摘要
第一部分犬脑梗死模型建立及影像学评估
第一章较大直径血栓栓塞犬大脑中动脉建立类腔隙性脑梗死模型及其影像学评估
目的：研究使用大直径血栓栓塞时，血管的栓塞部位、脑梗死的功能MRI表现，并探讨该模型的发生机制。
方法：选取六只成年健康比格犬，抽取自体静脉血，制备白色血栓。经股动脉插管至左侧颈内动脉近端，注射一条直径约1.7mm、长度约5mm的血栓，血管造影确认左侧大脑中动脉栓塞成功。栓塞后6小时内，每半小时进行DWI和T2WI扫描，之后在12小时、24小时及1周时间点再次进行扫描，通过Image J测量脑梗体积。栓塞后6小时、24小时及1周时，进行PWI及MRA扫描，评估脑灌注及栓塞血管情况。计算脑梗死的PWI-DWI不匹配比值（：PWI体积-DWI体积）/DWI体积。
结果：六只比格犬均出现左侧MCA供血区的单一或多发的，直径小于10mm的圆形或卵圆形类腔隙性脑梗死病灶，主要位于左侧尾状核、内囊及皮质下白质。DWI在栓塞后1.08±0.49小时可以检测到病灶，表现为高信号，24小时病灶直径为（6.38±1.56）mm。栓塞后DWI上病灶体积持续增加，从1小时的（87.19±67.16）mm~3增加至24小时的（368.98±217.05）mm~3（P=0.009）。同时PWI上缺血体积逐渐减小（P=0.002），6小时为（7315.00±2054.38）mm~3，24小时为（4900.33±1319.71）mm~3，一周时降至（3334.33±1195.11）mm~3。梗死后6小时，PWI-DWI不匹配比值为41.93±22.75，表现为“广泛性不匹配”，24小时减小至18.10±13.74（P=0.002）。左侧MCA栓塞后24小时内，MRA未见左侧MCA再通，一周时MCA存在不同程度再通。
结论：1.7mm较大直径血栓可以栓塞MCA近端，由于犬有丰富的颅内外血管吻合，形成了类腔隙性脑梗死。DWI可以早期检测到梗死灶，该模型特征性的MR表现为广泛性的PWI-DWI不匹配。
第二章犬大脑中动脉栓塞联合颈内动脉近端血流阻断建立脑梗死模型及其影像学评估
目的：联合应用MCA栓塞及同侧ICA短暂性或持续性血流阻断建立脑梗死模型，通过功能磁共振对比两种脑梗死模型的特征，探索合适的犬MCA供血区梗死模型。
方法：12只健康成年比格犬，分别抽取静脉血，离心后制备直径约1.7mm，长约5mm的自体白色血栓备用。将犬随机分为两组：组A（n=6只），左侧MCA近端自体白色血栓栓塞后，使用5F椎动脉导管对左侧ICA血流持续阻断2小时；组B（n=6只），左侧MCA近端自体白色血栓栓塞，联合左侧ICA近端明胶海绵条栓塞。在栓塞完成后24小时及1周时分别进行DWI、T2WI及PWI扫描。测量24小时DWI、T2WI及1周T2WI上脑梗死体积，计算24小时及1周rCBF比值（rrCBF），同时对两种模型分别进行神经功能评分。
结果：组A动物脑梗死主要累及左侧颞叶皮质、皮质下白质及左侧基底节，24小时DWI及T2WI体积分别为2154.00±1034.35mm~3、1417.57±926.83mm~3，PWI显示24小时rCBF下降明显，rrCBF为0.61±0.05。1周时T2WI体积下降至841.58±582.42mm~3，rrCBF升高为0.82±0.11。24小时及一周神经系统评分分别为6.53±1.58，4.80±0.98。组B动物脑梗死面积较组A明显增大（P <0.01），表现为左侧MCA供血区大面积脑梗死，24小时DWI及T2WI体积分别为8928.10±1515.52mm~3、6523.94±1460.33mm~3，rCBF下降更明显，rrCBF为0.21±0.09（P <0.01），神经系统评分较组A升高，为8.67±0.52（P <0.05）。一周时组B T2WI体积为4059.87±916.49mm~3，较组A脑梗死体积明显增加，rrCBF为0.56±0.12，神经系统评分为7.33±0.58。组A无动物死亡，而组B一周内出现两只动物死亡。
结论：犬MCA近端栓塞联合同侧ICA阻断2小时的脑梗死模型主要累及MCA供血区皮质、皮质下白质及基底节区，与MCA及ICA近端均栓塞模型相比，梗死体积、脑血流量下降程度和神经功能障碍适中，可以用于脑梗死诊疗相关的实验研究。
第二部分犬骨髓间充质干细胞的磁粒子标记和体外MR成像
目的：探讨超顺磁性氧化铁纳米颗粒（Fe3O4-DMSA-PLL，SPIO）体外标记犬骨髓间充质干细胞（BMSCs）的合适方案，以及体外MR成像特点及示踪时效性。
方法：分离培养犬BMSC，分别用不同浓度SPIO（5,10,20,40,80μg/mL）标记犬BMSC，37℃5%CO2孵育24小时，通过标记效率指标（普鲁士蓝染色）确定最佳标记方案。测定标记后细胞毒性（使用台盼蓝排除试验、AnnexinV-FITC/PI双染细胞凋亡检测SPIO标记后的细胞毒性，并与未标记对照组比较。标记后细胞行3.0T磁共振体外成像，并对标记后BMSCs体外衰减进行长时间示踪。
结果：①20μg/mL及以上浓度的SPIO标记24小时后，BMSCs标记率可达95%以上；②20μg/mL SPIO进行犬BMSCs标记后，细胞凋亡检测显示标记组凋亡细胞比率约为8.86±3.56%，与对照组比较无统计学差异（P>0.05）；③标记细胞在3.0T MRI T2*WI和SWI序列上信号降低最明显，体外可检测的最低细胞量为5×10~4个， T2*值与细胞量呈负相关(P <0.05)；④随标记后培养时间延长，SPIO标记率及信号强度均下降，体外MRI仅可示踪到2周左右，T2*值可一定程度反映体外衰减。
结论： SPIO20μg/ml标记24小时是可行的BMSCs的标记方案，对细胞活力无明显影响。3.0T MRI的T2*WI及SWI序列可以敏感的检测到5×10~4个细胞。纳米铁标记后细胞体外示踪周期较短。
第三部分磁粒子标记犬骨髓间充质干细胞经颈内动脉颅内移植的MR示踪研究
目的：使用犬脑梗死模型，评估经颈内动脉移植超顺磁性纳米铁颗粒（SPIO）标记的犬骨髓间充质干细胞（BMSCs）的可行性，并对移植后细胞进行MR活体示踪研究。
方法：分离培养比格犬骨髓间充质干细胞，用20μg/mL SPIO进行体外标记。14只成年健康比格犬，通过左侧大脑中动脉近端自体血栓栓塞联合左侧颈内动脉血流阻断2小时建立犬脑梗死模型。12只犬于栓塞后一周进行BMSCs移植，2只为对照组。细胞移植前行DSA造影，根据左侧大脑中动脉再通情况，将比格犬分为三组：组A，左侧大脑中动脉完全性再通；组B，左侧大脑中动脉部分性再通；组C，左侧大脑中动脉完全未见再通。3×106个SPIO标记的BMSCs通过左侧颈内动脉进行颅内移植。移植前、移植后1小时、24小时，1周、2周、3周、4周，采用3.0T MRI对移植细胞进行活体示踪。24小时及4周时的MRI结果分别与病理结果（HE及普鲁士蓝染色）进行对照分析。
结果：组A、B、C比格犬数目分别为5只、4只、3只。SPIO标记的BMSCs经左侧颈内动脉移植后，组A比格犬可见左侧大脑半球广泛散在分布的小斑点状低信号，组B比格犬左侧大脑半球内散在的低信号细胞量较组A小，组C犬颅脑内未见明显低信号移植细胞。移植前脑梗死体积越大，移植后颅内细胞量越多。MRI可在四周内对磁粒子标记的BMSCs进行有效示踪。四周时，MRI显示梗死周边明显低信号，HE及普鲁士蓝染色显示梗死周边见聚集的蓝染铁颗粒。
结论：在犬的脑梗死模型中，经颈内动脉途径移植BMSCs技术上可行。移植侧大脑中动脉通畅情况及移植前脑梗死体积可能会影响颅内移植细胞量。MRI对经颈内动脉移植的SPIO-BMSCs可以进行至少四周的有效活体示踪。
Part one: Establishment of cerebral infarction and its MRevaluation in a canine model
Section Ⅰ: Magnetic resonance imaging for assessing a novelembolic stroke resembling lacunar infarction after proximal middlecerebral artery occlusion in a canine model
Purpose: We hypothesized that lacunar infarction could be induced by the proximalMCA occlusion involving the orifices of lenticulostriate arteries in animal models,which had abuntdant distal cerebral collateral anastomosis.This study established aproximal MCA occlusion model using thrombi (1.7mm in diameter and5mm inlength), investigated the MRI characterics of this model and discussed the potentialmechanisms of lacunar infarction.
Materials and Methods: The left proximal MCA was embolized with an autologousthrombus in six beagles. Diffusion-weighted imaging (DWI) and T2-weightedimaging (T2WI) were performed every half hour during the first six hours afterocclusion, followed by three time points at12hours,24hours, and one week.Perfusion-weighted imaging (PWI) and magnetic resonance angiography (MRA)were carried out at six hours,24hours and one week. The PWI-DWI mismatch ratiowas defined as (PWI-DWI)/DWI ischemic volume.
Results: Solitary or multiple small ischemic lesions resembling lacunar infarctionwere induced by MCA occlusion. They located in the left caudate nucleus, internalcapsule and/or deep white matter, with the diameter of6.38±1.56mm at24hour. Allthe lesions could be detected within two hours by DWI. Lesion volume on DWIincreased in a time dependent manner, from (87.19±67.16) mm~3at one hour up to (368.98±217.05) mm~3at24hours (P=0.009), while that on PWI gradually decreasedfrom (7315±2054.38) mm~3at six hours to (4900.33±1319.71) mm~3at24hours and(3334.33±1195.11) mm~3at one week (P=0.002). The mismatch ratio was41.93±22.75at six hours after ischemia, showing “extensive mismatch”, anddecreased to18.10±13.74at24hours (P=0.002). No MCA recanalization wasobserved within24hours after MCA occlusion.
Conclusions: Lacunar infarction could be induced by proximal MCA occlusion incanine model due to abundant collateral anastomosis. It could be detected early byDWI and was characterized by extensive PWI-DWI mismatch.
Section Ⅱ:MR evaluation of canine stroke models established bycombination of middle cerebral artery occlusion and ipsilateralinternal carotid artery blockage
Purpose: To establish two canine stroke models by combination of MCA occlusionand temporal blockage or consistent occlusion of ipsilateral internal carotid artery andto further compare these two models by MR examination.
Materials and Methods: Twelve beagle dogs were enrolled and randomly separatedinto two groups. Group A: left proximal MCA was embolized with autologous clot(1.7mm in diameter,5mm in length), the left ICA was then temporally blocked for2hours using5F vertebral catheter. Group B: left proximal MCA was embolized withautologous clot. The left ICA was also embolized by gelatin sponge. DWI, T2WI andPWI were performed at24hours and one week after embolization. The infarction volumes were measured at24h-DWI,24h-T2WI, and1w-T2WI. rrCBF was assessedfrom24h-and1w-PWI. The neurological scoring at24hours and one week afterembolization were also compared between the two groups.
Results: The ischemic infarctions were mainly located in the left basal ganglia andtemporal lobe in group A. The volume measured on24h-DWI and24h-T2WI were2154.00±1034.35mm~3and1417.57±926.83mm~3, respectively. rrCBF was0.61±0.05.One week later, the infarction volume on T2WI decreased to841.58±582.42mm~3while rrCBF increased to0.82±0.11. The neurological scores were6.53±1.58at24hours and4.80±0.98at one week after embolization, respectively. In group B, largecerebral infarctions involving the left MCA territory were observed. The volumemeasured on24h-DWI and24h-T2WI were8928.10±1515.52mm~3and6523.94±1460.33mm~3, obviously larger than those of group A (P <0.01). rrCBFsharply decreased to0.21±0.09, lower than that of group A (P <0.01). Theneurological scores at24hours was8.67±0.52, higher than that of group A (P <0.05).One week after embolization, the infarction volume on T2WI decreased to4059.87±916.49mm~3, but still much larger than that of group A (P <0.01). rrCBFand neurological score recovered to0.56±0.12and7.33±0.58, respectively. All thebeagles survived for one week in group A. But two beagles in group B sacrificedwithin one week.
Conclusions: Beagle dogs presented moderate volume of cerebral infarction,moderate decreased rCBF and mild neuro-behavioral disfunction after combination ofleft proximal MCA embolization and temporal blockage of left ICA for two hours.This canine stroke model is more suitable for experimental research than the modelinduced by occluding both proximal MCA and ICA.
Part Two: Magnetically labeling of canine bone marrowmesenchymal stem cells and MR imaging in vitro
Purpose: To explore the optimal labeling procedure of canine BMSCs withhome-synthesized superparamagnetic iron oxide (SPIO) and to obtain the in vitro MRimages of the labeled BMSCs by3.0T MR.
Materials and Methods: BMSCs isolated from canines were incubated with SPIOwith different concentrations (5,10,20,40,80μg/mL, respectively) at37℃5%CO2for24hours. The labeling ratio was assessed by Prussian blue staining andimmunofluorescence tests. Cell viability was evaluated by trypan-blue exclusion andAnnexin-FITC/PI apoptosis. Labeled-cells were imaged by3.0T MRI. MR signalattenuation of labeled BMSCs was monitored continuously after in vitro culture.
Results:①When SPIO concentration went up to20μg/mL or above, the labelingratio could reach95%or more;②The apoptosis ratio was8.86±3.56%after BMSCswere labeled with20μg/mL SPIO for24hours, which was not significant differentfrom that of the unlabeled BMSCs;③As few as5×10~4BMSCs could be detected by3.0T MR imaging with T2*WI and SWI sequences. T2*value and BMSCs numberwere inversely correlated (P <0.05);④The labeling ratio and MR signal of BMSCswere attenuated with time after in vitro culture. MR imaging could only track labeledBMSCs efficiently within2weeks.
Conclusions: BMSCs could be labeled with home-synthesized SPIO efficiently andsafely. T2*WI and SWI sequences could detected5×10~4BMSCs sensitively. However,the tracking time of SPIO-labeled BMSCs by3.0T MRI in vitro was short.
Part Three: In vivo MR imaging of intraarterially deliveredmagnetically labeled bone marrow mesenchymal stem cellsin a canine stroke model
Purpose: This study aimed to evaluate the feasibility of intraarterial (IA) delivery andin vivo MR imaging of superparamagnetic iron oxide (SPIO)-labeled bone marrowmesenchymal stem cells (BMSCs) in a canine stroke model.
Materials and Methods: BMSCs harvested from beagles’ bone marrow were labeledwith home-synthesized SPIO. Adult beagle dogs (n=14) were subjected to leftproximal middle cerebral artery (MCA) occlusion by autologous thrombus, followedby two-hour left internal carotid artery (ICA) occlusion with5French vertebralcatheter. One week later,12dogs were classified as three groups before transplantation:group A: complete MCA recanalization, group B: incomplete MCA recanalization,group C: no MCA recanalization.3×106labeled-BMSCs were delivered through leftICA. The left two dogs were distributed to the control group. Series in vivo MRIimages were obtained before cell grafting, one and24hours after transplantation andweekly thereafter until four weeks. MRI findings were compared with histologicalstudies at the time point of24hours and four weeks.
Results: Home-synthesized SPIO was useful to label BMSCs without cell viabilitycompromise. BMSCs scattered widely in the left cerebral hemisphere in group A,while fewer grafted cells were observed in group B and no cell was detected in group Cat one hour after transplantation. A larger infarction on the day of cell transplantationwas associated with more grafted cells in the brain. Grafted BMSCs could be trackedeffectively by MRI within four weeks and were found in peri-infarction area byPrussian blue staining.
Conclusions: It is feasible of IA BMSCs transplantation in a canine stroke model.Both the ipsilateral MCA condition and infarction volume before transplantation mayaffect the amount of grafted cells in target brain. In vivo MR imaging is useful fortracking IA delivered BMSCs after SPIO labeling.
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