多尺度光声显微成像用于在体微循环的初步研究
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摘要
微循环是微血管范畴内的血液循环,其主要功能是进行血液和组织之间的物质交换。很多重大疾病都涉及到微循环的异常改变,因此对微循环的在体成像研究具有重大的临床诊断意义。微血管网络的空间结构错综复杂,而且管径在几微米到200微米范围内变化,因此单一尺度的成像技术不能很好地对复杂的微循环网络进行成像。光声显微成像(photoacoustic microscopy, PAM)技术将光吸收编码成超声波,能够对生物组织的同一对比度源进行多尺度的成像研究,而且,由于超声波在组织中的散射远小于光的散射,该技术的成像深度更深。因此,PAM能够在深层组织对微循环网络进行多尺度的在体三维成像,在微循环的研究中具有明显的优势。本文旨在发展和利用多尺度PAM系统对微循环进行成像研究,具体内容如下：
(1)为了在深层组织对微循环进行成像,利用声学分辨功能光声显微成像(functional photoacoustic microscopy, fPAM)系统对微循环进行了在体成像研究。通过对系统的性能参数进行评估,得到系统的侧向分辨率为45μm,组织中的成像深度为3mm。通过对大鼠背部皮下、脑皮层以及人手掌皮下的微循环进行在体成像,证明系统具有在深层组织对微循环进行结构成像的能力。
(2)由于声学分辨的fPAM系统的分辨率不足以对毛细血管水平的微循环进行成像研究,同时为了提高高分辨率PAM系统在组织中的成像深度,采用一种新的光声探测结构设计,研制了一套基于反射物镜的高分辨光学分辨PAM系统。反射物镜一方面实现近光学衍射极限的光学聚焦,另一方面使得超声探头能够放置于其中间的空心光锥里以实现直接的超声探测,避免了超声传输过程中多界面反射造成的额外的超声能量损失,从而提高超声的收集效率。超声探头采用具有高灵敏度的聚乙二烯二氟化物(polyvinylidene difluoride, PVDF)薄膜作为压电换能材料,高效地探测到激发的超声波,使得系统具有足够的灵敏度探测单根毛细血管以及离散的红细胞的光声信号。对系统的性能进行评估,显示系统的侧向分辨率为1.2μm,同时具有相对深的穿透深度,在生物组织里最大成像深度可达到0.9mm,能够在体分辨单根毛细血管和离散的红细胞。通过对小鼠耳廓的微血管进行在体成像,证明该系统具备在相对深的组织范围对毛细血管水平的微循环进行在体成像研究的能力。
(3)为了实现对大脑皮层微循环的多信息成像,联合fPAM技术和LSI技术对大鼠大脑早期低灌注的脑皮层微循环进行了多参数成像研究。利用大鼠脑瞬时低灌注模型,在大鼠单侧颈总动脉结扎后,即刻检测同侧脑皮层不同深度处微血管的血流速度、血氧饱和度和总血红蛋白浓度的变化。在结扎后6s时刻,各参数均下降到最低,分别为结扎前的37±3%、72±7%和93±2%。随后各参数均有不同程度的恢复,其中血氧饱和度的恢复明显滞后于血流速度和总血红蛋白浓度的恢复。从整个过程来看,结扎后血流速度和血红蛋白浓度具有相似的响应速度和变化趋势。
Microcirculation is referred to as blood circulation within microvasculature, and the mass exchange between blood and tissue is the fundamental function of microcirculation. Since many serious diseases are involved with the abnormal change of microcirculation, it is of great clinical significance to study microcirculation by in vivo imaging techniques with high temporalspatial resolution. Because the spatial structure of the microcirculation network is complicated, and the diameters of the microvasculature vary from several micrometers to200micrometer, imaging techniques with single scale are not able to map microcirculation well. Photoacoustic microscopy (PAM) encodes the optical absorption to ultrasound, and can provide multiscale imaging for biolgy tissue with the same contrast source. Furthermore, due to that the ultrasound scattering is much lower than optical scattering in tissue, PAM can obtain higher image depth than other optical imaging tools. Therefore, PAM has advantages on imaging of the complicated microcirculation network in deep tissue in vivo with multiple scales in three dimensions (3-D). This study aimed to develop and utilize the multiscale PAM system for the research on microcirculation. More detail is desacribed as follows:
(1) In order to image the microcirculation in deep biology tissue, the previously built acoustic-resolution functional photoacoustic microscopy (fPAM) system in our lab was used. The system lateral resolution was measured to be45μm, and the system imaging depth was measured to be3mm in tissue. Microvasculatures in dorsal skin and cerebral cortex in rat and the palm of volunteers were studied by fPAM, it was demonstrated that this system of fPAM has the ability to image the strcuture of microcirculation in deep biology tissue.
(2) As the resolution of the acoustic-resolution fPAM described above is not sufficient to image capillaries of microcircution, meanwhile, in order to improve the imaging depth of high resolution PAM systems, a new photoacoustic probe was designed and a high resolution optical-resolution PAM (OR-PAM) system based on a reflective objective was developed. The reflective objective was used to obtain near optical diffraction-limited focus. Meanwhile, the ultrasound transducer was located into the hollow optical cone of the objective to realize direct ultrasonic detection, and the ultrasonic detection efficiency is improved without the loss of ultrasound transmission energy due to reflection on multiple interfaces. A polyvinylidene difluoride (PVDF) ultrasonic transducer with high sensitivity was utilized to collect the excited ultrasound, which guaranteed that the system could image a single capillaries and red blood cells with sufficient sensitivity. The lateral resolution of this new system at focus was measured to be1.2μm, and the system could image the targets with relatively high penetration depth of0.9mm in biological tissue. These make the system can resolve a single capillaries and discrete red blood cells in vivo. The system was demonstrated to have the capacity to study microcirculation in capillary level by imaging the microvasculature in mouse ear.
(3) In order to realize the multiple-information image of the cortex, the multiple-parameter imaging of the rat cortex microcirculation in early cerebral hypoperfusion was performed by combining the fPAM with laser speckle imaging (LSI). The transient changes in cerebral blood flow (CBF), oxygen saturation (SO2) and total hemoglobin concentration (HbT) in single micro blood vessels of ipsilateral cortex were observed during transient cerebral hypoperfusion by ligating the unilateral common carotid artery (CCA) in rats. CBF, SO2, and HbT respectively decreased to37±3%,72±7%, and93±2%of baseline in6seconds immediately after occlusion, and then recovered with different degree. In summary, these parameters showed the decrease with different degree and the following recovery over time after ligation, the recovery of SO2lagged behind those of CBF and HbT, which had the similar response.
(1)为了在深层组织对微循环进行成像,利用声学分辨功能光声显微成像(functional photoacoustic microscopy, fPAM)系统对微循环进行了在体成像研究。通过对系统的性能参数进行评估,得到系统的侧向分辨率为45μm,组织中的成像深度为3mm。通过对大鼠背部皮下、脑皮层以及人手掌皮下的微循环进行在体成像,证明系统具有在深层组织对微循环进行结构成像的能力。
(2)由于声学分辨的fPAM系统的分辨率不足以对毛细血管水平的微循环进行成像研究,同时为了提高高分辨率PAM系统在组织中的成像深度,采用一种新的光声探测结构设计,研制了一套基于反射物镜的高分辨光学分辨PAM系统。反射物镜一方面实现近光学衍射极限的光学聚焦,另一方面使得超声探头能够放置于其中间的空心光锥里以实现直接的超声探测,避免了超声传输过程中多界面反射造成的额外的超声能量损失,从而提高超声的收集效率。超声探头采用具有高灵敏度的聚乙二烯二氟化物(polyvinylidene difluoride, PVDF)薄膜作为压电换能材料,高效地探测到激发的超声波,使得系统具有足够的灵敏度探测单根毛细血管以及离散的红细胞的光声信号。对系统的性能进行评估,显示系统的侧向分辨率为1.2μm,同时具有相对深的穿透深度,在生物组织里最大成像深度可达到0.9mm,能够在体分辨单根毛细血管和离散的红细胞。通过对小鼠耳廓的微血管进行在体成像,证明该系统具备在相对深的组织范围对毛细血管水平的微循环进行在体成像研究的能力。
(3)为了实现对大脑皮层微循环的多信息成像,联合fPAM技术和LSI技术对大鼠大脑早期低灌注的脑皮层微循环进行了多参数成像研究。利用大鼠脑瞬时低灌注模型,在大鼠单侧颈总动脉结扎后,即刻检测同侧脑皮层不同深度处微血管的血流速度、血氧饱和度和总血红蛋白浓度的变化。在结扎后6s时刻,各参数均下降到最低,分别为结扎前的37±3%、72±7%和93±2%。随后各参数均有不同程度的恢复,其中血氧饱和度的恢复明显滞后于血流速度和总血红蛋白浓度的恢复。从整个过程来看,结扎后血流速度和血红蛋白浓度具有相似的响应速度和变化趋势。
Microcirculation is referred to as blood circulation within microvasculature, and the mass exchange between blood and tissue is the fundamental function of microcirculation. Since many serious diseases are involved with the abnormal change of microcirculation, it is of great clinical significance to study microcirculation by in vivo imaging techniques with high temporalspatial resolution. Because the spatial structure of the microcirculation network is complicated, and the diameters of the microvasculature vary from several micrometers to200micrometer, imaging techniques with single scale are not able to map microcirculation well. Photoacoustic microscopy (PAM) encodes the optical absorption to ultrasound, and can provide multiscale imaging for biolgy tissue with the same contrast source. Furthermore, due to that the ultrasound scattering is much lower than optical scattering in tissue, PAM can obtain higher image depth than other optical imaging tools. Therefore, PAM has advantages on imaging of the complicated microcirculation network in deep tissue in vivo with multiple scales in three dimensions (3-D). This study aimed to develop and utilize the multiscale PAM system for the research on microcirculation. More detail is desacribed as follows:
(1) In order to image the microcirculation in deep biology tissue, the previously built acoustic-resolution functional photoacoustic microscopy (fPAM) system in our lab was used. The system lateral resolution was measured to be45μm, and the system imaging depth was measured to be3mm in tissue. Microvasculatures in dorsal skin and cerebral cortex in rat and the palm of volunteers were studied by fPAM, it was demonstrated that this system of fPAM has the ability to image the strcuture of microcirculation in deep biology tissue.
(2) As the resolution of the acoustic-resolution fPAM described above is not sufficient to image capillaries of microcircution, meanwhile, in order to improve the imaging depth of high resolution PAM systems, a new photoacoustic probe was designed and a high resolution optical-resolution PAM (OR-PAM) system based on a reflective objective was developed. The reflective objective was used to obtain near optical diffraction-limited focus. Meanwhile, the ultrasound transducer was located into the hollow optical cone of the objective to realize direct ultrasonic detection, and the ultrasonic detection efficiency is improved without the loss of ultrasound transmission energy due to reflection on multiple interfaces. A polyvinylidene difluoride (PVDF) ultrasonic transducer with high sensitivity was utilized to collect the excited ultrasound, which guaranteed that the system could image a single capillaries and red blood cells with sufficient sensitivity. The lateral resolution of this new system at focus was measured to be1.2μm, and the system could image the targets with relatively high penetration depth of0.9mm in biological tissue. These make the system can resolve a single capillaries and discrete red blood cells in vivo. The system was demonstrated to have the capacity to study microcirculation in capillary level by imaging the microvasculature in mouse ear.
(3) In order to realize the multiple-information image of the cortex, the multiple-parameter imaging of the rat cortex microcirculation in early cerebral hypoperfusion was performed by combining the fPAM with laser speckle imaging (LSI). The transient changes in cerebral blood flow (CBF), oxygen saturation (SO2) and total hemoglobin concentration (HbT) in single micro blood vessels of ipsilateral cortex were observed during transient cerebral hypoperfusion by ligating the unilateral common carotid artery (CCA) in rats. CBF, SO2, and HbT respectively decreased to37±3%,72±7%, and93±2%of baseline in6seconds immediately after occlusion, and then recovered with different degree. In summary, these parameters showed the decrease with different degree and the following recovery over time after ligation, the recovery of SO2lagged behind those of CBF and HbT, which had the similar response.
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