弹力酶及胶原酶诱导兔动脉瘤模型的建立与生物力学实验
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摘要
目的：1.使用被弹力酶和胶原酶共同处理过的动脉段通过显微手术移植建立新型兔颈总侧方动脉瘤模型。2.采用体外模拟实验的方法对复制成功的动脉瘤进行生物力学评估; 以期获得其本构关系方程、材料常数以及应力应变关系曲线。
方法：1.取大白兔一侧颈总动脉约2cm制成动脉段浸泡于弹性蛋白酶溶液（0.1ml,6units）和胶原酶溶液（1mg/ml）中各20分钟后，利用显微手术将动脉段移植至另一侧颈总动脉侧方，复制出侧方动脉瘤模型。 2.实验动物经饲养四天后，对其再次手术将制作的动脉瘤模型连同载瘤动脉完整取下。将其作为试件置于一套模拟人体血液循环的加压装置中，并按照预先设计好的压力数对实验试件进行加载、卸载；同时利用高速摄影机在显微镜下记录试件的整体形态的变化。然后利用图形分析软件测量试件的变化值，对其进行数学计算，得到动脉瘤模型的本构方程、材料常数和应力应变关系曲线。3.取相同数量的正常血管作为对照组进行相同的生物力学实验，与实验组相比较。
结果：1. 实验组7只动物均成功吻合出侧方动脉瘤。但饲养后取材时发现有两个模型出现完全闭塞及不完全闭塞。最终得到有效实验试件5枚。2. 实验结果与理论假设基本吻合。经计算成功得出了实验组及对照组的环箍Euler应力和Green应变的非线性本构关系方程、材料常数和应力应变关系曲线。3. 实验组与对照组结果的对比有很大的不同。 通过比较实验组与对照组的材料系数发现材料常数Ｘ１实验组远远小于对照组，而材料常数Ｘ２均远远大于对照组。统计学分析表明实验组与对照组的材料系数Ｘ１，Ｘ２分别比较均有统计学上的显著性差异（P<0.05）。通过将两组应力应变取曲线比较
发现实验组的理论曲线曲度明显较正常组增大。应力>00Kpa后，实验组曲线几乎是陡直上升，显示出几乎无应变。而对照组曲线曲度较平缓，应变随着应变逐渐增大。其说明正常血管可经受十分大的应力，在受到应力后可持续产生较大位移的应变，在曲线上表现为曲线曲度较小。而实验组的动脉瘤模型在受到极小的应力后就会产生明显的应变，但如继续加大应力后则只能产生极小的应变。理论曲线表现为曲度较大。说明经过弹力酶和胶原酶处理过后的动脉瘤模型弹性储备极差，在受到很小的压力后就可以变形很大，但当压力逐渐加大后，其也不产生较大的变形。而正常血管弹性储备极好，随着压力的加大，变形也不断增大，且可以经受超出正常血压极高的压力而不破裂。
结论：1、联合使用弹力酶及胶原酶并通过显微手术移植法制作的新型兔颈总动脉动脉瘤模型在形态学、病理学上与人体AN极为相近，且与传统AN模型相比有着可自发破裂倾向的特性。是一种新的动脉瘤模型制作方法。虽然我们试验的最终想创造出可自发破裂的AN模型的目标尚未达到，但这种同时腐蚀动脉壁不同部分的设想与努力，为复制可自发破裂的动脉瘤模型开创了先例。利用此方法制作的模型将在AN研究中具有广阔的前景。
2、本实验使用体外模拟的方法对动物动脉瘤模型进行研究的方法在方法学上完全可行。并得到了大量的相关数据，构建出了其本构关系方程，得到了对应的应力应变理论曲线。并证明了弹力酶及胶原酶对血管的作用。此方法为本课题组首创，国内外尚无此方面报道。
3、目前对于动脉瘤的治疗以手术及介入治疗为主，但并不能对所有的患者进行有效、安全的治疗。只有通过大体解剖学，病理学，生
物力学，分子生物学甚至基因科学等方面的综合研究方可得到动脉瘤发生及破裂的真正原因。从而找到快速安全有效的治疗方法。
Elastase & Collagenase-Induced Saccular Aneurysms in Rabbits and biomechanical experiment
Objective: 1.To construct a new saccular aneurysm model in Rabbit’s common carotid arteries with Artial segments digested by both elastase and collagenase. 2.Evaluation of the model by in vitro modeling experiment and to investigate the exponential relationless equation, material constant and the curve of the stress and straining of aneurysm models.
Methods: 1. Rabbits were manipulated under general anesthesia and snipped a segmen about 2cm long from the animal’s common carotid arteries. Artial segments were digested by both elastase（0.1ml,6units） and collagenase（1mg/ml）20 min . Then anastomosing Artial segments onto lateral sides of arteries constructed lateral aneurysm models.The animals were fed in coops. 2. Four days later, full aneurysms and parent arterys were took from rabbit’s common carotid arteries.Models were placed in a circuit of pulsatile 0.9%brine that mimics the rheologic properties of blood. Images were recorded on computer and on a super VHS video at shutter speeds of 1/500 second. Analysis of the images were accomplished by softwire in computer. Indexs were dealt with biomechanical method .In the end, we gained the exponential relationless equation, material constant and the curve of the stress and straining of aneurysm models. 3.The same amount nomal arteries were experimented on the same way and compared by the models.
Results: 1. Successful 7 lateral aneurysms,but 2 models occluded spontaneously. We gained 5 effective models in the end.2.The results and the theoretical tentative was similar.The exponential equation constituted is suitable to match their relationship.We obtained the
exponential relationless equation, material constant and the curve of the stress and straining of the experiment group and the nomal group successfully.3.There are much difference between two groups in Results of biomechanical property.We found the material constant X1 、X2 have statistic difference(P<0.05).In nomal group,the curves of the stress and strain were not linear ,but similar to the exponential function in the nomal pressure of the arteries.The curves in experiment group were not linear, either ,and the curves shifted to the left evidently. The mechanical properties of both the normal arteries and the aneurysms can be defined by the equations of the exponential function.
Conclution: 1. The strength of aneurismal wall was destroyed as well as the elastic membrane disappeared in our new aneurysm model constructed by elastase & collagenase digested artial segment, which made this kind of experimental aneurysm similar to authentic aneurysms in both gross appearance and histological architectures and have the tendancy to rupture spontaneously. 2.We prove this new experiment method was feasible and obtained lots of biomechanical parameters which we want to kown. We first reported this experiment method in publication. 3. At present sugery and embolism was the primary treatment of intracranial aneurysms.But the curative effect by these treatment were not very satisfaction.The pathogeny of the aneurysms wound be shown by anatomy、pathology、biomechamics、molecular biology and gene study.They will help us find the most effective treatments of this disease.
方法：1.取大白兔一侧颈总动脉约2cm制成动脉段浸泡于弹性蛋白酶溶液（0.1ml,6units）和胶原酶溶液（1mg/ml）中各20分钟后，利用显微手术将动脉段移植至另一侧颈总动脉侧方，复制出侧方动脉瘤模型。 2.实验动物经饲养四天后，对其再次手术将制作的动脉瘤模型连同载瘤动脉完整取下。将其作为试件置于一套模拟人体血液循环的加压装置中，并按照预先设计好的压力数对实验试件进行加载、卸载；同时利用高速摄影机在显微镜下记录试件的整体形态的变化。然后利用图形分析软件测量试件的变化值，对其进行数学计算，得到动脉瘤模型的本构方程、材料常数和应力应变关系曲线。3.取相同数量的正常血管作为对照组进行相同的生物力学实验，与实验组相比较。
结果：1. 实验组7只动物均成功吻合出侧方动脉瘤。但饲养后取材时发现有两个模型出现完全闭塞及不完全闭塞。最终得到有效实验试件5枚。2. 实验结果与理论假设基本吻合。经计算成功得出了实验组及对照组的环箍Euler应力和Green应变的非线性本构关系方程、材料常数和应力应变关系曲线。3. 实验组与对照组结果的对比有很大的不同。 通过比较实验组与对照组的材料系数发现材料常数Ｘ１实验组远远小于对照组，而材料常数Ｘ２均远远大于对照组。统计学分析表明实验组与对照组的材料系数Ｘ１，Ｘ２分别比较均有统计学上的显著性差异（P<0.05）。通过将两组应力应变取曲线比较
发现实验组的理论曲线曲度明显较正常组增大。应力>00Kpa后，实验组曲线几乎是陡直上升，显示出几乎无应变。而对照组曲线曲度较平缓，应变随着应变逐渐增大。其说明正常血管可经受十分大的应力，在受到应力后可持续产生较大位移的应变，在曲线上表现为曲线曲度较小。而实验组的动脉瘤模型在受到极小的应力后就会产生明显的应变，但如继续加大应力后则只能产生极小的应变。理论曲线表现为曲度较大。说明经过弹力酶和胶原酶处理过后的动脉瘤模型弹性储备极差，在受到很小的压力后就可以变形很大，但当压力逐渐加大后，其也不产生较大的变形。而正常血管弹性储备极好，随着压力的加大，变形也不断增大，且可以经受超出正常血压极高的压力而不破裂。
结论：1、联合使用弹力酶及胶原酶并通过显微手术移植法制作的新型兔颈总动脉动脉瘤模型在形态学、病理学上与人体AN极为相近，且与传统AN模型相比有着可自发破裂倾向的特性。是一种新的动脉瘤模型制作方法。虽然我们试验的最终想创造出可自发破裂的AN模型的目标尚未达到，但这种同时腐蚀动脉壁不同部分的设想与努力，为复制可自发破裂的动脉瘤模型开创了先例。利用此方法制作的模型将在AN研究中具有广阔的前景。
2、本实验使用体外模拟的方法对动物动脉瘤模型进行研究的方法在方法学上完全可行。并得到了大量的相关数据，构建出了其本构关系方程，得到了对应的应力应变理论曲线。并证明了弹力酶及胶原酶对血管的作用。此方法为本课题组首创，国内外尚无此方面报道。
3、目前对于动脉瘤的治疗以手术及介入治疗为主，但并不能对所有的患者进行有效、安全的治疗。只有通过大体解剖学，病理学，生
物力学，分子生物学甚至基因科学等方面的综合研究方可得到动脉瘤发生及破裂的真正原因。从而找到快速安全有效的治疗方法。
Elastase & Collagenase-Induced Saccular Aneurysms in Rabbits and biomechanical experiment
Objective: 1.To construct a new saccular aneurysm model in Rabbit’s common carotid arteries with Artial segments digested by both elastase and collagenase. 2.Evaluation of the model by in vitro modeling experiment and to investigate the exponential relationless equation, material constant and the curve of the stress and straining of aneurysm models.
Methods: 1. Rabbits were manipulated under general anesthesia and snipped a segmen about 2cm long from the animal’s common carotid arteries. Artial segments were digested by both elastase（0.1ml,6units） and collagenase（1mg/ml）20 min . Then anastomosing Artial segments onto lateral sides of arteries constructed lateral aneurysm models.The animals were fed in coops. 2. Four days later, full aneurysms and parent arterys were took from rabbit’s common carotid arteries.Models were placed in a circuit of pulsatile 0.9%brine that mimics the rheologic properties of blood. Images were recorded on computer and on a super VHS video at shutter speeds of 1/500 second. Analysis of the images were accomplished by softwire in computer. Indexs were dealt with biomechanical method .In the end, we gained the exponential relationless equation, material constant and the curve of the stress and straining of aneurysm models. 3.The same amount nomal arteries were experimented on the same way and compared by the models.
Results: 1. Successful 7 lateral aneurysms,but 2 models occluded spontaneously. We gained 5 effective models in the end.2.The results and the theoretical tentative was similar.The exponential equation constituted is suitable to match their relationship.We obtained the
exponential relationless equation, material constant and the curve of the stress and straining of the experiment group and the nomal group successfully.3.There are much difference between two groups in Results of biomechanical property.We found the material constant X1 、X2 have statistic difference(P<0.05).In nomal group,the curves of the stress and strain were not linear ,but similar to the exponential function in the nomal pressure of the arteries.The curves in experiment group were not linear, either ,and the curves shifted to the left evidently. The mechanical properties of both the normal arteries and the aneurysms can be defined by the equations of the exponential function.
Conclution: 1. The strength of aneurismal wall was destroyed as well as the elastic membrane disappeared in our new aneurysm model constructed by elastase & collagenase digested artial segment, which made this kind of experimental aneurysm similar to authentic aneurysms in both gross appearance and histological architectures and have the tendancy to rupture spontaneously. 2.We prove this new experiment method was feasible and obtained lots of biomechanical parameters which we want to kown. We first reported this experiment method in publication. 3. At present sugery and embolism was the primary treatment of intracranial aneurysms.But the curative effect by these treatment were not very satisfaction.The pathogeny of the aneurysms wound be shown by anatomy、pathology、biomechamics、molecular biology and gene study.They will help us find the most effective treatments of this disease.
引文
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Ljunggren B, Brandt L, Saveland H, et al . Management of ruptured intracranial aneurysm: a review. Br J Neurosurg 1987,1: 9-32
Kerber CW,Heilman CB. Flow dynamics in the human carotid artery:I.preliminary observation using transparentelastic model.AJNR,1992;13:173-180
Hashimoto N,Kim C,Kikuchih,et al.Experimental induction of cerebral aneurysms in monkeys.J Neurosury,1987;67:903-905
Hunter J, Palmer JF. Lectures on the principles of surgery. Haswell, Barrington & Haswell, Philadelphia, 1839; p.309
Halsted WS, Burket WC. Surgical Papers, 1.Johns Hopkins Press, Baltimore, 1924, pp 469-475
McCune WS, Samadi A, Blades B. Experimental aneurysms. Ann Surg 1953; 138: 216-218
German WJ, Black PW. Experimental production of carotid aneurysms, N Engl J Med 1954;250:104-106
Andrews EJ,White WJ,Bullock LP Spontaneous aortic aneurysms in blochy mice. American J Pathol1975：78: 199-207
T.F Massond,Jic,Gugliemi ,et al.Experimantal saccular aneurysms[J].Neurradiology.1994;26:537
Heilman CB,Kwan ESK,Wu JK Aneurysm recurrence following endovascular balloon occlusion. J Neurosurg1992：77: 260-264
Young PH,Yasargil MD Experimental carotid artery aneurysms in rats: a new model for microsurgical practice. J microsurg1982 3: 135-146
Yonekawa Y,Yasargil MG,Handa H Practice of microvascular anastomosis. Neurol Surg1973：1: 345-351
Hashimoto H,Handa H,Hazama F. Experimentally induced cerebral aneurysms in rats. Surg Neurol. 1978;10:3-8.
Osterman FA,Bell WR,Montali RJ,et al Natural history of autologous blood clot embolization in swine. Invest Radiol 1976：11:267-276.
Orlin JR,Osen KK,Hovig T Subdural compartment in pig: a morphologic study with blood and horseradish peroxidase infused subdurally.Anat Rec1991:230:22-37.
Guglielmi G, Ji C, Massoud TF, Kurata A, Lownie SP, Vinuela F, Robert J. Experimental saccular aneurysms. II. A new model in swine. Neuroradiology 1994 Oct;36(7):547-50
Kang Y, Hazama F: Experimental induction of cerebral aneurysms in monkeys. J Neurosurg 67:903-905,1987
Forrest MD, O’Reilly GV. Production of experimental aneurysms at a surgically created arterial bifurcation. AJNR 1989; 10: 400-402
Strother CM, Graves VB, Rappe A. Aneurysm hemodynamics: an experimental study. AJNR 1992; 13: 1089-1095
Stebhens WE: Intracranial berry aneurysms and atherosclerosis. University of Sydney, Sydney, Australia(Thesis)
Hashimoto N, Handa H, Hazama F: Experimentally induced cerebral aneurysms in rats. Surg Neurol 1978；10:3-8。
Kang Y, Hazama F: Experimental induction of cerebral aneurysms in monkeys. J Neurosurg 67:903-905,1987
Hashimoto N, Handa H, Hazama F. Experimentally induced cerebral aneurysms in rats, part II. Surg Neurol.. 1979;11:243-246
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Rebecca LP,Holdsworth FDW.An analysis of the geometry of the geometry of saccular intracranial aneurysms.AJNR,1999,20:1079-1089
Niim i H,Kawano Y,sugiyama I.Structure of blood flow through a curved vessel with an aneurysm[J].Biorh-eology,1984,21:603-615
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Nakatani H,Hashimoto N,Kang Y.Cerebaral blood flow patterns at major vessel bbifurcations and aneurysms in rats . Neurosurg,1991,74:258-262
Steiger H J,Reulen H J.Slow frequency flow fluctuations in saccular aneurysms.Acta Neurochir(wien),1986,83:131-137
Ljunggren B, Brandt L, Saveland H, et al . Management of ruptured intracranial aneurysm: a review. Br J Neurosurg 1987,1: 9-32
Kerber CW,Heilman CB. Flow dynamics in the human carotid artery:I.preliminary observation using transparentelastic model.AJNR,1992;13:173-180
Hashimoto N,Kim C,Kikuchih,et al.Experimental induction of cerebral aneurysms in monkeys.J Neurosury,1987;67:903-905
Hunter J, Palmer JF. Lectures on the principles of surgery. Haswell, Barrington & Haswell, Philadelphia, 1839; p.309
Halsted WS, Burket WC. Surgical Papers, 1.Johns Hopkins Press, Baltimore, 1924, pp 469-475
McCune WS, Samadi A, Blades B. Experimental aneurysms. Ann Surg 1953; 138: 216-218
German WJ, Black PW. Experimental production of carotid aneurysms, N Engl J Med 1954;250:104-106
Andrews EJ,White WJ,Bullock LP Spontaneous aortic aneurysms in blochy mice. American J Pathol1975：78: 199-207
T.F Massond,Jic,Gugliemi ,et al.Experimantal saccular aneurysms[J].Neurradiology.1994;26:537
Heilman CB,Kwan ESK,Wu JK Aneurysm recurrence following endovascular balloon occlusion. J Neurosurg1992：77: 260-264
Young PH,Yasargil MD Experimental carotid artery aneurysms in rats: a new model for microsurgical practice. J microsurg1982 3: 135-146
Yonekawa Y,Yasargil MG,Handa H Practice of microvascular anastomosis. Neurol Surg1973：1: 345-351
Hashimoto H,Handa H,Hazama F. Experimentally induced cerebral aneurysms in rats. Surg Neurol. 1978;10:3-8.
Osterman FA,Bell WR,Montali RJ,et al Natural history of autologous blood clot embolization in swine. Invest Radiol 1976：11:267-276.
Orlin JR,Osen KK,Hovig T Subdural compartment in pig: a morphologic study with blood and horseradish peroxidase infused subdurally.Anat Rec1991:230:22-37.
Guglielmi G, Ji C, Massoud TF, Kurata A, Lownie SP, Vinuela F, Robert J. Experimental saccular aneurysms. II. A new model in swine. Neuroradiology 1994 Oct;36(7):547-50
Kang Y, Hazama F: Experimental induction of cerebral aneurysms in monkeys. J Neurosurg 67:903-905,1987
Forrest MD, O’Reilly GV. Production of experimental aneurysms at a surgically created arterial bifurcation. AJNR 1989; 10: 400-402
Strother CM, Graves VB, Rappe A. Aneurysm hemodynamics: an experimental study. AJNR 1992; 13: 1089-1095
Stebhens WE: Intracranial berry aneurysms and atherosclerosis. University of Sydney, Sydney, Australia(Thesis)
Hashimoto N, Handa H, Hazama F: Experimentally induced cerebral aneurysms in rats. Surg Neurol 1978；10:3-8。
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