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传统光学显微镜系统发展经过了两个重要阶段,即有限远光学系统和无限远光学系统。20世纪90年代,传统显微镜系统从有限远光学系统转变为无限远光学系统。其光学成像过程可以通过图1来解释,光源发出的光线照射放置在物镜的前焦面上的待测样本,经样本散射或透射的光线不通过物镜成像,而是作为无限远的平行光线进入管镜,由管镜形成中间像,而后通过目镜观察或直接成像于图像传感器。无限远成像系统带给了光学显微系统稳定的、优质的光学成像能力(包括成像分辨率和对比度),然而这种严格的光学系统配置同时也使得光学显微镜的成像配置较为复杂,难以适应便捷检测的需求[52]。
智能手机平台的光学成像能力为显微成像系统提供了简化的光学系统替换方案,其后端摄像镜头和传感器可以被引入显微成像光路中作为光学成像和采集的装置(即筒镜和成像传感器),形成可视化的观察图像。相比于传统显微镜严格的显微物镜的硬件配置,智能手机平台的强大的光学变焦能力和数字变焦能力允许不同的光学放大透镜配置以实现多样化的显微成像表现。根据光学放大透镜的不同配置,可将基于智能手机平台的新型显微成像光路设计分为三大类,即基于标准显微成像光路、定制化单透镜以及倒置手机摄像头镜头的自校正显微成像系统设计。
图2显示了三类基于智能手机平台的新型显微成像光路结构[53]。第一类结构使用标准显微镜物镜和目镜构成无限远显微光学系统,智能手机平台仅作为图像记录和显示装置,如图2 (a) 所示。相比于传统相机传感器采集设备,智能手机平台集成化的图像采集与显示特性提供了强大的兼容性,使显微镜具备即时成像和观察的优势。第二类结构将智能手机平台的成像镜头和传感器作为光学成像和图像采集设备,其光学结构如图2 (b) 所示。在这种结构下,单个具有光学放大能力的定制化单透镜作为显微成像的物镜,如球透镜、非球面透镜、液体透镜等。这些定制化单透镜对本身到智能手机摄像头镜头的距离不敏感,因此可缩短镜头和智能手机摄像头镜头的距离,从而大大缩短成像光路,减小系统体积。区别于定制化单透镜设计,倒置手机摄像头镜头作为最匹配智能手机平台图像传感器的镜头组,提供了第三类成像光路设计,可以很好地校正图像像差且较好地利用智能手机平台图像传感器的面积,其光路结构如图2 (c) 所示。表1分别概述了三类基于智能手机平台的新型显微成像光路设计的优缺点。
图 2 基于智能手机平台的显微系统中的物镜类型。(a) 标准显微成像光路;(b) 定制化单透镜;(c) 倒置手机摄像头镜头的自校正显微光路
Figure 2. Type of objective lens in microscope system based on smartphone platform. (a) Standard microscopic imaging light path; (b) Customized single lens; (c) Self-correcting microscopic optical path of inverted camera lens of smartphone
表 1 三类基于智能手机平台的新型显微成像光路设计的优缺点
Table 1. Advantages and disadvantages of three types of new microscopic imaging optical path designs based on smartphone platforms
Lens type Advantage Disadvantage Standard microscope objective and eyepiece High resolution images are obtained in a limited field of view with small aberrations The system structure is complex and the cost is high Single lens (spherical lens, aspheric lens, liquid lens) The lens has the advantages of low cost, easy fixation and large optical magnification The off-axis aberration of the system is large; In color imaging, serious color difference will appear in any single lens method Inverted camera lens of mobile phone It can make full use of smartphone image sensor and obtain high-resolution image. The optical magnification of the system is M = 1, which is limited in applications requiring large magnification -
传统光学显微镜主要包括目镜和物镜两个镜头。显微物镜具有放大目标物体的作用。数值孔径和放大倍率是显微镜物镜的主要性能参数。在保证成像质量的情况下,为了分辨物体的精细结构,应选尽可能大数值孔径的物镜,且其放大率需与分辨率相匹配。显微镜目镜相当于放大镜,对于具有正常视力的观察者,物镜的像应与目镜的物方焦平面重合,这对系统的稳定性提升非常关键[54-56]。用于特殊疾病诊断的光学显微镜因其昂贵的价格和需要专业人员操作的要求,使得这些光学显微镜在农村和发展中地区无法获得。
为了解决这一问题,在2009年,最早的基于标准显微成像光路的手机平台显微成像系统由Breslauer[40]团队提出,该系统将传统的光学显微系统连接到移动手机上,在有限的视场范围内生成高分辨率图像,仅填充部分相机传感器面积,花费了几百美元。手机在这个系统中仅仅作为成像器件,即使把手机去除,也能通过目镜观察到样品。其光路结构如图3 (a) 所示,此基于标准显微成像光路的手机平台显微成像系统被用于检测疟原虫、血液中镰状红细胞和痰液中结核杆菌。文中提出的显微系统由传统光学显微镜的物镜和目镜系统来实现了明场成像和荧光显微成像两种成像模式,明场成像模式只需要将激发滤光片(Excitation filter)和发射滤光片(Emission filter)移除,其中目镜距离物镜160 mm,光路用黑色套筒包裹,目镜和手机摄像头镜头的距离等于摄像头镜头的焦距(图3 (a) )。此系统中使用的广角目镜和消色差物镜的放大倍率分别是20×和60×,产生了直径约为180 μm、有效放大率约为28×、空间分辨率为1.2 μm的FOV。通过朗奇刻线(Ronchi rulings)测试得到该系统的真实分辨率为2.7 μm,在所有测试情况下,分辨率都超过了检测血细胞和微生物形态所需的分辨率;对于结核病样品,Breslauer[40]等人进一步利用智能手机平台采集到的数字化图像,通过图像分析软件ImageJ演示了自动芽孢杆菌技术,图3 (a) 分别展示了荧光珠在荧光显微成像模式和明场成像模式下的图像。上述手持式手机显微成像系统虽然得到了高分辨率图像,但是视场面积较小,仅填充部分相机传感器。整套系统并不是经济高效的,其所用的光学元件价格昂贵,且物镜包含在光学套管中,由此产生的结构看起来很笨重。
图 3 各种基于标准显微成像光路的智能手机平台显微成像系统示意图。(a) Breslauer等提出的基于手机平台的显微镜示意图[40];(b) Shan等提出的基于智能手机平台的显微镜示意图[57];(c) Shrivastava等提出的基于智能手机平台的显微镜示意图[58]
Figure 3. Schematic diagram of various microscopic imaging systems of smartphone platform based on standard microscopic imaging optical path. (a) Schematic diagram of microscope based on mobile phone platform proposed by Breslauer et al[40]; (b) Schematic diagram of microscope based on smartphone platform proposed by Shan et al[57]; (c) Schematic diagram of microscope based on smartphone platform proposed by Shrivastava et al[58]
随着研究人员不断地探索,如图3 (b) 所示,Shan[57]等设计了小型化基于智能手机平台的荧光显微系统,此系统的光学模块中集成了激光二极管、显微物镜、目镜、发射滤光片和反射镜等光学元件,并与智能手机连接,可采集荧光信号。Shrivastava[58]团队也利用了相似的光学结构搭建了基于智能手机平台的荧光显微成像系统,如图3 (c) 所示。与Shan团队不同的是,此系统用白光发光二极管(Light-emitting diode, LED)作为激发光,并在系统中集成了一个定制的细菌检测盒,展现了在病原体现场检测的巨大潜力。用标准的显微物镜作为成像透镜的好处在于可以很好地校正常见的像差,通常可以获得质量较高的图像,但目镜镜头针对瞳孔直径为4 mm的人眼进行了优化,而智能手机摄像头镜头的瞳孔直径通常在2 mm左右,因此当智能手机摄像头直接安装在目镜上时,物镜的有效数值孔径会降低,达不到理想的系统分辨率。Breslauer也提到可以通过使用具有更高数值孔径(Numerical aperture, NA)的物镜和通过将照明源以倾斜角度照明样品来增强对比度,可以改善图像质量,但这无疑增加了整个手机显微成像系统成本和复杂性。
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许多基于智能手机平台的新型显微成像系统都使用定制化单透镜作为物镜,这类定制化单透镜的成本低,且重量轻,使得定制化单透镜对基于智能手机平台的显微系统很有吸引力。基于手机的显微成像系统中通常使用的定制化单透镜包括球透镜、非球面透镜和液体透镜。球透镜焦距很短,从而使整个系统具有较高的图像分辨率和较大的光学放大率。非球面透镜通常用于准直和耦合来自激光二极管的光,一般具有较高的数值孔径(>0.25)。液体透镜可以通过改变固化液体的体积和温度,从而改变液体透镜的焦距,这为科研人员提供了一个以较低价格制造固定焦距物镜的方案。由于上述定制化单透镜的成本都很低,因此可准备不同焦距的单透镜在一个极低的成本下实现不同的光学放大率。引入这些定制化单透镜作为基于智能手机平台的新型显微成像系统的物镜替代传统光学显微镜中物镜-目镜光学系统,从而降低了系统的成本和复杂性。
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在基于智能手机平台的新型显微成像系统中,使用传统显微镜光学元件和制造笨重附件增加了系统的成本、复杂性和所需的维护技能。使用标准显微镜物镜和目镜作为基于手机平台的显微镜的物镜,手机相机取代了传统显微镜出瞳中的人眼。这种方案导致了一个相当庞大的系统结构,因为它需要一个完整的标准实验室显微镜结构适当地耦合到智能手机平台上,且因手机摄像头镜头的直径小于人眼瞳孔的平均直径,其往往会减小系统的数值孔径和分辨率。而使用球透镜作为系统的物镜,这时手机镜头作为管镜。它实现了一个非常紧凑的结构,将球透镜直接安装在手机上,仅需双面胶带便可固定[59-60]。
为了改善笨重光学附件的缺点,Smith[61]等使用球透镜连接至手机设计了基于智能手机平台的新型显微成像系统可成功诊断镰状细胞贫血,球透镜紧贴着手机摄像头镜头,且因球透镜极短的焦距,样品距离球透镜非常近,由此整个手机显微成像系统非常紧凑。Bogoch[62]等证明了使用单个3 mm球形透镜检测粪便样本中土壤蠕虫的成像能力,3 mm的球透镜利用双面胶带固定在手机摄像头镜头上,无需制造笨重的光学附件。使用球透镜成像,它允许一个非常紧凑的系统结构,外部镜头直接安装在手机上,如图4 (a) 所示。使用球透镜作为手机显微成像系统的成像镜头,系统的光学放大率为手机摄像头镜头焦距和球透镜焦距的比例,一般的手机摄像头镜头焦距为3~5 mm,为了获得光学放大率M>1,球透镜应具有非常短的焦距。
图 4 各种基于球透镜的智能手机平台显微成像系统示意图。(a) Bogoch提出的基于智能手机平台的显微镜示意图[62];(b) Jahan-Tigh等提出的基于智能手机平台的显微镜示意图[42]; (c) Kutay等提出的基于智能手机平台的显微镜示意图[65];(d) Zeng等提出的基于智能手机平台的显微镜示意图[63]; (e) Agbana等提出的基于智能手机平台的显微镜示意图[64]
Figure 4. Schematic diagram of microscopic imaging systems of various smartphone platforms based on spherical lens. (a) Schematic diagram of microscope based on smartphone platform proposed by bogoch et al[62]; (b) Schematic diagram of microscope based on smartphone platform proposed by Jahan Tigh et al[42]; (c) Schematic diagram of microscope based on smartphone platform proposed by kutay et al[65]; (d) Schematic diagram of microscope based on smartphone platform proposed by Zeng et al[63]; (e) Schematic diagram of microscope based on smartphone platform proposed by Agbana et al[64]
Jahan-Tigh[15] 等将Smith和Bogoch的系统改良提出了基于智能手机平台的显微镜。同样的,球透镜通过双面胶带固定,但在此之前,球透镜被固定在一张对折的透明塑料中,其结构如图4 (b) 所示。整个系统可通过手持的方式观察样品。而Zeng[63]等则使用商用手柄冲床在硅膜上制造一个2 mm的小孔并将3 mm的球透镜固定住,选用硅膜作为球透镜固定装置是因为其具有良好的柔性结构,可装配不同直径的球透镜,系统如图4 (d) 所示。2018年,Agbana[64]等对使用球透镜的手机显微成像系统的光学设计进行优化,使其达到最佳性能。其系统外观如图4 (e) 所示。Agbana从球透镜的材料和直径以及球透镜到手机摄像头镜头的距离等参数进行分析,并将衍射极限设置为可达到的分辨率,最佳效果应是在白光照明下可以在最宽的视场内得到较高分辨率的图像。Agbana对球透镜成像光学方案进行了多参数优化,得出了以下实用结论:(1)手机摄像头镜头的数值孔径应小于0.2,限制可达到的最大分辨率;(2)手机显微成像系统的孔径光阑应放置于球透镜的正后方;(3)手机摄像头镜头距离球透镜的距离可以很短(0.3~0.5 mm)且可通过固有的像差将手机摄像头镜头和球透镜的光轴对齐,便于调整系统;(4)系统的成像视场受到球透镜离轴像差的限制,主要来自场曲;(5)用油浸没样品和球透镜之前的空间可消除球透镜前表面的影响来减少像差,并将得到更大的视场。
球透镜因其焦距短、体积小、便于固定等优点被应用于各类基于智能手机平台的显微成像系统,Agbana使用了50 μm的铝箔,球透镜被双面胶带安装在两片金属铝箔之间。使用球透镜作为物镜的手机显微成像系统虽能得到较高的图像分辨率,但图像边缘的像差十分严重,导致拥有高分辨率的真实视场很小。这是因为研究人员使用了一个简单的球透镜作为放大元件,导致了显著的平场畸变,球透镜的焦平面由一个球体描述,聚焦的部分是与该球体相交的部分。畸变在球透镜成像中显得尤为明显。畸变是指当物体通过透镜成像时,会在物体的不同部位产生不同放大倍率差,从而破坏了物体与成像之间的相似性。球透镜会产生正畸变,即成像周围的放大倍率比成像中心区域的放大倍率要大。这两种像差都可以通过数字图像处理在图像采集后进行表征和校正。
因此,在2016年,Kutay[65]等报告了一种基于超低成本球透镜和图像处理算法的智能手机显微镜,用于分析印刷光栅上免疫磁珠的数量,其系统结构如图4 (c) 所示。通过的图像后处理算法,基于球透镜的智能手机显微镜采集到图像的噪声比可大大降低,提高图像质量。
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非球面单透镜可以更好地减少球面像差。非球面单透镜通常用于准直或耦合来自激光二极管的光,并提供足够大的数值孔径,通常大于0.25。大多数非球面透镜都是通过模压工艺制造的,因此透镜价格相对较低。
在2012年,Arpa[66]等将一个非球面单透镜放置在显微镜样品上,样品放置在另一个手机屏幕上(非照相手机),按镜头的焦距分开,用该手机屏幕作为整个系统的照明光源,发出结构性的背景光,最终在照相手机上成像,这样就可以观察样品的不同视角并记录下来。其系统结构如图5 (a) 所示。该系统的放大倍率取决于手机摄像头焦距和透镜焦距,而与它们之间的焦距无关。与使用标准显微物镜和目镜的系统相比,此系统更加灵活,轻便,整个系统的光学元件仅需一个单透镜镜头,且该单透镜可与多个不同类型的智能手机平台相匹配,单透镜与智能手机平台之间的间距可以调整,但此系统所采集到的显微图像的边缘还是会受到像差的困扰。2016年,Felton[67]等提出了一种基于智能手机平台的设备,该设备将磁铁、毛细管和NA为0.72的非球面透镜集成到一个紧凑且便携的装置中,该装置可通过智能手机平台的相机获取图像,并利用该系统对细胞的密度进行分析,可用于区分不同类型或相同类型的细胞,其结构如图5 (b) 所示。
图 5 各种基于非球面透镜的智能手机平台显微成像系统示意图。(a) Arpa等提出的基于智能手机平台的显微镜示意图[66];(b) Felton等提出的基于智能手机平台的显微镜示意图[67]
Figure 5. Schematic diagram of various micro imaging systems of smart phone platform based on aspheric lens. (a) Schematic diagram of microscope based on smart phone platform proposed by ARPA et al[66]; (b) Schematic diagram of microscope based on smartphone platform proposed by Felton et al[67]
与球形和半球形镜头类似,在计算有效数值孔径时,应考虑智能手机摄像头镜头的小孔径直径。虽然非球面单透镜可以提高同轴性能,但由于非球面透镜主要用于同轴光准直或耦合,因此离轴像差仍然很大。当对多种颜色成像时,在任何单透镜方法中都会出现严重的色差,不同波长的光聚焦在不同的位置。
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传统的镜片是由玻璃或塑料等刚性材料的机械抛光或注射成型而成。高光学质量的透镜表面需要良好控制的制造参数,这增加了复杂性和操作成本。相比之下,由于表面能最小化而形成的透镜(如液体透镜)提供了一种替代方法,用于制造高质量的小透镜,无需模具或复杂的参数控制[68]。然而,自由流动的液体透镜需要一个系统来提供机械稳定性并防止液体蒸发,可以通过固化液体聚合物来制造透镜,从而永久地固定透镜轮廓[69]。例如,焦距为1 mm的微透镜已通过光刻胶回流焊制成。毫米范围焦距的小镜头非常适用于各种商业电子产品,如智能手机和数码相机。
聚二甲基硅氧烷(Polydimethylsiloxane, PDMS)在可见光谱中是光学透明的(透射率T>95%)且具有高折射率,并具有随时间变化最小的黄变。自20世纪90年代以来,PDMS已被用于构建微流控器件,至今仍保持其广泛的适用性。因此,固化液体聚合物的透镜逐渐被科研人员用于基于智能手机平台的显微成像系统的开发中[70-72]。
在2015年,Sung[73]等人提出了一种通过在加热表面上喷墨打印聚二甲基硅氧烷(PDMS)液滴来制造透镜的方法。PDMS液滴从喷墨打印头以规定的高度释放。撞击表面时,动能和表面能、惯性、重力和流体粘度的复杂相互作用使液滴呈现平凸形状,可以用作透镜。该透镜打印程序稳定耐用,无需洁净室设施便可操作。由于PDMS是一种热固化弹性体,其液滴变形可通过热加速原位固化进行干预。如图6 (a) 所示,Sung通过控制PDMS液滴的体积和液滴下的预热表面温度固化速度,从而控制液滴的表面曲率和焦距。PDMS在玻璃和塑料表面上的粘合性能允许PDMS镜头非永久性地连接到相机窗口上,无需额外支撑,并且能够在实验中一次使用至少30 min而不会脱落。10 μL容量的PDMS液滴在200 ℃的快速加热表面形成的焦距为5.6 mm的透镜连接到低成本智能手机上,可达到1 μm的成像分辨率和120×的光学放大率。因此基于PDMS喷墨打印透镜的手机显微成像系统可达到不错的显微成像效果,且其成本极低,质量轻,没有笨重的光学附件。
图 6 各种基于PDMS透镜的智能手机平台显微成像系统示意图。(a) Sung等提出的PDMS喷墨打印透镜制作过程及其基于智能手机平台的显微镜示意图[73];(b) Sung等提出的基于智能手机平台的显微镜示意图[74];(c) Fuh等提出的液体驱动透镜的制作过程和基于智能手机平台的显微镜示意图[75]
Figure 6. Schematic diagram of microscopic imaging systems of various smartphone platforms based on PDMS lens. (a) Schematic diagram of the manufacturing process of PDMS inkjet printing lens and its microscope based on smartphone platform proposed by Sung et al[73]; (b) Schematic diagram of microscope based on smartphone platform proposed by Sung et al[74]; (c) Schematic diagram of fabrication process of liquid-driven lens and microscope based on smartphone platform proposed by Fuh et al[75]
在2017年,Sung[74]等利用自己之前提出的PDMS喷墨打印镜头设计了一款基于智能手机平台的多色荧光显微系统,其结构如图6 (b) 所示。该显微镜利用光线在载玻片全内反射照明,用于研究荧光显微镜中的三个常见应用:自体荧光、荧光染色和免疫荧光。
2016年,Fuh[75]等介绍了一种带有内置非球面聚二甲基硅氧烷透镜的液体驱动非球面透镜(Liquid-actuated Aspheric Lens, LAL)的新概念,以实现具有变焦显微成像的紧凑型光学系统的设计。通过调整注入液体体积的变化来控制压差可以改变液体驱动非球面透镜的焦距,该透镜的制造过程和物理结构如图6 (c) 所示,先通过PDMS喷墨打印技术制造APL透镜,并组装成液体驱动非球面透镜,焦距范围为4.3~2.3 mm。
PDMS喷墨打印透镜可通过改变液滴体积和表面温度来制作具有不同焦距的液体透镜。这个透镜打印过程是半自动化的,并且可以修改,方便以更大的生产量并行制造。未来可通过此项技术来制作更小的透镜,这些透镜将产生更大的光学放大率,但是可能由于尺寸较小,难以制作。
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专门设计智能手机摄像头镜头用于收集大角度的光线,并在成像传感器上以最小的像差生成图像。此类透镜的F数为3.0~1.5,对应于0.17~0.33的数值孔径。数值孔径决定显微镜的横向分辨率和聚焦深度。智能手机摄像头的焦距通常较短,约为3~5 mm,可集成在比较薄的智能手机中。例如,iPhone XS智能手机使用了F数为1.8、焦距为4.25 mm的摄像头镜头。为了在最小像差的情况下获得大视场,智能手机摄像头镜头中使用了多种镜头元件。每个透镜元件通常采用塑料成型工艺制造,以降低成本。镜头光圈位于摄像机前端附近。光圈直径通常在几毫米左右。智能手机摄像头镜头位于音圈电机(Voice Coil Motor, VCM)的运动部件中,VCM用于调整透镜的焦距。调焦功能在显微镜中非常有用,它可以免除显微镜物镜对附加调焦装置的需求,并且可以方便地进行交互式调焦。
由于内置摄像头镜头的专门设计,通过在手机摄像头模块外添加放大光学元件而创建的基于智能手机平台的显微镜无法使用全图像传感器,这加剧了光学系统固有的分辨率和视场之间的权衡。这种折衷在诊断应用中尤为明显,基于图像的诊断速度和成本与能够以足够分辨率查看的样本面积有关。
图7 (a) 展示的基于球透镜的智能手机显微成像系统由于严重的场曲效应以及球面和其他像差导致可用的高分辨率的视场非常有限。相比之下,显微镜目镜的设计目的是将光线耦合到具有最小像差的广角视场中,并且它可以与标准物镜结合使用来构建基于智能手机平台的显微成像系统,如图7 (b) 所示。但是,这种配置也无法使用完整的手机传感器进行高分辨率成像,而且标准显微镜物镜和目镜昂贵的价格和其构建系统所带来的额外的光学附件使此方法显得笨重。而手机摄像头镜头本身专门设计用于收集高角度光线的镜头,非常适合与智能手机平台进行光学耦合。倒置手机摄像头镜头还提供了与摄像头镜头本身完全匹配的角度视场,因此可以完全填充智能手机图像传感器,如图7 (c) 所示。与球透镜、标准显微镜物镜和目镜配置的系统相比,基于倒置手机镜头的自校正智能化手机平台显微成像系统所观察到的样本的细胞形态和细胞核在整个视场中都很容易辨别,而球透镜和标准显微镜物镜和目镜配置的系统的视场和和分辨率受到明显限制。
图 7 基于智能手机平台的显微镜结构的比较[76]。(a) 基于球形镜头手机显微镜示意图;(b) 基于标准有限远显微系统的手机显微镜的示意图;(c) 基于倒置手机镜头显微镜示意图
Figure 7. Comparison of microscope structures based on smartphone platforms[76]. (a) Schematic diagram of a spherical lens-based cell phone microscope; (b) Schematic of a cell phone microscope based on a standard infinity microscope system; (c) Schematic diagram of a microscope based on an inverted mobile phone lens
2014年,Switz[76]等基于倒置手机镜头的自校正智能化手机平台显微成像系统设计,在比标准显微镜大得多的视场上实现高质量成像,其系统结构如图8 (a) 所示。由于从均匀照明的样品收集高视场角的光,具有反向相机镜头的手机显微镜会受到图像显著的${\rm cos}^{\rm 4 th}$渐晕,这可能会限制大视场的实用性。因此Switz修改单个 LED 的照明轮廓并使用高动态范围成像来校正渐晕效应,这种方法几乎可以在整个传感器上生成高质量图像。
图 8 各种基于倒置手机镜头的自校正智能化手机平台显微成像系统示意图。(a) Switz等提出的基于智能手机平台的显微镜示意图[76];(b) D’Ambrosio等提出的基于智能手机平台的显微镜示意图[77];(c) Kim等提出的基于智能手机平台的显微镜示意图[78];(d) Kheireddine等基于智能手机平台的显微镜示意图[79]
Figure 8. Schematic diagram of various self-correcting intelligent mobile phone platform microscopic imaging systems based on inverted mobile phone lenses. (a) Schematic diagram of the smartphone platform-based microscope proposed by Switz et al[76]; (b) Schematic diagram of the smartphone platform-based microscope proposed by D’Ambrosio et al[77]; (c) Schematic diagram of the smartphone platform-based microscope proposed by Kim et al[78]; (d) Schematic diagram of the microscope based on smartphone platform by Kheireddine et al[79]
2015年,D’Ambrosio[77]团队利用倒置手机摄像头镜头和LED阵列设计了基于智能手机平台的显微成像系统,可在图像分辨率<6.5 μm的情况下获得大于4 mm×3.16 mm的视场,系统如图8 (b) 所示。
Kim[78]等在智能手机相机的外部添加手机相机镜头模块,构建了基于智能手机平台的荧光显微镜,外置镜头模组与内置手机摄像头形成中继系统,通过LED或LD激发样品。该系统可获得2.5 μm的图像分辨率及1.2 mm×1.2 mm的视场,其系统结构见图8 (c) 。
2018年,Kheireddine[79]等使用倒置手机摄像头镜头作为基于智能手机平台的显微镜物镜,利用另外一部手机屏幕作为照明光源,手机屏幕照明允许轻松生成可用于不同显微镜模式的照明模式,成像手机提供高空间分辨率和大视场。系统结构如图8 (d) 所示。因为智能手机本身的极高制造量,使得相应的手机摄像头镜头的成本较低,这种配置的手机显微系统可进一步推进资源有限、偏远的农村地区的医疗诊断、细菌检测等方面的发展。但使用倒置手机摄像头镜头的手机显微成像系统的光学放大率M=1,在需要较大的光学放大率和较高分辨率的应用中,这种系统配置还是无法满足目标需求。
Review of computational optical microscopy imaging technology based on smartphone platform
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摘要: 计算光学显微成像技术将光学编码和计算解码相结合,通过光学操作和图像算法重建来恢复微观物体的多维信息,为显微成像技术突破传统成像能力提供了强大的助力。这项技术的发展得益于现代光学系统、图像传感器以及高性能数据处理设备的优化,同时也被先进的通信技术和设备的发展所赋能。智能手机平台作为高度集成化的电子设备,具有先进的图像传感器和高性能的处理器,可以采集光学系统的图像并运行图像处理算法,为计算光学显微成像技术的实现创造了全新的方式。进一步地,作为可移动通信终端,智能手机平台开放的操作系统和多样的无线网络接入方法,赋予了显微镜灵活智能化操控能力与丰富的显示和处理分析功能,可用于实现各种复杂环境下多样化的生物学检测应用。文中从四个方面综述了基于智能手机平台的计算光学显微成像技术,首先综述了智能手机平台作为光学成像器件的新型显微成像光路设计,接下来介绍了基于智能手机平台先进传感器的计算光学高通量显微成像技术,然后介绍了智能手机平台的数据处理能力和互联能力在计算显微成像中的应用,最后讨论了这项技术现存在的一些问题及解决方向。Abstract: Computational optical microscopy imaging technology combines optical encoding and computational decoding to retrieve multi-dimensional information of microscopic objects through optical manipulation and image algorithm reconstruction, providing a powerful boost for microscopy imaging technology to break through traditional imaging capabilities. The development of this technology has benefited from the optimization of modern optical systems, image sensors, and high-performance data processing equipment, and is also enabled by the development of advanced communication technologies and equipment. As a highly integrated electronic device, the smartphone platform has an advanced image sensor and a high-performance processor, which can collect the image of the optical system and run the image processing algorithm, creating a new way for the realization of computational optical microscopy imaging technology. Furthermore, as a mobile communication terminal, the open operating system and various wireless network access methods of the smartphone platform endow the microscope with flexible and intelligent control capabilities and rich display and processing analysis functions, which can be used to realize diversified biological detection applications in various complex environments. In this paper, the computational optical microscopy imaging technology based on the smartphone platform was reviewed from four aspects. First, the design of the new microscopic imaging optical path based on the smartphone platform as an optical imaging device was reviewed. Next, the computational optical high-throughput microscopy imaging technology based on the advanced sensor of the smartphone platform was introduced. Then, the application of the data processing and interconnection capabilities of the smartphone platform in computational microscopy imaging was introduced, and finally some of the existing problems and solutions of this technology were discussed.
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图 2 基于智能手机平台的显微系统中的物镜类型。(a) 标准显微成像光路;(b) 定制化单透镜;(c) 倒置手机摄像头镜头的自校正显微光路
Figure 2. Type of objective lens in microscope system based on smartphone platform. (a) Standard microscopic imaging light path; (b) Customized single lens; (c) Self-correcting microscopic optical path of inverted camera lens of smartphone
图 3 各种基于标准显微成像光路的智能手机平台显微成像系统示意图。(a) Breslauer等提出的基于手机平台的显微镜示意图[40];(b) Shan等提出的基于智能手机平台的显微镜示意图[57];(c) Shrivastava等提出的基于智能手机平台的显微镜示意图[58]
Figure 3. Schematic diagram of various microscopic imaging systems of smartphone platform based on standard microscopic imaging optical path. (a) Schematic diagram of microscope based on mobile phone platform proposed by Breslauer et al[40]; (b) Schematic diagram of microscope based on smartphone platform proposed by Shan et al[57]; (c) Schematic diagram of microscope based on smartphone platform proposed by Shrivastava et al[58]
图 4 各种基于球透镜的智能手机平台显微成像系统示意图。(a) Bogoch提出的基于智能手机平台的显微镜示意图[62];(b) Jahan-Tigh等提出的基于智能手机平台的显微镜示意图[42]; (c) Kutay等提出的基于智能手机平台的显微镜示意图[65];(d) Zeng等提出的基于智能手机平台的显微镜示意图[63]; (e) Agbana等提出的基于智能手机平台的显微镜示意图[64]
Figure 4. Schematic diagram of microscopic imaging systems of various smartphone platforms based on spherical lens. (a) Schematic diagram of microscope based on smartphone platform proposed by bogoch et al[62]; (b) Schematic diagram of microscope based on smartphone platform proposed by Jahan Tigh et al[42]; (c) Schematic diagram of microscope based on smartphone platform proposed by kutay et al[65]; (d) Schematic diagram of microscope based on smartphone platform proposed by Zeng et al[63]; (e) Schematic diagram of microscope based on smartphone platform proposed by Agbana et al[64]
图 5 各种基于非球面透镜的智能手机平台显微成像系统示意图。(a) Arpa等提出的基于智能手机平台的显微镜示意图[66];(b) Felton等提出的基于智能手机平台的显微镜示意图[67]
Figure 5. Schematic diagram of various micro imaging systems of smart phone platform based on aspheric lens. (a) Schematic diagram of microscope based on smart phone platform proposed by ARPA et al[66]; (b) Schematic diagram of microscope based on smartphone platform proposed by Felton et al[67]
图 6 各种基于PDMS透镜的智能手机平台显微成像系统示意图。(a) Sung等提出的PDMS喷墨打印透镜制作过程及其基于智能手机平台的显微镜示意图[73];(b) Sung等提出的基于智能手机平台的显微镜示意图[74];(c) Fuh等提出的液体驱动透镜的制作过程和基于智能手机平台的显微镜示意图[75]
Figure 6. Schematic diagram of microscopic imaging systems of various smartphone platforms based on PDMS lens. (a) Schematic diagram of the manufacturing process of PDMS inkjet printing lens and its microscope based on smartphone platform proposed by Sung et al[73]; (b) Schematic diagram of microscope based on smartphone platform proposed by Sung et al[74]; (c) Schematic diagram of fabrication process of liquid-driven lens and microscope based on smartphone platform proposed by Fuh et al[75]
图 7 基于智能手机平台的显微镜结构的比较[76]。(a) 基于球形镜头手机显微镜示意图;(b) 基于标准有限远显微系统的手机显微镜的示意图;(c) 基于倒置手机镜头显微镜示意图
Figure 7. Comparison of microscope structures based on smartphone platforms[76]. (a) Schematic diagram of a spherical lens-based cell phone microscope; (b) Schematic of a cell phone microscope based on a standard infinity microscope system; (c) Schematic diagram of a microscope based on an inverted mobile phone lens
图 8 各种基于倒置手机镜头的自校正智能化手机平台显微成像系统示意图。(a) Switz等提出的基于智能手机平台的显微镜示意图[76];(b) D’Ambrosio等提出的基于智能手机平台的显微镜示意图[77];(c) Kim等提出的基于智能手机平台的显微镜示意图[78];(d) Kheireddine等基于智能手机平台的显微镜示意图[79]
Figure 8. Schematic diagram of various self-correcting intelligent mobile phone platform microscopic imaging systems based on inverted mobile phone lenses. (a) Schematic diagram of the smartphone platform-based microscope proposed by Switz et al[76]; (b) Schematic diagram of the smartphone platform-based microscope proposed by D’Ambrosio et al[77]; (c) Schematic diagram of the smartphone platform-based microscope proposed by Kim et al[78]; (d) Schematic diagram of the microscope based on smartphone platform by Kheireddine et al[79]
图 11 基于手机平台的计算光学高通量显微镜示意图。(a) Tseng等提出的基于智能手机平台的显微镜示意图[87];(b) Seung等提出的基于智能手机平台的显微镜示意图[88]
Figure 11. Schematic diagram of the computational optics high-throughput microscope based on the mobile phone platform. (a) Schematic diagram of the microscope based on the smartphone platform proposed by Tseng et al.[87]; (b) Schematic diagram of the microscope based on the smartphone platform proposed by Seung et al[88]
图 12 各种基于智能手机平台的显微镜应用程序示意图。(a) Zhu等提出的“血液分析”应用程序的总体工作流程图[93];(b) Navruz 等定制开发的Android应用程序的工作流程图[94];(c) Wei等提出的手机荧光显微镜和应用程序的示意图[95];(d) Phillips等提出的Android应用程序工作流程图[96]
Figure 12. Schematic diagram of various microscope applications based on smartphone platforms. (a) Overall work flow chart of "blood analysis" application proposed by Zhu et al[93]; (b) Work flow chart of Android application customized and developed by Navruz et al[94]; (c) Schematic diagram of mobile phone fluorescence microscope and application proposed by Wei et al[95]; (d) Workflow diagram of Android application proposed by Phillips et al[96]
图 13 使用基于智能手机平台的显微镜实现定量、可再现成像的步骤[97]。(a) 标准化光源和亮度;(b) 在具有已知尺寸或特征的区域上设置焦点状态;(c) 使用清晰的视场设置曝光和增益; (d) 获取样本图像,同时保持采图设置不变;(e) 可以通过选择无损或高质量压缩设置来保留信息内容
Figure 13. Steps for quantitative, reproducible imaging using a smartphone platform-based microscope[97]. (a) Standardize illumination source and brightness; (b) Set focal state on a field with known dimensions or features; (c) Set exposure and gain using a clear field of view; (d) Acquire images of samples while keeping capture settings constant; (e) Information content can be preserved by selecting lossless or high quality compression settings
图 14 (a) Zimic等提出的利用智能手机平台无线传输的工作流程图[101];(b) Rabha等提出的基于智能手机平台的显微系统的工作流程图[110];(c) Wan等提出的基于智能手机平台的显微系统实时无线观察的工作流程图[103]
Figure 14. (a) Work flow chart of wireless transmission using smart phone platform proposed by Zimic[101]; (b) Workflow diagram of micro system based on smart phone platform proposed by Rabha et al[110]; (c) Work flow chart of real-time wireless observation of microscope system based on smart phone platform proposed by Wan et al[103]
图 15 各种结合深度学习的基于智能手机平台的显微镜。(a) Rivenson等提出的智能手机显微镜系统结构和深度学习结果示意图[117];(b) Han[118]等提出的智能手机显微镜系统结构示意图和两个深度学习网络的工作流程图;(c) Bian[119]等提出的智能手机显微镜系统结构示意图和基于深度学习风格迁移方法的工作流程图
Figure 15. Various smartphone platform-based microscopes combined with deep learning. (a) Schematic diagram of smartphone microscope system structure and deep learning results proposed by Rivenson et al[117]; (b) The structure diagram of smartphone microscope system and the workflow diagram of two deep learning networks proposed by Han et al [118]; (c) The structure diagram of smartphone microscope system and the workflow diagram based on deep learning style transfer method proposed by Bian et al[119]
图 16 各种基于智能手机平台的明场显微镜示意图。(a) Hutchison等提出的基于智能手机平台的明场显微镜示意图[128];(b) Orth等提出的基于智能手机平台的明场显微镜示意图[129];(c) Cai等提出的基于智能手机平台的明场显微镜示意图[130]
Figure 16. Schematic diagrams of various brightfield microscopes based on smartphone platforms. (a) Schematic diagram of the brightfield microscope based on the smartphone platform proposed by Hutchison et al[128]; (b) Schematic diagram of the smartphone platform-based brightfield microscope proposed by Orth et al[129]; (c) Schematic diagram of brightfield microscope based on smartphone platform proposed by Cai et al[130]
图 17 各种基于智能手机平台的暗场显微镜示意图。(a) Sun等提出的基于智能手机平台的显微镜示意图[134];(b) Ogasawara等提出的基于智能手机平台的显微镜示意图[135];(c) Kheireddine等提出的基于智能手机平台的显微镜示意图[131];(d) Rabha等提出的基于智能手机平台的显微镜示意图[110]
Figure 17. Schematic diagram of various darkfield microscopes based on smartphone platforms. (a) Schematic diagram of the microscope based on the smartphone platform proposed by Sun et al[134]; (b) Schematic diagram of the smartphone platform-based microscope proposed by Ogasawara et al[135]; (c) Schematic diagram of the smartphone platform-based microscope proposed by Kheireddine et al[131]; (d) Schematic diagram of the microscope based on the smartphone platform proposed by Rabha et al[110]
图 18 各种基于智能手机平台的差分相衬显微镜示意图。(a) Jung等提出的基于智能手机平台的显微镜示意图[136];(b) Ogasawara等提出的基于智能手机平台的显微镜示意图[135];(c) Kheireddine等提出的基于智能手机平台的显微镜示意图[131]
Figure 18. Schematic diagram of various differential phase contrast microscopes based on smartphone platforms. (a) Schematic diagram of the smartphone platform-based microscope proposed by Jung et al[136]; (b) Schematic diagram of the smartphone platform-based microscope proposed by Ogasawara et al[135]; (c) Schematic diagram of the smartphone-based microscope proposed by Kheireddine et al[131]
图 19 各种基于智能手机平台的定量相位成像显微镜示意图。(a) Lee等提出的基于智能手机平台的显微镜示意图[88];(b) Meng等提出的基于智能手机平台的显微镜示意图[153];(c) Phillips等提出的基于智能手机平台的显微镜示意图[96]
Figure 19. Schematic diagram of various quantitative phase imaging microscopes based on smartphone platforms. (a) Schematic diagram of the smartphone platform-based microscope proposed by Lee et al[88];(b) Schematic diagram of the microscope based on the smartphone platform proposed by Meng et al[153]; (c) Schematic diagram of the smartphone platform-based microscope proposed by Phillips et al[96]
图 20 各种基于智能手机平台的荧光显微镜示意图。(a) Coskun等提出的基于智能手机平台的显微镜示意图;(b) Cai等提出的基于智能手机平台的显微镜示意图[130];(c) Zhu等提出的基于智能手机平台的显微镜示意图[162];(d) Wei等提出的基于智能手机平台的显微镜示意图[95];(e) Dai等提出的基于智能手机平台的显微镜示意图[165]
Figure 20. Schematic diagrams of various smartphone-based fluorescence microscopes. (a) Schematic diagram of the microscope based on the smartphone platform proposed by Coskun et al; (b) Schematic diagram of the microscope based on the smartphone platform proposed by Cai et al[130]; (c) Schematic diagram of the microscope based on the smartphone platform proposed by Zhu et al[162]; (d) Schematic diagram of the microscope based on the smartphone platform proposed by Wei et al[95]; (e) Schematic diagram of the microscope based on the smartphone platform proposed by Dai et al[165]
图 21 (a) Pirnstill等提出的基于智能手机平台的偏振显微镜系统结构示意图;(b) 没有偏光片采集的淀粉分子的图像;(c) 偏光器和检偏器以 90°交叉采集的淀粉分子的图像[170]
Figure 21. Schematic diagram of the polarization microscope system based on the smartphone platform proposed by Pirnstill et al; (b) No polarizer images of starch molecules were collected; (c) The polarizer and polarizer cross collect the images of starch molecules at 90°[170]
表 1 三类基于智能手机平台的新型显微成像光路设计的优缺点
Table 1. Advantages and disadvantages of three types of new microscopic imaging optical path designs based on smartphone platforms
Lens type Advantage Disadvantage Standard microscope objective and eyepiece High resolution images are obtained in a limited field of view with small aberrations The system structure is complex and the cost is high Single lens (spherical lens, aspheric lens, liquid lens) The lens has the advantages of low cost, easy fixation and large optical magnification The off-axis aberration of the system is large; In color imaging, serious color difference will appear in any single lens method Inverted camera lens of mobile phone It can make full use of smartphone image sensor and obtain high-resolution image. The optical magnification of the system is M = 1, which is limited in applications requiring large magnification -
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