode Detection (SM-MM) configured to obtain the pig intestines epithelial another ー demonstration of SECM image;

[0019] 图2C是猪肠上皮的SECM图像的放大图; [0019] FIG. 2C is an enlarged view of porcine intestinal epithelial SECM image;

[0020] 图3A是在以50 Pm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; [0020] FIG. 3A is an exemplary SECM image chitterlings epithelium after imaging with 50 Pm deep compression obtained in vitro intestinal wall;

[0021] 图3B是在以100 um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; [0021] FIG. 3B is after imaging to 100 um deep compression obtained in vitro intestinal epithelial pig intestines exemplary SECM image;

[0022] 图4是示范性SECM设备的示意性图示; [0022] FIG. 4 is a schematic illustration of an exemplary SECM apparatus;

[0023] 图5是USAF图表的示范性SECM图像; [0023] FIG. 5 is an exemplary SECM image USAF chart;

[0024] 图6A是以Ix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; [0024] FIG. 6A is based on data taken from the lens tissue samples Ix exemplary SECM image magnification display;

[0025] 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; [0025] FIG. 6B is based on data taken from the lens tissue sample exemplary SECM 4. 5x magnification image display;

[0026] 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; [0026] FIG. 6C is based on data taken from the lens tissue sample exemplary SECM 16. 7x magnification image display;

[0027] 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; [0027] FIG. 6D is based on data taken from the lens tissue sample exemplary SECM 50x magnification of the image displayed;

[0028] 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; [0028] FIG. 6E is based on data taken from the lens tissue sample exemplary SECM 125x magnification image display;

[0029] 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; [0029] FIG. 7 is a series of exemplary SECM data in five different focus position obtained from the lens tissue samples as well as a combination of image data generated by a combination of five each image;

[0030] 图8A是以Ix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; [0030] FIG. 8A is based on data taken from pig intestines tissue fragments exemplary SECM Ix magnification image display;

[0031] 图SB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; [0031] Based on data taken from pig intestines tissue fragments exemplary SECM image Figure SB is a 4x magnification display;

[0032] 图SC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; [0032] Exemplary SECM image based on data taken from pig intestines tissue fragments in Figure SC 20x magnification is displayed;

[0033] 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; [0033] Based on data taken from pig intestines tissue fragments exemplary SECM image Figure 8D is a 40x magnification display;

[0034] 图9A是在体内的猪食道的微观图像的前视图和侧视图,其使用根据本发明的方法和装置的示范性实施例示出了黏膜下层之内的脉管网络,而没有使用图像增强剂或外在的造影剤; [0034] FIG. 9A is hogwash Road in vivo microscopic image of a front view and a side view, the use of the method and apparatus according to an exemplary embodiment of the present invention shows the vascular network within the submucosa, without the use of image Ji contrast enhancer or external;

[0035] 图9B是通过图9A中图示的位置处的食道壁的纵向横截面的微观图像的侧视图; [0035] FIG. 9B is illustrated in Fig. 9A through the wall of the esophagus at the location of a longitudinal cross section of a side view of the microscopic images;

[0036] 图9C是A中图示的位置处的打开横断截面的侧视图;[0037] 图9D是图9C中图示的图像的选择截面的展开图的侧视图; [0036] FIG. 9C is illustrated at the position A side view of a transverse section of the opening; [0037] FIG. 9D is a select section of the image shown in FIG. 9C expanded view of a side view;

[0038] 图9E是从对应于图9D中图示的图像的解剖区域获得的代表性组织截面的示范性图像; [0038] FIG. 9E is obtained from a representative organization corresponds to FIG. 9D illustrates a cross-sectional images of the anatomical region of an exemplary image;

[0039] 图10是本发明的用于渐进变焦到解剖结构的微观数据集中的方法的示范性实施例的流程图; [0039] FIG. 10 is used in the present invention, an exemplary progressive zoom to microscopic anatomy dataset flowchart of a method according to an embodiment;

[0040] 图11是使用光学相干断层扫描(“0CT”)技术获得的食道黏膜的一系列示范性图像,展示了用于识别与Barrett的食道和腺癌相比较的正常鳞状黏膜的自动处理过程的示范性实施例的实施; [0040] FIG. 11 is an optical coherence tomography ("0CT") a series of exemplary imaging technology acquired esophageal mucosa, showing the normal squamous mucosa automated processing for identifying Barrett's esophagus and adenocarcinoma compared with the Example exemplary embodiment of the process;

[0041] 图12是使用OCT技术获得的动脉粥样硬化斑的ー组示范性图像,其已被处理以识别巨噬细胞密度;以及[0042] 图13是根据本发明的方法的另ー个示范性实施例的流程图,该方法用于基于经由信号处理技术获得的結果,渐进变焦到解剖结构的微观数据集,以自动识别可以以高放大率观察的所关心区域。 [0041] FIG. 12 is obtained by using the OCT technique atherosclerotic plaques ー set an exemplary image, which has been processed to identify macrophage density; and [0042] FIG. 13 is another method according to the present invention ー solo a flow chart of an exemplary embodiment, the method is used based on the results obtained through the signal processing technology, progressive zoom to microdata sets anatomy, to automatically identify regions of interest can be viewed at high magnification.

[0043] 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。 [0043] Throughout the drawings, unless otherwise stated, the same reference numerals and characters are used for the same characteristics indicative of the illustrated embodiment, elements, components or parts. 此外,虽然现在将參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。 In addition, although the present invention will now be described in detail with reference to the accompanying drawings, but it will combine exemplary embodiments. 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。 The described embodiments can be changed and modified without departing from the true scope and that the spirit as defined in the appended claims the invention.

具体实施方式 DETAILED DESCRIPTION

[0044] 根据本发明的示范性实施例,能够提供根据本发明的示范性实施例的方法和装置,用于以渐进增加的分辨率观察和分析ー个或多个生物样品和解剖结构。 [0044] According to an exemplary embodiment of the present invention to provide a method and apparatus according to an exemplary embodiment of the present invention for a gradual increase of the resolution observation and analysis ー or more biological samples and anatomic structures. 这样的示范性方法和装置能够和数据的目视检查一起使用,或者通过数据的自动处理过程使用,以引导最有可能包含异常和/或不健康组织的区域的可视化。 Such exemplary method and apparatus capable of and used in conjunction with visual inspection of the data, or through the use of automated processing of data to guide the most likely to contain abnormalities and / or unhealthy tissue area visualization.

[0045] 在图I中示出了示范性SECM技术。 [0045] In Figure I shows an exemplary SECM technology. 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(诸如像透射衍射光栅120)。 The output from the distal end of the probe may be located in the single mode fiber 100 can be calibrated collimator lens 110, and then irradiated with a dispersive optical element (such as transmission diffraction grating 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。 The objective lens 130 can then be focused onto each diffraction wavelength different spatial positions within the sample, leading to transverse line focus 140, wherein each point line characterized by different wavelengths. 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。 It can, for example, a sample from the biological tissue after reflection, the optical signal can be reassembled diffraction element 120 by a single-mode optical fiber 100 collects. 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。 Single-mode fiber core aperture 100 can provide spatial filtering mechanism that can filter out defocused light. 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。 External probe (and optionally within the system console), the spectrum of the light can be returned as measured in the sample and converted into a function of transverse displacement confocal reflection. 能够快速执行谱解码。 Spectrum can quickly perform decoding. 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。 In this way, by a relatively slow and direct mechanical action, it is possible to complete the image by the direction orthogonal to the line focus of the scanning beam is generated.

[0046] 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CXD摄像机以极高速率提供图像数据。 [0046] SECM techniques may allow the use of an endoscope RCM, and provides the image data by using a camera with a high speed linear CXD rate. 商业上可用的线性CCD阵列能够以大于大约毎秒60兆像素的速率获得数据。 Commercially available linear CCD arrays can be greater than about every 60 seconds to obtain data rate megapixels. 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ー直到100倍于某些内窥镜RCM技术的速度产生共焦图像。 When incorporated into the SECM spectrometer, these arrays can be about 10 times the typical video rate and up to 100 times the speed ー certain endoscopic RCM art confocal images produced. 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。 Fast imaging speed and fiber design typical SECM system allows a large area through a comprehensive examination of the endoscope probe microscope.

[0047] 使用光学相干断层扫描(“0CT”)的技术及其变体可以用于全面的构造筛选。 [0047] using optical coherence tomography ("0CT") technology and its variants can be used to construct a comprehensive screening. 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。 OCT signal acquisition wavelength domain rather than the time domain, it is possible to provide an order of magnitude improvement in imaging speed, while maintaining good image quality. 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。 Using spectral domain OCT ("SD-OCT") technology, the resolution spectral interference by analyzing tissue samples and reference between the high resolution can be implemented ranging in biological tissue. 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0CT( “TD-0CT”)系统的速率。 Because the SD-OCT system can be used with the same speed SECM systems linear CCD, they can be 60 megapixels per second captured image, which is similar to the traditional time-domain rate 0CT two orders of magnitude ("TD-0CT") system . 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。 With this acquisition rate and resolution, SD-OCT system can be configured in a clinical setting to provide a full volume level microscopic examination.

[0048] 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。 [0048] SD-OCT and SECM system information may be complementary, and the use of these two technologies can provide mixed-platform configuration information that may be relevant for the cell structure and organization necessary for an accurate diagnosis. 尽管不同技术的结合典型地需要大范围的工程并且可能使性能折衷,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。 Although the combination of different technologies typically require a wide range of engineering and may make performance tradeoffs, but SECM and SD-OCT systems to share key components, and can provide high-performance multi-modal system without a significant increase in individual systems complexity or cost.

[0049] 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。 [0049] to obtain the spectrum as a function of time according to SECM system coding information to certain exemplary embodiments of the present invention can be used 1300nm wavelength scanning light source and single element detector. 使用这个系统,能够以在400 视场(“F0V”)之上具有高横向(1.4iim)和轴向分辨率的高达约30帧/秒的速率获取图像。 Using this system, capable of 400 field ("F0V") above having a high transverse (1.4iim) and up to 30 frames / sec acquisition rate of axial resolution image. 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,该亚细胞结构可以在专化肠上皮化生(“SM”)即BE的化生变化中发现。 Image swine duodenum fragments in vitro with high-speed imaging system recently removed to show the ability to subcellular structures SECM system identification, the subcellular structures can metaplasia ("SM") in the specialization of the intestine that is BE Students changing discovery.

[0050]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”)。 [0050] Figures 2A-2C depict the in vitro epithelial pig intestines obtained exemplary SECM image, which uses two imaging modes and the corresponding optical fiber arrangement: a single-mode single-mode detecting irradiation ("SM-SM") and singlemode irradiation ("SM-MM") with multi-mode detection. 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100 um的上皮结构。 Fig. 2A SM-SM image shows the use of single-mode and single-mode source-surface distance detection of epithelial tissue structures of 100 um. 使用具有I : 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显得更加平滑并且可以更加容易地解释。 Having I: 4 core - single-mode and multimode source detection aperture ratio (SM-MM) obtained shows images of the same tissue region in Fig. 2B, because of reduced speckle noise and appears smoother and can more easily explained. 图2C是图2B中示出的图像的放大图,其示出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证据。 2C is shown in Fig. 2B an enlarged view of the image, which shows the core contains inappropriate reflective (for example lamina propria or "lp") and a higher scattering evidence columnar epithelium of the villi. 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),在图2C中是明显的。 At the bottom of columnar cells visible bright image density, which is consistent with the core (indicated by arrows), FIG. 2C is evident.

[0051] 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減少例如大约ニ分之一。 [0051] Using an inflatable balloon, OCT technology can be used in vivo imaging of the esophagus wall thickness reduction such as the writing is about one-half. 图2A-2C中示出的猪肠样品被減少相同的量,并且使用SECM技术观察到的亚细胞特征被很好地保存。 Chitterlings in Figures 2A-2C illustrates a sample is reduced by the same amount, and observed using SECM technology sub-cellular characteristics are well preserved. 图3A和3B分别示出了在50 ii m和100 um的深度获得的该变薄样品的图像。 3A and 3B show the image in 50 ii m and a depth of 100 um obtained in this thin sample.

[0052] 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%。 [0052] Commercial 800nm laser scanning confocal microscope penetration depth was observed in comparison with the penetration depth with 1300nmSECM systems was reduced by approximately 20%. 减少的穿透可能是较短波长源的散射增加的結果。 Reduce penetration may be the source of a shorter wavelength scattering increase results. 这样ー来,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。ー Thus, the use of a source of 840nm SECM system can provide sufficient penetration to identify subcellular structures such as the intestinal epithelium.

[0053] 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。 [0053] In Figure 4 schematically illustrates a SECM configured to provide a comprehensive picture of the device in accordance with certain exemplary embodiments of the present invention. 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 This exemplary device is configured to obtain an image from the cylindrical sample, the sample having a cylindrical

2. 5cm的长度和2. Ocm的直径,这近似为远端食道的尺度。 2. Ocm length and diameter of 2. 5cm, which is approximately the distal esophagus scale. 具有以800nm为中心的波长和45nm 的带宽的光纤稱合的2. OmW超福射ニ极管200 (QSSL-790-2, qPhotonics, Chesapeake,VA),被配置成照射50/50单模光纤分束器405。 Optical fiber having a center wavelength of 800nm to 45nm bandwidth and said bonding 2. OmW Super Fu Ni shot diode 200 (QSSL-790-2, qPhotonics, Chesapeake, VA), is configured to illuminate 50/50 single-mode optical fiber beamsplitter 405. 被传输通过分束器的ー个端ロ的光被准直仪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(17801pmm,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. Omm 的通光孔径和0. 55的NA。 It is transmitted through a beam splitter ー ro end light collimator 410 is calibrated, and is transmitted through the optical fiber 412 reaches the focusing device 415 and reaches the grating lenses of the raster lens including: a grating 420 (17801pmm, Holographix, LLC , Hudson, MA); and 350230-B aspherical lens 425 (Thor Labs, Inc., Newton, NJ), which has a 4. 5mm focal length f, 5 Omm clear aperture and 0.55 of 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500 纵向线性阵列或线。 This arrangement can produce a focused spectrum encoding spots on the inner surface 430 of sample 500 of the cylindrical linear array or longitudinal lines. 光栅透镜对通过壳体440附着到马达435(1516SR,15mm直径,MicroMoElectronics, Inc. ,Clearwater,FL)的轴。 Lenticular lens through housing 440 is attached to the motor 435 (1516SR, 15mm diameter, MicroMoElectronics, Inc., Clearwater, FL) axis. 随着马达435旋转,跨越圆柱形样品的内圆周扫描谱编码线。 As the motor 435 rotates, the inner circumference of the scan line across the spectrum coding cylindrical samples. 使用计算机控制的线性级445 (Nanomotion 11,2. 5cm range,Melles Griot,Rochester, NY),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。 Use computer-controlled linear stage 445 (Nanomotion 11,2. 5cm range, Melles Griot, Rochester, NY), during the rotation of the motor 435 is translated along the longitudinal axis of the cylindrical sample motor 435, the housing 440 and the lenticular lens pair. 这个过程产生了圆柱形样品的整个内表面的螺旋扫描。 This process produces a spiral scan the entire inner surface of the cylindrical sample.

[0054] 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CXD 455,该线性CXD 455包括2048个像素并且具有30kHz的线速率(Basler L104K, Basler VisionTechnologies, Exton, PA)。 [0054] The light reflected from the sample is transmitted back through the optical system into a single-mode optical fiber 412, and is supplied to the optical fiber 412 spectrometer 450 and linear CXD 455, the linear CXD 455 includes 2048 pixels and has a line rate of 30kHz (Basler L104K, Basler VisionTechnologies, Exton, PA). 计算机460 用于存储、分析和显示分光计450和CXD 455提供的图像数据。 Computer 460 is used to store, analyze and display image data 450 and CXD 455 spectrometer provided. 每周马达旋转大约有60,000点(以0. 5Hz或30rpm)被数字化,以实现I. Oiim的圆周采样密度。 Weekly motor rotation around 60,000 points (to 0. 5Hz or 30rpm) are digitized in order to achieve the circumference of the sampling density I. Oiim. 马达的纵向速度为0. 25mm/s,并且圆柱形样品的ー个完整扫描所需的时间为100秒。 Portrait of a motor speed of 0. 25mm / s, and the cylindrical sample ー time required to complete the scan to 100 seconds.

[0055] 光栅透镜对上的准直束的1/e2直径为4. Omm。 [0055] The collimated beam raster lenses on 1 / e2 diameter 4. Omm. 结果,这个示范性设备的有效NA近似为0. 4,这对应于近似I. 2 ii m的理论斑点直径和近似2. 5 ii m的共焦參数。 As a result, the effective NA of the exemplary device is approximately 0.4, which corresponds to an approximate theoretical I. 2 ii m spot diameter and approximately 2. 5 ii m confocal parameter. 在没有光学像 In the absence of an optical image

差的系统中,样品上的理论谱分辨率可以为0.8人,其能够跨越谱编码线430得到高达近 Poor system, the theoretical spectral resolution of 0.8 can sample on people across the spectrum coding line can get it up to nearly 430

似630个可分辨点。 Like 630 distinguished points. 检测臂中的分光计450被设计成超过探针的预测谱分辨率。 The spectrometer detection arm 450 is designed to predict the spectral resolution over the probe.

[0056] 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。 [0056] In Figure 5 illustrates the use of such equipment SECM scans obtained 1951 USAF resolution chart. 被分开2. 2pm的这个图中的最小条被分辨。 2. 2pm separated this figure shall be resolved minimum. 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. I ym和5. 5 ym。 Transversal focus using a scanning mirror obtained by extension functions FWHM ("FWHM") and axial FWHM functions are measured respectively 2. I ym and 5. 5 ym. 观察到视场大约为500 u m0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。 Observed field of view of approximately 500 u m0 these measurements slightly lower than the corresponding theoretical value, which may be attributed to aberrations in the optical path. 这些实际的參数表明,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。 The actual parameter indicates, in this description of the exemplary device can provide sufficient resolution for biological tissue confocal microscopy.

[0057] 在图6中示出了用于2. 5cm体模样品的完全回拉图像的SECM图像数据。 [0057] In Figure 6 shows a SECM image data products for 2. 5cm body look completely pull back the image. 在生成这些显示的图像之前,将极坐标转换成直角坐标。 Before generating display these images, the polar coordinates into Cartesian coordinates. 使用附着到2. Icm内径的特氟隆(Teflon)管的内表面的镜头纸来制作体模样品。 2. Icm use attached to the inner diameter of the inner surface of Teflon (Teflon) tube lens paper to make the body look like goods. 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。 In FIG. 6A shows a low magnification image can be observed macroscopic structures include paper folds and voids. 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。 Visible circumference stripes may result from the presence in or near the lower end of the spectrum of power and a lens aberration spectrum coding lines. 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。 As shown in FIG. 6B-6E, the data set in this region to provide high magnification, it is possible to clearly distinguish between the individual fibers and fiber microstructure.

[0058] 通过调整图4A中的聚焦设备415,在120 ii m的范围的5个离散聚焦深度处获取仿真样品的圆柱形ニ维(“2D”)图像。 [0058] 415, at 120 ii 5 discrete focal depths range at m sample to obtain simulation by adjusting the focusing device in Fig. 4A cylindrical Ni-dimensional ("2D") images. 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。 Figure 7 shows these five images 710-750 are then summed to generate integrated image 760, which shows the almost complete coverage of the surface of the body of product appearance.

[0059] 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。 [0059] Because of the lack of a centering device for the optical scanning head, using the apparatus as described herein SECM imaging biological samples to be complicated. 为了提供进ー步的改进以便生成宽视场显微图像和数据,在2. Ocm直径的透明圆柱之上放置猪肠的样品。 In order to provide further improvements ー into in order to generate wide-field microscope images and data, over 2. Ocm diameter transparent cylindrical sample is placed in the chitterlings. 在图8A中示出了I秒内获取的这个样品的360扫描。 In Figure 8A shows a second 360 scan I acquired within the sample. 成像的组织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。 Imaging of tissue sections in a cylindrical scanned appears only because the probe is not at the center, and the sample is not completely wrapped around the cylinder. 图8B-8D示出了这个组织样品的一系列放大区域。 Figure 8B-8D shows a series of enlarged area of the tissue sample. 图SB中示出的图像是图8A中的打点矩形框出的I. 5cm区段的扩展。 Figure SB image shown in Fig. 8A is an extension of the RBI rectangle out of the I. 5cm segments. 类似地,图SC中的图像表示了图SB中框出的矩形的扩展,而图8D中的图像则表示了图SC中框出的矩形的扩展。 Similarly, Figure SC The image shows a block diagram of the SB in a rectangular extension, and Fig. 8D shows a rectangular image is expanded view of the SC out of the box. 图SB中的组织的放大图像暗示了腺结构。 Figure SB enlarged image of the tissue structure implies gland. 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。 Figure 8C-8D enlarged image shows the fluff and nuclear characteristics, which are similar to FIG. 2 and 3 using 1300nm SECM system observed in Figure fluff and nuclear characteristics. 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。 Other regions in Fig. 8A shows SECM scan artifacts (artifact), including a mirror reflection from a transparent cylinder and full signal loss, both of which can result from improper positioning focused SECM beam.

[0060] 对患者实施全面共焦显微镜检查提出了多种技术挑战。 [0060] for patients with comprehensive confocal microscopy proposed a variety of technical challenges. 这样的挑战可能包括例如増加成像速率、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木。 Such challenges may include, for example to increase in imaging speed, the probe of the optical and mechanical components miniaturization, combined centering mechanism and the implementation of techniques for dynamically changing the focal plane trees.

[0061] 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。 [0061] Compared with the above described exemplary system, the image acquisition rate can be improved SECM systems e.g. about 2-4 times that of the exemplary system. 通过提供某些修改能够实现这样的改进。 Certain modifications can be achieved by providing such improvements. 例如,更高功率半导体光源(诸如像超辐射ニ极管T-840HP :25mff,840nm, IOOnm谱带宽)能够提供1000个谱可分辨点。 For example, higher power semiconductor light source (such as superluminescent diodes ni T-840HP: 25mff, 840nm, IOOnm spectral bandwidth) to provide 1000 Spectrum distinguished points. 光功率的増加能够改进灵敏度,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。 Optical power to increase in sensitivity can be improved, and larger bandwidth to broaden the field of view, making it possible to approximately twice the speed of scanning SECM beam. 而且,使用光环行器诸如像0C-3-850(0ptics 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。 Moreover, the use of optical circulator such as 0C-3-850 (0ptics for Research, Caldwell, NJ) can be transmitted to the probe and increase the efficiency of collecting light from the probe. 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。 Use faster and more sensitive, such as a linear CCD having 2048 pixels and 60kHz readout rate AVIIVA M4-2048 (Atmel Corporation) provides twice the speed of data acquisition and for generating image data of the wavelength range of the spectral response improved . 还可以通过使用例如Camera Link (摄像机链接)接ロ来改进性能,所述Camera Link接ロ能够以近似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。 Also, for example Camera Link (Camera Link) then ro to improve performance by using the Camera Link can be connected at a rate of approximately ro 120MB / S from the camera to the hard drive for transferring data storage arrays.

[0062] 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參数。 [0062] is understood to mean the minimum detectable sensitivity affecting reflectance confocal image quality and depth of penetration of the system parameters. 当使用近红外RCM技术时,能够从一直到近似300 um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。 When using a near-infrared RCM technology to from up to a depth of approximately 300 um skin reflection at a fraction of the incident light, which may be approximated as 10_4 to 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3X 10_4到3X 10_7的从组织之内深处反射的照射光。 Based on the objective demonstration of the system described herein in accordance with certain exemplary embodiments of the present invention used in the NA and horny skin than non-epithelial mucosa more significant attenuation of light can make the observation, in this description of the exemplary SECM probe lens can collect approximate depths from within the organization reflected irradiation light 3X 10_4 to 3X 10_7 of. 25mW光源可以被分成例如近似1000个独立的射束。 25mW light sources can be divided, for example approximately 1000 independent beam. 最大双程插入损耗被估计为近似IOdB (6dB来自探针,4dB来自光纤和分光计)。 The largest two-way insertion loss is estimated to be approximately IOdB (6dB from the probe, 4dB from the fiber and spectrometers). 基于这些估计的參数,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。 These estimated parameters based on the integration period for each line, which may be approximately 50 to 50,000 photons / pixel to illuminate each pixel in the array.

[0063] 使用多模检测技术,可以实现10倍的信号増益,使得对于这样的配置每次扫描有近似500到500,000光子/像素。 [0063] Using multi-mode detection technology, can achieve 10 times the signal Zeng Yi, so that for such an arrangement each scan has approximately 500 to 500,000 photons / pixel. 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。 If the signal is above the dark current fluctuations at approximately 240 photons occurrence, such as a single pixel on the camera Atmel AVIIVA M4 can reliably detect light. 如果这个装置在这些波长处具有近似50%量子效率,则能够以每次扫描有近似480光子/像素产生最小可检测信号。 If this means these wavelengths have approximately 50% quantum efficiency, it is possible to have approximately 480 photons per scan / pixel minimal detectable signal. 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。 Based on these approximations, Atmel camera may have sufficient sensitivity to allow SECM imaging deeper tissue depths. 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。 By using multimode fiber to collect or by increasing the source power to achieve quantum noise limit detection of minimum reflectivity forecast conducted.

[0064] 根据本发明的一个示范性实施例,能够提供用于导航、分析和显示来自解剖结构的大的微观数据集的方法和装置。 [0064] According to an exemplary embodiment of the present invention to provide for navigation, analysis and display method and apparatus for large data sets from the microscopic anatomy.

[0065] 图9A-9E图示了使用全面的显微镜检查与本发明的方法和装置的示范性实施例获得的体内猪食道的各种图像。 Example various images obtained in vivo hogwash Road exemplary method and apparatus [0065] FIG. 9A-9E illustrate the use of a comprehensive microscopic examination of the present invention. 这些示范性图像由图4中示出的计算机460(例如个人计算机、微型计算机等等)生成,或者由别的处理装置生成,所述计算机460或处理装置可以(例如通过软件)被配置成将这样的图像转发到图4的显示器470或别的输出装置。 The exemplary image shown in Figure 4 the computer 460 (e.g., a personal computer, microcomputer, etc.) is generated, or generated by other processing means, said computer processing means 460 or may be (e.g., via software) is configured to Such an image is forwarded to display 470 of FIG. 4 or other output device. 另夕卜,计算机460控制图4的示范性系统的各种部件(例如马达435、线平移器445、聚焦设备415等等),以自动地和/或在人工控制之下聚焦在解剖结构的各个区域上,这将使得能够导航、分析和显示与解剖结构相关联的大的微观数据集。 Another evening Bu, various components of the computer 460 of FIG. 4 exemplary control system (such as a motor 435, line pan 445, a focusing device 415, etc.), in order to automatically and / or focus under manual control in anatomy On each area, which would make it possible to navigate, analyze, and display anatomical structures associated with large micro data sets.

[0066] 例如,图9A分别示出了在体内的猪食道的微观图像的前视图和侧视图900、905,其使用根据本发明的方法和装置的示范性实施例提供了黏膜下层之内的脉管网络,而没有使用图像增强剂或外在的造影剤。 [0066] For example, Figure 9A show a front view of the body in the path of the microscopic images of hogwash and side 900,905, using the method and apparatus according to an exemplary embodiment of the present invention provides within the submucosa of the vascular network, without using an image enhancer or extrinsic contrast Ji. 事实上,可以对图9A的例如14GB容量的数据集进行再现和降采样,以用于在任意的取向和透视图中呈现。 In fact, figures such as 14GB capacity may dataset 9A is reproduced and downsampling, for presentation in any orientation and perspective. 在没有使用这样的图像增强剂或外在的造影剤的情况下,示出了黏膜下层之内的脉管网络。 In the absence of the use of such an image enhancer or contrast Ji external case, it shows vascular network within the submucosa. 使用为(ー个或多个)这样的示范性任务配置的计算机460和图4的系统的其它部件,能够在体积图像上定位横截面图像,用于更高分辨率观察。 Use of (ー or more) other components such exemplary task configuration computer system 460 and 4, can be positioned on the volume of cross-sectional images of the image for higher resolution observation.

[0067] 图9B示出了通过图9A中图示的位置处的食道壁的纵向横截面的微观图像的侧视图910。 [0067] FIG. 9B shows a microscopic image by longitudinal cross-section illustrated in Fig. 9A esophageal wall at the side view of the 910 positions. 例如,这个图像910以上皮在顶部的方式反转;尺度:水平45mm,垂直2. 6mm。 For example, the image 910 over the skin on top of the inversion mode; scale: horizontal 45mm, vertical 2. 6mm. 在原始数据中,能够观察到对应于心跳运动的周期性垂直偏移。 In raw data, corresponding to the heartbeat can be observed cyclical movement vertical offset. 表面对准过程的示范性实施例用于减少这种伪像而只剩余垂直条带,该剩余的垂直条带仍然可以以对应于90次/分钟的心率的300微米的周期被观察到。 300 microns periodic surface alignment process of an exemplary embodiment for reducing such artifacts and only the remaining vertical stripes, vertical stripes of the still remaining may correspond to 90 beats / min heart rate were observed. 相邻A线之间的示范性纵向间距被示出为32 um。 A demonstration of the adjacent longitudinal spacing between the lines is shown as 32 um.

[0068] 图9C示出了图9A中图示的位置处的打开横断截面(例如圆柱坐标r和0被映射到垂直和水平坐标)的侧视图920。 [0068] Figure 9C shows the position illustrated in FIG. 9A open transverse cross section (e.g., cylindrical coordinates r and 0 are mapped to the vertical and horizontal coordinates) of the side view 920. 例如,图示的示范性尺度如下:57mm-水平,2. 6mm_垂直。 For example, the illustrated exemplary scale as follows:. 57mm- level, 2 6mm_ vertical. 图9B和9C都图示了通过整个食道壁的成像,并且能够识别鱗状上皮(e)、固有层(lp)、黏膜肌层(mm)、黏膜下层(s)和固有肌层(mp)。 9B and 9C are illustrated through the entire esophageal wall imaging, and can identify squamous epithelium (e), lamina propria (lp), muscularis mucosa (mm), the submucosa (s) and muscularis propria (mp). 图9D示出了有助于这样的识别的图9C中图示的图像的选择截面的展开图的侧视图930。 9D shows that facilitates such identification Figure 9C selection section illustrated an expanded view of a side view of the image 930. 图9E示出了从对应于图9D中图示的图像的解剖区域获得的代表性组织截面(H&E染色)的示范性图像。 Figure 9E shows a representative cross-section from the tissue corresponding to Fig. 9D illustrates an image of the anatomical region obtained (H & E staining) exemplary image.

[0069] 例如,图10描绘了流程图,其描述了能够使用图4中示出的计算机460来执行的用于以渐进更高的分辨率分析和/或观察数据集的根据本发明的方法或过程的示范性实施例。 [0069] For example, Figure 10 depicts a flow chart describing the method according to the present invention, the computer can be used is shown in Figure 4 460 to perform a progressive higher resolution analysis and / or observation data sets for or exemplary embodiment of a process. 具体地,在步骤1000中,在组织的大面积之上,或者从组织或其中的器官的体积中,可以获取具有小于10 Pm的分辨率的微观数据集。 Specifically, in step 1000, on a large area of tissue or from a volume of tissue or organ in which the microstructure can be obtained with less than 10 Pm dataset resolution. 然后能够以如下的表达(在步骤1010中)将数据格式化:可以图示整个数据集或数据集的一部分的低放大率或低倍视图。 It can then be expressed as follows (in step 1010) to format the data: the entire data set can be shown or part of the data set of low power or low magnification view. 在步骤1020中,用户可以观察数据集,并且使用计算机接ロ选择(a)矩形区域、(b)点、(c)任意成形区域和/或(d)深度,以目视更高放大率视图。 In step 1020, the user can observe the data set, and using a computer connected to ro choose (a) a rectangular area, (b) point, (c) any shaped region and / or (d) depth, visually higher magnification view . 在步骤1020中观察新的区域,并且用户在数据集之内(a)选择另ー个区域、(b)在点处放大、(c)縮小、(d)在三维中平移当前视图和/或(e)改变观察的深度位置。 Viewed in step 1020 a new area, and the user within the data set (a) select another ー areas, (b) at the point amplification, (c) narrow, (d) translate the current view and / or in three dimensions (e) changing the depth position of observation.

[0070] 重复图10中图示的整个示范性过程,直到所关心的ー个或多个区域被可视化地识别为止。 Entire exemplary process [0070] illustrated in FIG. 10 is repeated until ー concern one or more regions are visually identify so far. 用户以任何放大率或视图来选择不同的图像,以存储用于稍后的检查。 Users to choose any magnification or view different images to be stored for later examination. 在示范性导航过程期间还能够对每个单独视图进行标记。 During an exemplary navigation process can also be marked for each individual view. 不同放大率/位置的各种区域/图像能够被标上书签,以便用户能够在随后的导航会话期间返回到相同的区域/图像。 Various regions of different magnifications / locations / image can be marked with bookmarks, so that users can navigate during the subsequent session returns to the same regional / image. 图6A-6E、7和9A-9E图示了观察大面积微观数据集时的渐进放大率的例子。 FIG. 6A-6E, 7 and 9A-9E illustrates an example of a progressive magnification microscopic observation large data sets when.

[0071] 在此描述的导航过程的示范性实施例通过计算机460来实施,并且还利用各种处理技术辅助用户确定各种区域以放大和观察样品及其不同的部分和区域。 Example be implemented by the computer 460, and also the use of various processing techniques assist the user to zoom in and define areas and different parts of the sample was observed and regional exemplary [0071] in the navigation process embodiments described herein. 例如,图11描绘了使用光学相干断层扫描(“0CT”)技术获得的食道黏膜的一系列示范性图像,展示了用于经由OCT图像空间频率的分析而识别与Barrett的食道和腺癌相比较的正常或良性鳞状黏膜的自动处理过程的示范性实施例的实施。 For example, Figure 11 depicts the use of optical coherence tomography ("0CT") a series of exemplary imaging technology acquired esophageal mucosa, showing OCT images via a spatial frequency analysis and identification compared with Barrett's esophagus and adenocarcinoma Examples of normal or benign squamous mucosa exemplary automated process of implementation.

[0072] 如图11所示,示出了不同病状的OCT图像1100、1110和1120以及空间频率分布1105、1115和1125。 As shown in [0072] FIG. 11, showing different pathologies OCT image 1100,1110 and 1120 as well as spatial frequency distribution 1105,1115 and 1125. 鳞状上皮IlOO(SE)具有垂直空间频率(见面板1105中的箭头1007),其对应于在SIM中可能不存在的水平层。 Squamous IlOO (SE) has a vertical spatial frequency (see arrow 1007 in plate 1105), which corresponds to the SIM may not exist in horizontal layers. 与SIMND 1110和1115相对照,在腺癌(CA) 1120的示范性OCT图像及其相应的空间频率1125中示出了广泛变化的空间频率分布。 In contrast with SIMND 1110 and 1115, in adenocarcinoma (CA) 1120 of an exemplary OCT image and the corresponding spatial frequency 1125 it is shown widely varying spatial frequency distribution. 图12描绘了通过确定归ー化的标准偏差參数(NSD)而从动脉粥样硬化斑1200的OCT图像中获得的巨噬细胞含量1210的图示。 Figure 12 depicts the cellular content of macrophages by determining the standard deviation of the normalized ー parameters (NSD) obtained from atherosclerotic plaque OCT image 1200 shown in 1210. 使用色表1220,可以获得巨噬细胞的密度并将其显示为图像。 Use color table 1220, can obtain a density of macrophages and displayed as an image.

[0073] 这些以及其它的示范性图像处理分析过程和步骤能够被应用于微观数据集并用于突出潜在疾病的区域,用于随后的定向导航。 [0073] These and other exemplary image processing and analysis processes and procedures can be applied to microeconomic data sets and for the region to highlight the underlying disease, for subsequent directional navigation. 图13描绘了用于导航和评估微观图像数据集的根据本发明的方法和过程的示范性实施例的流程图。 Figure 13 depicts a flow chart for navigation and evaluate the microscopic image data set according to an exemplary method and process of the present invention embodiment. 在这个示范性方法/过程中,在步骤1300中获得微观数据集,其优选地具有在组织的大面积之上或者从组织或其中的器官的体积中获取的小于10 Pm的分辨率。 In this exemplary method / process to obtain micro data set in step 1300, it is preferable to have a resolution or volume of tissue obtained from or which organ of the organization over a large area of less than 10 Pm. 然后在步骤1310中通过处理装置(例如使用计算机460)自动地处理数据,以识别包含疑似疾病区域或相反地疑似不包含疾病区域(亦即健康部位)的区域/位置。 Region and then processing apparatus (e.g., a computer 460) in step 1310, the data is automatically processed, to identify the region containing the suspected disease or conversely suspected disease area is not included (i.e., a healthy portion) / position. 在步骤1320中,不健康区域通过使用顔色或其它标记方法而被表达,然后在步骤1330中以整个微观数据体积的低放大率而被观察。 In step 1320, the unhealthy region through the use of color or other labeling methods are expressed at low magnification and then the entire micro-data volume is observed in step 1330. [0074] 用户然后能够由处理数据及其表达引导,在步骤1340中选择区域来观察。 [0074] The user is then able to process the data and its expression by a guide, select the area to observe in step 1340. 然后用户可以观察数据集,并且使用计算机接ロ来选择(a)矩形区域、(a)点、(C)任意成形区域和/或(d)深度,以目视更高放大率视图。 The user can then observe the data set, and then using a computer to select ro (a) a rectangular region, (a) point, (C) an arbitrary shaped region, and / or (d) depth, visually higher magnification view. 可以观察新的区域,并且用户(或计算机460)可以在数据集之内手动或自动地(a)选择另ー个区域、(b)在点处放大/縮小(步骤1350)、(d)在三维中平移当前视图和/或(e)改变观察的深度位置。 You can observe a new area, and the user (or computer 460) may be in the data set of manually or automatically (a) select another ー areas, (b) at the point where the enlargement / reduction (step 1350), (d) in Pan the current view in three dimensions and / or (e) changing the depth position of observation. 进ー步,在步骤1360中,用户观察新近图示的区域。 Step into ー, in step 1360, a user viewing area recently shown. 可以重复示范性的方法/过程,直到所关心的(ー个或多个)区域被可视化地识别为止。 You can repeat the exemplary methods / process until concern (ー or more) regions are visually identify so far. 用户或计算机460可以选择任何放大率或视图的不同图像,以存储用于稍后检查。 User or computer 460 can select different image magnification or any view, to store for later examination. 在示范性导航过程期间还可以对每个单独视图进行标记。 During an exemplary navigation process can also be marked for each individual view. 不同放大率/位置的各种区域/图像可以被标上书签并存储,以便用户能够在随后的导航会话期间返回到相同的区域/图像。 Various regions of different magnifications / locations / images can be marked and stored bookmarks, so that users can navigate during the subsequent session returns to the same regional / image.

[0075] 前述仅仅表明了本发明的原理。 [0075] foregoing merely indicates the principles of the invention. 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。 Taking into account the teachings herein, various modifications and changes to the described embodiments of the skill in the art will be apparent. 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。 In fact, according to the apparatus, system and method for an exemplary embodiment of the present invention can be used with any OCT system, OFDI system, SD-OCT system or other imaging systems used in conjunction with, and for example, submit and September 8, 2004 of the International Patent Application PCT / US2004 / 029148, US Patent November 2, 2005 filed No. 11 / 266,779 and US Patent July 9, 2004 to submit those used with the Application No. 10 / 501,276 described, the entire contents of these patents are incorporated by reference herein. 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。 As a result, it will be appreciated that those skilled in the art will design a number of systems, devices and methods which although not explicitly shown or described, but it reflects the principles of the invention, and thus place within the spirit and scope of the present invention. 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。 Further, the above prior art has not been explicitly incorporated by reference herein in terms of knowledge, expressly incorporated herein in its entirety. 上面引用在此的所有公布都以其整体通过引用结合于此。 All the above-cited publication are herein incorporated by reference in their entirety.

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Referenced by
Citing PatentFiling datePublication dateApplicantTitle
CN104224117A *10 Sep 201424 Dec 2014南京航空航天大学Spectrally encoded confocal and optical coherence tomography cooperative imaging method and system
CN104224117B *10 Sep 201430 Jun 2017南京航空航天大学一种光谱编码共焦与光学相干层析协同成像方法与系统
Classifications
International ClassificationA61B5/00, G01B11/24, G06T3/40, G01B9/02
Cooperative ClassificationG01N2223/419, G01N21/25, G01N2021/1765, G01N33/4833, G01N21/27, G01B9/02064, G01N21/4795, G01B9/02049, A61B5/0073, G02B23/2461, G02B21/0028, A61B5/0068, A61B5/0062, G02B23/2423, A61B5/6852, A61B5/0084, A61B5/0075, G01N23/046, G01N21/6458, G01B9/02027, G02B23/243, G02B23/2476, A61B5/0066, G01B9/02087, G01B9/02091, G01N21/6486, G01B9/02, G01B9/04
European ClassificationA61B5/00P1C, G01N23/04D, G02B23/24D, A61B5/00P12B, G01N21/64P4C, G02B23/24B2, G02B23/24B5, A61B5/00P1E, G02B23/24B2B, A61B5/68D1H, G01N21/47S, A61B5/00P1, A61B5/00P6
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