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摘要:
生物医学光学成像技术因其高分辨率和无辐射毒性的优势成为了连接基础科学研究与临床应用的桥梁，对推动医学进步和提高公共健康水平起到了重要作用。然而，生物医学光学成像系统往往需要将光、机、电、控元件整合为一体，导致设备笨重且昂贵，难以满足人们对即时诊断和体内微创高分辨率成像的需求。随着元件加工手段的进步和新式技术的引入，微型化生物医学光学成像系统的设计制造逐渐开始成为了新的研究热点之一。本文分别对用于体外和体内检测的微型化生物医学光学成像系统的基本原理、关键技术以及在临床中的具体应用进行了深入地综述和总结，最后展望了该领域的发展方向。
Abstract:Biomedical optical imaging techniques have become essential for bridging fundamental scientific research and clinical applications, owing to their high resolution and absence of radiation toxicity. These advancements are crucial for driving medical innovation and improving public health outcomes. However, the integration of optical, mechanical, electrical, and control components in biomedical optical imaging systems often leads to bulky and costly equipment. This complexity limits their capacity to fulfill the growing demand for point-of-care testing (POCT) and high-resolution, minimally invasive imaging. Recent advancements in component fabrication techniques and the emergence of new technologies have positioned the design and manufacture of miniaturized biomedical optical imaging systems as a significant area of research. This review comprehensively addresses the fundamental principles, key technologies, and specific clinical applications of these systems for both in vitro and in vivo detection. Lastly, we provide insights into potential future directions in this evolving field.
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Key words:
- biomedical /
- optical imaging systems /
- miniaturization /
- endoscopic imaging systems
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Overview: Recent advancements in biomedical optical imaging have profoundly reshaped medical diagnostics and research, offering high-resolution, non-invasive methods that effectively connect fundamental science with clinical applications. Despite their potential, traditional imaging systems are often hindered by issues of size, complexity, and cost, limiting their utility in real-time diagnostics and in vivo imaging. This manuscript provides an in-depth explanation of miniaturized biomedical optical imaging systems, emphasizing their design principles, technological innovations, and varied applications in both in vitro and in vivo contexts.This study highlights pivotal advancements in miniaturization techniques that have led to the development of compact imaging systems capable of delivering high-quality images while being user-friendly and cost-effective. We examine the fundamental principles underlying these systems, particularly the integration of optical components with micro-electromechanical systems (MEMS) and innovative imaging modalities such as two-photon and three-photon microscopy.In this investigation, we categorize miniaturized imaging systems into two primary modules: in vitro detection systems, which encompass microfluidic optical systems and miniaturized microscopy, and in vivo detection systems, including macro-endoscopic and microscopic endoscopic imaging. We present a series of experimental results that demonstrate the efficacy of these systems across various applications, such as sensitive cellular analysis, real-time monitoring of biological processes, and early disease detection. Importantly, our findings indicate that these miniaturized systems not only enhance imaging resolution but also significantly reduce the invasiveness of procedures, thereby improving patient comfort and clinical outcomes.The manuscript also discusses the integration of artificial intelligence (AI) and machine learning (ML) algorithms with miniaturized imaging systems, highlighting their potential to revolutionize image analysis and interpretation. By leveraging AI and ML, we foresee advancements in automated diagnostics, enabling rapid and accurate assessments in clinical settings.In conclusion, miniaturized biomedical optical imaging systems represent a paradigm shift in medical imaging, offering unprecedented opportunities for improving diagnostic capabilities and therapeutic monitoring. As research continues to advance in this field, these systems are poised to address critical global health challenges, ultimately leading to enhanced patient care and outcomes. Our study underscores the importance of continued innovation in imaging technologies, advocating for further exploration into their integration with emerging computational techniques to maximize their potential impact in healthcare.
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图 3 光路图无透镜集成成像系统光路图
Figure 3. Optical schematic of the lens-free integrated imaging system
图 4 无透镜集成显微成像系统。(a) 基于非相干全息成像技术的紧凑型无透镜系统[45]；(b) 由(a)设备拍摄的聚苯乙烯颗粒组成的样品的全视场DIC图像；(c) 高对比度无透镜系统[48]；(d) 由(c)设备拍摄的固定水螅样本的重建的深度颜色编码图像；(e) 高分辨率3D荧光无透镜成像系统FlatScope[49]。标尺：100 μm；(f) 由(e)设备拍摄的荧光粒子重建图像。标尺：100 μm(插图中为50 μm)；(g) 基于随机微透镜漫射器的高信噪比无透镜成像系统[51]；(h) 由(g)设备拍摄的斑马鱼幼鱼样本。
Figure 4. Lensless integrated microscopic imaging system. (a) Compact lensless system based on incoherent holographic imaging system[45]; (b) A full-field DIC image of the sample composed of polystyrene particles, acquired using the (a) device; (c) High contrast lensless system[48]; (d) A reconstructed depth-coded image of the fixed Hydra sample, captured using the (c) device; (e) High-resolution 3D fluorescent lensless imaging system, FlatScope[49]. Scale bars of 100 μm; (f) A reconstructed image of fluorescent particles, acquired using the (e) device. Scale bars of 100 μm (50 μm in inset); (g) High SNR lensless imaging system based on a random microlens diffuser[51]; (h) Zebrafish larval sample imaged using the (g) device.
图 5 集成光流控成像系统光路图
Figure 5. Optical schematic of the integrated optofluidic imaging system
图 6 微型化光流控流式细胞仪。(a) 基于手机平台的流式细胞仪[56]; (b) 图(a)系统的细胞计数界面; (c) 无泵式流式细胞仪[57]; (d) 图(c)系统的细胞计数界面; (e) 集成式微型流式细胞仪[58]; (f) 智能掌上光流控血细胞计数仪[35]; (g) 图(f)系统流道内白细胞的成像效果
Figure 6. Miniaturized optofluidic flow cytometer. (a) Miniaturized optofluidic flow cytometer based on a mobile platform[56]; (b) The cell counting interface of the system in Figure (a); (c) Pumpless flow cytometer[57]; (d) The cell counting interface of the system in Figure (c); (e) Integrated miniaturized flow cytometer[58]; (f) Smart palm-size optofluidic hematology analyzer[35]; (g) Figure (f) Imaging effect of white blood cells in the system channel
图 7 图2D宏观内窥成像系统光路图
Figure 7. Optical schematic of the 2D macroscopic endoscopic imaging system
图 8 3D宏观内窥成像系统光路图
Figure 8. Optical schematic of the 3D macroscopic endoscopic imaging system
图 9 基于光场技术的3D内窥镜。(a) 基于微透镜阵列的刚性光场内窥镜[86]; (b) 基于Grin lens阵列的光场内窥镜验证机[76]; (c) 基于图(b)设备拍摄的指纹样本，比例尺：2.0 mm; (d) 基于Grin lens阵列的光场内窥镜原型机(GLAM)[36]; (e) 基于图(d)系统拍摄的三维样品; (f) 高柔性光场内镜[11]; (g) 基于图(f)系统拍摄的兔子胃部深度图，比例尺：500 μm
Figure 9. 3D endoscopes based on light-field method. (a) Rigid light-field endoscope based on microlens[86]; (b) Verification machine of light-field endoscope based on Grin lens array[76]; (c) Fingerprint sample taken by the device based on Figure (b), scale bar of 2.0 mm; (d) Prototype of light-field endoscope based on Grin lens array[36]; (e) 3D samples taken based on Figure (d) system; (f) Highly flexible light-field endoscope[11]; (g) Rabbit stomach depth map based on system of Figure (f), scale bar of 500 μm
图 10 胶囊内窥成像系统光路图
Figure 10. Optical schematic of the capsule endoscopic imaging system
图 11 共聚焦内窥成像系统光路图
Figure 11. Optical schematic of the confocal endoscopic imaging system
图 12 共聚焦内窥成像系统。(a) 手持双轴刚性共聚焦内窥镜[94]; (b) 通过图(a)设备拍摄的小鼠离体组织图像; (c) 基于光纤谐波仪的手持式共聚焦内窥成像系统[96]; (d) 由图(c)设备拍摄的小鼠离体结肠图片，比例尺：10 μm; (e) 基于电热MEMS激光扫描内窥成像系统[99]，比例尺：2 mm； (f) 基于双光子和二次谐波成像的内窥成像系统[102]; (g) 由图(f)设备拍摄的小鼠离体肝细胞图片，比例尺：20 μm
Figure 12. Confocal endoscopic imaging system. (a) Handheld dual-axes confocal endoscope[94]; (b) Image of a mouse tissue taken in vitro by the device in Figure (a); (c) Handheld endomicroscope using a fiber-optic harmonograph[96]; (d) Ex vivo image of isolated mouse colon cells taken by the device in Figure (c), scale bar of 10 μm; (e) Electrothermal MEMS fiber scanner for optical endomicroscopy[99], scale bar of 2 mm; (f) Endoscopic imaging system based on two-photon and second harmonic imaging[102]; (g) Image of isolated mouse liver cells taken by the device in Figure (f), scale bar of 20 μm
图 14 OCT内窥系统。(a) 高消色差OCT微探针[123]; (b) 由图(a)中的设备拍摄的4 mm长的大鼠食管; (c) 带有相位滤波器的光学探针[124]; (d) 纳米光学OCT内窥镜[125]; (e) 由图(d)中的设备对猪气道的离体成像，比例尺：500 μm; (f) 超薄单片三维打印OCT内窥镜[32]; (g) 由图(f)中的设备对健康小鼠动脉血管的成像
Figure 14. OCT endoscopic system. (a) Super-achromatic OCT microprobe[123]; (b) 4 mm-long rat esophagi imaged by the device shown in Figure (a); (c) Optical probe with a phase filter[124]; (d) Nano-optic OCT endoscope[125]; (e) Ex vivo imaging of the pig trachea using the device shown in Figure (d), scale bar of 500 μm; (f) Ultrathin monolithic 3D printed OCT endoscope[32]; (g) Imaging of the arterial vasculature in healthy mice using the device shown in Figure (f)
图 15 头戴式微型化显微成像系统光路图
Figure 15. Optical schematic of the head-mounted miniaturized microscopy imaging system
图 16 微型化显微成像系统。(a) 大视场微型化显微镜(MiniLFOV)[133]; (b) 微型化全脑中微镜(mini-mScope)[134];(c) 微型化双光子显微镜(FHIRM-TPM)[142]; (d) 微型化三光子显微镜(m3PM)[144]
Figure 16. Miniaturized microscopic imaging system. (a) Large-field-of-view miniscope(MiniLFOV)[133]; (b) Miniaturized microscope for whole-cortex mesoscale imaging(mini-mScope)[134]; (c) Miniaturized two photon microscope(FHIRM-TPM)[142]; (d) Miniaturized three photon microscope(m3PM)[144]
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