创伤性脑损伤大鼠有限元模型生物力学研究
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摘要
研究背景及目的：创伤性脑损伤(traumatic brain injury, TBI)是神经外科的常见病、多发病,始于致伤外力作用于头部导致的组织机械形变,进而引起原发性损伤和继发性损伤引起广泛的临床症状和功能障碍,对人类健康危害极大,已经成为目前社会公共卫生问题,对于原发性脑损伤详尽的生物力学机制尚未完全阐明。明确致伤时不同脑组织结构的生物力学机制,可以有效地对TBI损伤程度进行判断和预防。由于人类发生TBI时实际头部受力后的应力应变关系很难获取,而活体脑损伤力学实验研究显然是不现实的,因此各种不同的实验方法如动物实验、尸体实验、脑组织生物材料学实验等,在脑损伤生物力学研究方面得到不同程度的应用和开展,由于这些相关的实验方法对脑组织不同结构受力后的生物力学反应无法直接准确获取和分析,很多研究人员,尤其是医学生物学领域的学者将研究侧重点转向了数学模型,其中有限元方法(finite element method, FEM)作为结构分析的一种方法,因其在复杂几何形态、非均质类物质分析方面的优势,开始被应用于求解相应物质的力学响应。近年来随着计算机技术和高等数学,尤其是计算机辅助设计(computer aided design, CAD)技术的发展,越来越多的有限元模型被建立并用来进行对人类颅脑损伤后引起的生物力学变化进行相应的分析。但是在进行人类颅脑损伤有限元模型建立和分析过程中,一方面人类不同脑组织的生物力学参数的获取存在一定局限性,另一方面其所获得的有限元模型分析数据很难去和实际损伤现场的数据进行对比,因此,本研究出发点为选择合适的动物模型实验数据与有限元模型分析数据进行比较,我们选择大鼠可控性皮层撞击(controlled cortical impact, CCI)动物模型作为研究对象,构建正常大鼠脑部结构三维(three dimensional,3D)有限元模型,模拟动物实验中的损伤过程,分析不同皮层撞击深度下大鼠脑内部不同结构的生物力学反应,并应用最大主应变(maximum principal strain, MPS)参数变化对比动物实验引起的皮层损伤神经元消亡比例的变化,以期利用有限元模型参数的计算和分析来预测实验动物的损伤程度。主要研究工作包括：
一大鼠可控性皮层损伤动物模型的建立和皮层、海马损伤定量分析
目的：建立大鼠CCI实验动物模型,不同损伤程度皮层、海马损伤定量
方法：应用带立体定向装置的可控性皮层损伤装置,建立对照组、2.4mm、2.8mm和3.2mmm的动物损伤组。应用Cresyl Violet染色观察各实验组大鼠皮层损伤范围和海马存活神经元。皮层损伤定量输出值为损伤侧皮层缺失体积占对侧半球体积的百分数,海马神经元输出值为锥体层CA3高倍镜视野(high power field, HPF)下存活数。数据以均数±标准差表示,多个样本均数比较采用单因素方差分析(one-way ANO VA)。
结果：皮层损伤定量2.4mmm组损伤侧缺失体积占对侧半球的百分数3.65±2.11,2.8mm组为7.83±2.53,3.2mm组为12.85±3.02(P<0.05)。海马CA3锥体层2.4mm组别中神经元存活数26.50±4.18/HPF和2.8mm组别中神经元存活数17.67±4.08/HPF较对照组35.67±6.38/HPF明显减少(P<0.05),3.2mm组撞击出现锥体层损伤,未进行计数。
结论：大鼠CCI模型可以有效造成皮层结构和海马结构的损伤,其损伤参数的可控性为分析损伤过程的生物力学提供了方便性；不同撞击深度调节可作为不同损伤程度的参数；在撞击参数设定为撞击物直径5mm、撞击速度4m/s条件下,3.2mm撞击深度不建议作为大鼠重度脑损伤分级建立标准。
二正常大鼠脑三维有限元模型
目的：构建正常大鼠脑部结构三维有限元模型
方法：根据正常大鼠立体定向解剖图谱,选取冠状位25张切片为对象,利用Photoshop CS软件对选择切片数字化处理,留取皮层、皮层下、海马、侧脑室结构,保留立体定向图片中定位网格线,利用软件SolidWorks 2007在每个基准面上按前后顺序,以立体定向网格线提供的坐标、轮廓数据进行二维草绘,以放样命令连结各个剖面,并应用切除放样命令先后切除海马结构和侧脑室结构,建立装配体,选择海马、侧脑室结构配合形成镜像实体,保存为xt格式。在软件Unigraphics NX中导入镜像实体,建立撞击物物模型,撞击物直径5mm,撞击方向垂直,撞击接触面为皮层结构。在软件Ansys WorkBench中的Mechanical环境下按默认设置生成网格,定义单元类型,选择solid164四面体单元,目前对模型和撞击物接触的半球采用0.3mm的网格密度划分,海马结构内部组织密度为0.5mm,对侧未与撞击物接触的半球采用0.5mm的网格密度划分。
结果：成功构建出含皮层、海马及侧脑室结构的三维大鼠脑有限元模型,同实际解剖几何形态相似。成功构建制作损伤的撞击物模型。模型总单元数205348,总节点数40412。
结论：构建完成三维大鼠脑有限元模型。带有立体坐标标记的大鼠图谱切片为构建复杂形态结构的脑有限元模型建立提供经济、简单和准确的解剖信息；通过图像处理软件、计算机辅助分析软件和有限元软件,可以有效地建立复杂结构数学模型,并提高有限元建模的效率。
三CCI动物模型有限元模拟、生物力学分析及皮层损伤与MPS相关性初步研究
目的：
1.建立大鼠脑简单化2D模型,有限元模拟皮层撞击过程,检验不同网格化密度、不同组织衰变常数下生物力学参数变化,选择合理的网格密度和衰变常数；
2.CCI动物模型有限元模拟、生物力学分析及皮层神经元损伤与MPS相关性初步研究方法：
1.利用大鼠脑立体定向图谱冠状缝后方3.48mm层面冠状位切片提供的解剖信息,在软件Unigraphics NX 6.0中建立四边形区域的平面模型和撞击物模型,在软件Ansys WorkBench软件中建立Explicit dynamic分析模块,设置脑组织属性,包括密度值、杨氏模量、泊松比和粘性剪切模量,设置边界条件和初始条件,标记2个不同区域AREA1、AREA2,选择不同网格密度进行对比,分别以2mm、1mm、0.8mm、0.3mm、0.2mm和0.1mm的网格密度进行撞击模拟,计算选定区域AREA1中MPS值；网格划分密度为0.5mm的条件下计算不同的组织衰变常数5ms、10ms、20ms和40ms下选定区域AREA1和AREA2的MPS值。
2.模拟CCI动物实验制作过程,利用软件AnsysWorkbench设置符合动物实验条件下的撞击物参数,包括撞击物材料属性、撞击物直径和撞击速度,撞击深度分别为2.4mm、2.8mm和3.2mm,设置大鼠脑灰质、脑室及海马材料属性,包括密度值、杨氏模量、泊松比和粘性剪切模量,设置边界条件和初始条件,分别设定浅表皮层、深部皮层、海马和侧脑室中部分区域作为感兴趣区域,利用软件Ansys 12软件分别模拟不同撞击深度下的不同脑组织结构应力、应变、变形关系。模型计算的不同损伤程度下皮层感兴趣区域MPS值与动物实验计算获取的皮层损伤定量数据行初步一元线性回归分析。
结果：
1.随着网格密度的增加模型的节点数和网格数成倍增加,不同的网格密度撞击后选定区域内MPS的值存在差异；撞击分析的计算时间随着网格密度值减小而增加；在选定区域,随着网格密度的减小,区域内MPS相应增加,其增加的趋势随着密度值的进一步减小而降低,2mm和1mm网格密度之间MPS的差别是29.5%,0.2mmm和0.1mm网格密度之间的MPS的差别是4.0%,0.3mm和0.2mm、0.8mm网格密度之间的MPS差别分别为6.5%和10.4%,鉴于大鼠脑模型外形及内部结构欠规整,放置大曲率和薄壳均可导致划分的失败,选择0.3mm作为损伤侧半球大部分结构的网格密度,兼顾研究有限元模型预测MPS值过程中的准确性和效率性。网格密度0.5mm下改变不同衰变常数,以衰变常数20ms为基数进行比较,选定的浅部区域AREA1计算MPS值变化范围未超过3.2%,深部区域AREA2模型计算MPS值变化范围为0.1%。
2撞击深度的增加相对应的von Mises应力增加,2.4mm、2.8mm和3.2mm撞击深度时von Mises应力最大值分别为0.57064Mpa、0.64684Mpa和3.0449Mpa。在所有三组不同撞击深度的模型中,撞击物下方的区域均具有最大变形,并随着辐射方向逐渐减弱。达到最大撞击深度后,随着撞击物回缩变形程度逐渐减小,在2.4mm撞击深度组别中,变形组织主要涉及皮层、皮层下和海马结构,随着撞击深度增加,变形累及丘脑及深部组织。在所有三组不同撞击深度的模型中,应变值随着撞击深度增加而递增,在2.4mm组中达到最大撞击深度后0.05ms时间步出现应变最大值1.1179,之后随着时间步增加而减低,在2.8mmm组中达到最大撞击深度时应变值为1.2535,随后出现减低,在最大撞击深度后0.1ms时间步再次出现高峰,达到1.5571,而后逐渐降低。在3.2mmm组中达到最大撞击深度时应变值为1.5658,并持续性对高峰至计算结束。在四组感兴趣区域中,不同深度的撞击模拟中,最高MPS出现在撞击侧皮层区域,并以从皮层向深部结构传导。感兴趣区域MPS时间步曲线图提示撞击后最高值均出现在撞击设定时间范围内。在不同撞击深度组别中,2.4mm和3.2mm中浅部皮层的MPS值最高,分别较深部皮层高1.2%,11.1%,在2.8mm中深部皮层的获得MPS最高值,较浅部皮层高4.4%。脑室结构内感兴趣区域标记计算MPS值显示所受到的最大主应变值变化范围较小,曲线幅度变化较其他三组感兴趣区域小,在2.4mm和2.8mm组别中海马结构较侧脑室结构MPS值分别高29.2%和40.8%,而在3.2mm组中脑室结构在撞击物达到最大深度后MPS值超过海马结构,其最大值较海马结构高27.8%。动物实验中皮层损伤缺失范围和有限元模型对应感兴趣区域计算MPS值行线性回归分析,浅部皮层和深部皮层区域与动物实验皮层缺失百分数进行线性相关性比较,R2值分别为0.9953和0.9685。
结论：
1.在进行有限元模型前处理过程中,网格密度越小,模型的网格数越多,计算结果越精确,计算时间越长,网格密度0.3mm能满足计算精确性要求,且计算时间合理；不同的衰变常数对结果存在影响,20ms的衰变常数对本研究结果影响可接受。
2.实验很好的模拟了CCI动物实验制作流程,就撞击深度2.4mm、2.8mm和3.2mm分别进行了计算机模拟撞击大鼠脑皮层过程。当撞击物达到最大撞击深度后,在撞击载荷下,脑组织表面的变形、应力和应变随时间步向深部移动变化。有限元模型可以有效、直接的分析外力作用下脑组织内部不同结构的力学反应变化。结果提示MPS的变化与动物实验皮层损伤存在相关关系,该初步研究所能进行分析的数据偏少,需要更多的实验数例和不同前处理条件下有限元模型预测的MPS值进行对比,来求证MPS作为预测皮层神经元损伤定量生物力学参数之一的可行性。
Background and objective:Traumatic Brain Injury (TBI) is the frequently-occurring disease in the neurosurgery department. The mechanical deformation by the vulnerant force affected on the head induces the primary injury and the secondary injury. The TBI can cause the extensive clinical symptoms and dysfunctions. It has been the social public health problem now, because it is one of the major causes of the human death and disability. The understanding of the biomechanics in the different brain tissue can effectively estimate and prevent the TBI degree. But the detailed machanism of the human TBI is not completely illuminated. The stress-strain relation in the human TBI is difficult to be acquired, and the biomechanics research of brain injury in the living body is impossible. Over the half-century years, many different experimental methods are utilized and developed in the brain injuries such as animal experiment, corpse experiment and biomaterial experiment. Due to the difficulties of direct obtaining and analysis the different structures biomechanics with these relative experimental method, most researchers attempt to utilize the mathematical model for the TBI field. The finite element method (FEM) is the one of numerical method in structural analysis. It has been applied to solve the mechanics response of the several materials with the adventages in the analysis of complicated geometry shape and anisotropic material.
For the past few years, with the development of computer technologies and the higher mathematics, especially the computer aided design system (CAD), more and more finite element models are created and used to analyse the biomechanics changes in the human TBI. Some FEMs include the detailed human anatomical structures for the different tissues stress-strain research. But the human brain finite element models have some disadvantages in the TBI simulation and analysis. On one hand there are several limitations in the acquisition of the different human brain biomechanics parameter, on the other hand the analytic datas of the human brain finite element models are difficult to compare with datas of the actual human TBI. So this study uses the rat as the research object to develop its brain three dimensional (3-D) finite element model. With this model the biomechanics relationships between the different tissues are analysed. Also this study comfirms the changes of maximum principal strain (MPS) is related with the rat cortex injury. The further research purpose is to predict the neuron injury in TBI. The research work includes:
1. Establishment of the rat controlled cortical injury (CCI) model and the injury analysis of the cortex and the hippocampus
Objective:Establishment of the rat controlled cortical injury model and the injury analysis of the cortex and the hippocampus
Methods:We establish the rat CCI model using the special CCI device with the stereotaxis equipment. The impact velocity is 4m/s, the impact depth is 2.4mm, 2.8mm and 3.2mm. The animals are randomly devided into control group and groups at 2.4mm,2.8mm and 3.2mm. To evaluate the injury of the cortex and the hippocampus of every experiment groups, Cresyl Violet staining is performed to calculate the cortex injury area and hippocampus survival neurons.
Result:The rat CCI models are established successfully. The cortex of impacted side is sharply damaged in the different impacted depth. The defective percent area in cortex of the contralateral hemisphere is 3.65±2.11 in the 2.4mm group,7.83±2.53 in the 2.8mm group and 12.85±3.02 in the 3.2mm group. The surviving neuron number in ipsilateral CA3 hippocampus 35.67±6.38/hpf in controlled group,26.50±4.18/hpf in 2.4mm group,17.67±4.08/hpf in 2.8mm,. In 3.2mm group, the impactor penetrate into the pyramidal layer, we do not count the neurons number.
Conclusion:The rat CCI model is the scientific and advisable animalmodel for the TBI research with the controlled impacted force parameter. In the rat CCI model, the severe brain injury parameter should set that the impacted depth is 2.8mm with the 4m/s velocity.
2. Construction of the 3-D finite element model of normal rat brain
Objective:Construction of the 3-D finite element model of normal rat brain
Methods:According to the normal rat stereotactic anatomical atlas, we confirm the reconstruction targets with the 25 coronal slice. Each slice anatomies are processed and digitizing with Photoshop CS software. The detailed anatomies includes the cortex, subcortex, hippocampus and lateral ventricles structures. All digital atlas are located in the stereoscopic coordinate. Each slice is saved as the TIFF format. Then with the SolidWorks 2007 software, two-dimension (2-D) draw of each slice is done according to the anatomical shapes and stereoscopic coordinates of each tissue. Each cross section is connected with the lofting order in SolidWorks 2007 software, the hippocampus and lateral ventricle structures are exsected. The assembly is built with the each part and saved as the xt format. Then this format is imported into the Unigraphics NX 6.0 software. In this software the impactor is constructed and the impactor tips located on the cortex surface. The impactor diameter is 5mm, the impacted direction is perpendicular. Then the total model is imported into the ANSYS Workbench software to define the elements type with solid 164 tetrahedron. The mesh is constructed according to the mechanical environment default setup. The mesh density in the most of ipsilateral part is 0.3mm, in the impacted side hippocampus and contralateral hemisphere is 0.5mm.
Result:Construction of the 3-D finite element model of normal rat brain is completed. The model includes the cortex, subcortex, hippocampus and lateral ventricles structures. The FEM has a good geometric similarity with the anatomical atlas. The total number of elements was 205348, the total number of nodes is 40412.
Conclusion:The rat anatomical atlas in the stereoscopic coordinate provides a effective, simple, economic and accurate information for the construction of finite element model of the complex shapes and structures. With the image processing software, CAD software and finite element software, it can be effective to construct the mathematical model of the complicated organism.
3. The finite element method simulation of the CCI animals model, the biomechanical analysis and the initial research in prediction of the cortical neuron loss
Objective:
1) Construction of the simple rat cortex impacted model, simulation of the rat CCI model process, collating of the mesh density and decay constant
2)The finite element simulattion and analysis of rat CCI model with the FEM, initial prediction of the neurons injury with the parameter MPS
Methods:
1)According to the cross section of the 3-D FE model, a plane FE model is constructed in the quadrilateral elements with the simple brain structure and the impactor by the Unigraphics NX 6.0 software. In the ANSYS Workbench software, the Explicit dynamic is built. The viscoelastic material properties of the brain grey matter and white matter are set. The properties include density, Young's modulus, poisson ratio, viscosity shear modulus and elasticity shear modulus. Two different areas are marked to compare with the different mesh density. The density includes 2mm、1mm、0.8mm、0.3mm、0.2m mand 0.1mm. According the 0.5mm mesh density, the different decay constants are choosed to analyse the MPS changes. The decay constants include 5ms、10ms、20ms and 40ms.
2)The impacted parameters including the material attribute, impactor diameter and the impacted velocity according to the animal experiment are set in the Ansys WorkBench software. The impacted depth is 2.4mm,2.8mm and 3.2mm. The viscoelastic material properties of the brain grey matter and hippocampus and the ventricle are set. The properties include density, Young's modulus, poisson ratio, viscosity shear modulus and elasticity shear modulus. The boundary condition is set according to the skull density. And four regions in cortex, subcortex, hippocampus and ventricle are choosed as the regions of interest. In different impacted depths each regions has the different stress, strain and deformation relationship. The linear regression is carried out between cortex injury in the animal experiment and the MPSs in the FEA predicted for the regions of cortex.
Result:
1)There is the different MPS in the impacted simulation with different mesh density. The analysis time of the impact in the model increases obviously with the mesh density decreases. Total average MPS increases when the mesh density decreases, and the increase trend grows down. The MPS in selected region increases with the lower mesh density. The difference between 2mm mesh density and 1mm density was 29.5%. The differences between 0.3mm and 0.2mm,0.8mm were 6.5% and 10.4%. The MPSs do not have a large changes with the different decay constants. The MPS in surface selected region is 0.8165、0.8360、0.8423.0.8420 respectively, in deeper part is 0.0852、0.0852、0.0851、0.0850 respectively.
2)The rat 3-D FE model simulates the CCI animal experiment process well in the different impacted depth. The highest value of von Mises stress 0.57064Mpa, 0.64684Mpa, 3.0449Mpa were respectively in the different vimpacted depths. When the impactor reachs the maximum depth, the area under the impactor has the largest deformations, and decrease in the radial directions, the deep part structure has the relative small deformations. And the highest value of strain in increased impacted depths were 1.1179,1.2535 and 1.5571. In 3.2mm depth the high peak of strain continued until the computer simulation analysis ended. In the four interest regions, the hightest MPS value occurred on the cortex in impacted side. All highest values in different groups were present within the foreset analysis time. In 2.4mm and 3.2mm depths simulation, the surface cortex was present the higher value than subcortex, it was 1.2%and 11.1%respectively. In the another depth the subcortex was 4.4%higher than surface cortex. The lateral ventricles had the lower change range in MPS. In 2.4mm and 2.8mm depths groups, the hippocampus was taken the higher MPS than lateral ventricles. In the another group the ventricle was taken more higher. The differences were 29.2%,40.8%and 27.8%. The initial research in linear regression between the MPSs predicted by the FE model and the neuron injury of cortex in animals experiment. The correlation coefficient R~2 were 0.9953 and 0.9685.
Conclusion:
1)The analysis result is more exactly and the analysis time is more longer when the mesh density decreases. The mesh density in 0.3mm is good for the precision and reasonable computing time. The decay constant in 20ms has little influence in our study.
2)In the simulation of the CCI animal model, the different brain tissues have the complicated stress, strain and deformation relationship when the cortex has been impacted. The differences in the biomechanics responses induce the different levels of the TBIs in the primary injury and secondly injury. In the initial study the MPS can be the parameter that predicts the neurons injury in TBIs. More animals experiments and more different pre-processing conditions FE models should be developed to implore the feasibility of MPS acted as the quantitate parameter of cortical neuron injury in TBI.
一大鼠可控性皮层损伤动物模型的建立和皮层、海马损伤定量分析
目的：建立大鼠CCI实验动物模型,不同损伤程度皮层、海马损伤定量
方法：应用带立体定向装置的可控性皮层损伤装置,建立对照组、2.4mm、2.8mm和3.2mmm的动物损伤组。应用Cresyl Violet染色观察各实验组大鼠皮层损伤范围和海马存活神经元。皮层损伤定量输出值为损伤侧皮层缺失体积占对侧半球体积的百分数,海马神经元输出值为锥体层CA3高倍镜视野(high power field, HPF)下存活数。数据以均数±标准差表示,多个样本均数比较采用单因素方差分析(one-way ANO VA)。
结果：皮层损伤定量2.4mmm组损伤侧缺失体积占对侧半球的百分数3.65±2.11,2.8mm组为7.83±2.53,3.2mm组为12.85±3.02(P<0.05)。海马CA3锥体层2.4mm组别中神经元存活数26.50±4.18/HPF和2.8mm组别中神经元存活数17.67±4.08/HPF较对照组35.67±6.38/HPF明显减少(P<0.05),3.2mm组撞击出现锥体层损伤,未进行计数。
结论：大鼠CCI模型可以有效造成皮层结构和海马结构的损伤,其损伤参数的可控性为分析损伤过程的生物力学提供了方便性；不同撞击深度调节可作为不同损伤程度的参数；在撞击参数设定为撞击物直径5mm、撞击速度4m/s条件下,3.2mm撞击深度不建议作为大鼠重度脑损伤分级建立标准。
二正常大鼠脑三维有限元模型
目的：构建正常大鼠脑部结构三维有限元模型
方法：根据正常大鼠立体定向解剖图谱,选取冠状位25张切片为对象,利用Photoshop CS软件对选择切片数字化处理,留取皮层、皮层下、海马、侧脑室结构,保留立体定向图片中定位网格线,利用软件SolidWorks 2007在每个基准面上按前后顺序,以立体定向网格线提供的坐标、轮廓数据进行二维草绘,以放样命令连结各个剖面,并应用切除放样命令先后切除海马结构和侧脑室结构,建立装配体,选择海马、侧脑室结构配合形成镜像实体,保存为xt格式。在软件Unigraphics NX中导入镜像实体,建立撞击物物模型,撞击物直径5mm,撞击方向垂直,撞击接触面为皮层结构。在软件Ansys WorkBench中的Mechanical环境下按默认设置生成网格,定义单元类型,选择solid164四面体单元,目前对模型和撞击物接触的半球采用0.3mm的网格密度划分,海马结构内部组织密度为0.5mm,对侧未与撞击物接触的半球采用0.5mm的网格密度划分。
结果：成功构建出含皮层、海马及侧脑室结构的三维大鼠脑有限元模型,同实际解剖几何形态相似。成功构建制作损伤的撞击物模型。模型总单元数205348,总节点数40412。
结论：构建完成三维大鼠脑有限元模型。带有立体坐标标记的大鼠图谱切片为构建复杂形态结构的脑有限元模型建立提供经济、简单和准确的解剖信息；通过图像处理软件、计算机辅助分析软件和有限元软件,可以有效地建立复杂结构数学模型,并提高有限元建模的效率。
三CCI动物模型有限元模拟、生物力学分析及皮层损伤与MPS相关性初步研究
目的：
1.建立大鼠脑简单化2D模型,有限元模拟皮层撞击过程,检验不同网格化密度、不同组织衰变常数下生物力学参数变化,选择合理的网格密度和衰变常数；
2.CCI动物模型有限元模拟、生物力学分析及皮层神经元损伤与MPS相关性初步研究方法：
1.利用大鼠脑立体定向图谱冠状缝后方3.48mm层面冠状位切片提供的解剖信息,在软件Unigraphics NX 6.0中建立四边形区域的平面模型和撞击物模型,在软件Ansys WorkBench软件中建立Explicit dynamic分析模块,设置脑组织属性,包括密度值、杨氏模量、泊松比和粘性剪切模量,设置边界条件和初始条件,标记2个不同区域AREA1、AREA2,选择不同网格密度进行对比,分别以2mm、1mm、0.8mm、0.3mm、0.2mm和0.1mm的网格密度进行撞击模拟,计算选定区域AREA1中MPS值；网格划分密度为0.5mm的条件下计算不同的组织衰变常数5ms、10ms、20ms和40ms下选定区域AREA1和AREA2的MPS值。
2.模拟CCI动物实验制作过程,利用软件AnsysWorkbench设置符合动物实验条件下的撞击物参数,包括撞击物材料属性、撞击物直径和撞击速度,撞击深度分别为2.4mm、2.8mm和3.2mm,设置大鼠脑灰质、脑室及海马材料属性,包括密度值、杨氏模量、泊松比和粘性剪切模量,设置边界条件和初始条件,分别设定浅表皮层、深部皮层、海马和侧脑室中部分区域作为感兴趣区域,利用软件Ansys 12软件分别模拟不同撞击深度下的不同脑组织结构应力、应变、变形关系。模型计算的不同损伤程度下皮层感兴趣区域MPS值与动物实验计算获取的皮层损伤定量数据行初步一元线性回归分析。
结果：
1.随着网格密度的增加模型的节点数和网格数成倍增加,不同的网格密度撞击后选定区域内MPS的值存在差异；撞击分析的计算时间随着网格密度值减小而增加；在选定区域,随着网格密度的减小,区域内MPS相应增加,其增加的趋势随着密度值的进一步减小而降低,2mm和1mm网格密度之间MPS的差别是29.5%,0.2mmm和0.1mm网格密度之间的MPS的差别是4.0%,0.3mm和0.2mm、0.8mm网格密度之间的MPS差别分别为6.5%和10.4%,鉴于大鼠脑模型外形及内部结构欠规整,放置大曲率和薄壳均可导致划分的失败,选择0.3mm作为损伤侧半球大部分结构的网格密度,兼顾研究有限元模型预测MPS值过程中的准确性和效率性。网格密度0.5mm下改变不同衰变常数,以衰变常数20ms为基数进行比较,选定的浅部区域AREA1计算MPS值变化范围未超过3.2%,深部区域AREA2模型计算MPS值变化范围为0.1%。
2撞击深度的增加相对应的von Mises应力增加,2.4mm、2.8mm和3.2mm撞击深度时von Mises应力最大值分别为0.57064Mpa、0.64684Mpa和3.0449Mpa。在所有三组不同撞击深度的模型中,撞击物下方的区域均具有最大变形,并随着辐射方向逐渐减弱。达到最大撞击深度后,随着撞击物回缩变形程度逐渐减小,在2.4mm撞击深度组别中,变形组织主要涉及皮层、皮层下和海马结构,随着撞击深度增加,变形累及丘脑及深部组织。在所有三组不同撞击深度的模型中,应变值随着撞击深度增加而递增,在2.4mm组中达到最大撞击深度后0.05ms时间步出现应变最大值1.1179,之后随着时间步增加而减低,在2.8mmm组中达到最大撞击深度时应变值为1.2535,随后出现减低,在最大撞击深度后0.1ms时间步再次出现高峰,达到1.5571,而后逐渐降低。在3.2mmm组中达到最大撞击深度时应变值为1.5658,并持续性对高峰至计算结束。在四组感兴趣区域中,不同深度的撞击模拟中,最高MPS出现在撞击侧皮层区域,并以从皮层向深部结构传导。感兴趣区域MPS时间步曲线图提示撞击后最高值均出现在撞击设定时间范围内。在不同撞击深度组别中,2.4mm和3.2mm中浅部皮层的MPS值最高,分别较深部皮层高1.2%,11.1%,在2.8mm中深部皮层的获得MPS最高值,较浅部皮层高4.4%。脑室结构内感兴趣区域标记计算MPS值显示所受到的最大主应变值变化范围较小,曲线幅度变化较其他三组感兴趣区域小,在2.4mm和2.8mm组别中海马结构较侧脑室结构MPS值分别高29.2%和40.8%,而在3.2mm组中脑室结构在撞击物达到最大深度后MPS值超过海马结构,其最大值较海马结构高27.8%。动物实验中皮层损伤缺失范围和有限元模型对应感兴趣区域计算MPS值行线性回归分析,浅部皮层和深部皮层区域与动物实验皮层缺失百分数进行线性相关性比较,R2值分别为0.9953和0.9685。
结论：
1.在进行有限元模型前处理过程中,网格密度越小,模型的网格数越多,计算结果越精确,计算时间越长,网格密度0.3mm能满足计算精确性要求,且计算时间合理；不同的衰变常数对结果存在影响,20ms的衰变常数对本研究结果影响可接受。
2.实验很好的模拟了CCI动物实验制作流程,就撞击深度2.4mm、2.8mm和3.2mm分别进行了计算机模拟撞击大鼠脑皮层过程。当撞击物达到最大撞击深度后,在撞击载荷下,脑组织表面的变形、应力和应变随时间步向深部移动变化。有限元模型可以有效、直接的分析外力作用下脑组织内部不同结构的力学反应变化。结果提示MPS的变化与动物实验皮层损伤存在相关关系,该初步研究所能进行分析的数据偏少,需要更多的实验数例和不同前处理条件下有限元模型预测的MPS值进行对比,来求证MPS作为预测皮层神经元损伤定量生物力学参数之一的可行性。
Background and objective:Traumatic Brain Injury (TBI) is the frequently-occurring disease in the neurosurgery department. The mechanical deformation by the vulnerant force affected on the head induces the primary injury and the secondary injury. The TBI can cause the extensive clinical symptoms and dysfunctions. It has been the social public health problem now, because it is one of the major causes of the human death and disability. The understanding of the biomechanics in the different brain tissue can effectively estimate and prevent the TBI degree. But the detailed machanism of the human TBI is not completely illuminated. The stress-strain relation in the human TBI is difficult to be acquired, and the biomechanics research of brain injury in the living body is impossible. Over the half-century years, many different experimental methods are utilized and developed in the brain injuries such as animal experiment, corpse experiment and biomaterial experiment. Due to the difficulties of direct obtaining and analysis the different structures biomechanics with these relative experimental method, most researchers attempt to utilize the mathematical model for the TBI field. The finite element method (FEM) is the one of numerical method in structural analysis. It has been applied to solve the mechanics response of the several materials with the adventages in the analysis of complicated geometry shape and anisotropic material.
For the past few years, with the development of computer technologies and the higher mathematics, especially the computer aided design system (CAD), more and more finite element models are created and used to analyse the biomechanics changes in the human TBI. Some FEMs include the detailed human anatomical structures for the different tissues stress-strain research. But the human brain finite element models have some disadvantages in the TBI simulation and analysis. On one hand there are several limitations in the acquisition of the different human brain biomechanics parameter, on the other hand the analytic datas of the human brain finite element models are difficult to compare with datas of the actual human TBI. So this study uses the rat as the research object to develop its brain three dimensional (3-D) finite element model. With this model the biomechanics relationships between the different tissues are analysed. Also this study comfirms the changes of maximum principal strain (MPS) is related with the rat cortex injury. The further research purpose is to predict the neuron injury in TBI. The research work includes:
1. Establishment of the rat controlled cortical injury (CCI) model and the injury analysis of the cortex and the hippocampus
Objective:Establishment of the rat controlled cortical injury model and the injury analysis of the cortex and the hippocampus
Methods:We establish the rat CCI model using the special CCI device with the stereotaxis equipment. The impact velocity is 4m/s, the impact depth is 2.4mm, 2.8mm and 3.2mm. The animals are randomly devided into control group and groups at 2.4mm,2.8mm and 3.2mm. To evaluate the injury of the cortex and the hippocampus of every experiment groups, Cresyl Violet staining is performed to calculate the cortex injury area and hippocampus survival neurons.
Result:The rat CCI models are established successfully. The cortex of impacted side is sharply damaged in the different impacted depth. The defective percent area in cortex of the contralateral hemisphere is 3.65±2.11 in the 2.4mm group,7.83±2.53 in the 2.8mm group and 12.85±3.02 in the 3.2mm group. The surviving neuron number in ipsilateral CA3 hippocampus 35.67±6.38/hpf in controlled group,26.50±4.18/hpf in 2.4mm group,17.67±4.08/hpf in 2.8mm,. In 3.2mm group, the impactor penetrate into the pyramidal layer, we do not count the neurons number.
Conclusion:The rat CCI model is the scientific and advisable animalmodel for the TBI research with the controlled impacted force parameter. In the rat CCI model, the severe brain injury parameter should set that the impacted depth is 2.8mm with the 4m/s velocity.
2. Construction of the 3-D finite element model of normal rat brain
Objective:Construction of the 3-D finite element model of normal rat brain
Methods:According to the normal rat stereotactic anatomical atlas, we confirm the reconstruction targets with the 25 coronal slice. Each slice anatomies are processed and digitizing with Photoshop CS software. The detailed anatomies includes the cortex, subcortex, hippocampus and lateral ventricles structures. All digital atlas are located in the stereoscopic coordinate. Each slice is saved as the TIFF format. Then with the SolidWorks 2007 software, two-dimension (2-D) draw of each slice is done according to the anatomical shapes and stereoscopic coordinates of each tissue. Each cross section is connected with the lofting order in SolidWorks 2007 software, the hippocampus and lateral ventricle structures are exsected. The assembly is built with the each part and saved as the xt format. Then this format is imported into the Unigraphics NX 6.0 software. In this software the impactor is constructed and the impactor tips located on the cortex surface. The impactor diameter is 5mm, the impacted direction is perpendicular. Then the total model is imported into the ANSYS Workbench software to define the elements type with solid 164 tetrahedron. The mesh is constructed according to the mechanical environment default setup. The mesh density in the most of ipsilateral part is 0.3mm, in the impacted side hippocampus and contralateral hemisphere is 0.5mm.
Result:Construction of the 3-D finite element model of normal rat brain is completed. The model includes the cortex, subcortex, hippocampus and lateral ventricles structures. The FEM has a good geometric similarity with the anatomical atlas. The total number of elements was 205348, the total number of nodes is 40412.
Conclusion:The rat anatomical atlas in the stereoscopic coordinate provides a effective, simple, economic and accurate information for the construction of finite element model of the complex shapes and structures. With the image processing software, CAD software and finite element software, it can be effective to construct the mathematical model of the complicated organism.
3. The finite element method simulation of the CCI animals model, the biomechanical analysis and the initial research in prediction of the cortical neuron loss
Objective:
1) Construction of the simple rat cortex impacted model, simulation of the rat CCI model process, collating of the mesh density and decay constant
2)The finite element simulattion and analysis of rat CCI model with the FEM, initial prediction of the neurons injury with the parameter MPS
Methods:
1)According to the cross section of the 3-D FE model, a plane FE model is constructed in the quadrilateral elements with the simple brain structure and the impactor by the Unigraphics NX 6.0 software. In the ANSYS Workbench software, the Explicit dynamic is built. The viscoelastic material properties of the brain grey matter and white matter are set. The properties include density, Young's modulus, poisson ratio, viscosity shear modulus and elasticity shear modulus. Two different areas are marked to compare with the different mesh density. The density includes 2mm、1mm、0.8mm、0.3mm、0.2m mand 0.1mm. According the 0.5mm mesh density, the different decay constants are choosed to analyse the MPS changes. The decay constants include 5ms、10ms、20ms and 40ms.
2)The impacted parameters including the material attribute, impactor diameter and the impacted velocity according to the animal experiment are set in the Ansys WorkBench software. The impacted depth is 2.4mm,2.8mm and 3.2mm. The viscoelastic material properties of the brain grey matter and hippocampus and the ventricle are set. The properties include density, Young's modulus, poisson ratio, viscosity shear modulus and elasticity shear modulus. The boundary condition is set according to the skull density. And four regions in cortex, subcortex, hippocampus and ventricle are choosed as the regions of interest. In different impacted depths each regions has the different stress, strain and deformation relationship. The linear regression is carried out between cortex injury in the animal experiment and the MPSs in the FEA predicted for the regions of cortex.
Result:
1)There is the different MPS in the impacted simulation with different mesh density. The analysis time of the impact in the model increases obviously with the mesh density decreases. Total average MPS increases when the mesh density decreases, and the increase trend grows down. The MPS in selected region increases with the lower mesh density. The difference between 2mm mesh density and 1mm density was 29.5%. The differences between 0.3mm and 0.2mm,0.8mm were 6.5% and 10.4%. The MPSs do not have a large changes with the different decay constants. The MPS in surface selected region is 0.8165、0.8360、0.8423.0.8420 respectively, in deeper part is 0.0852、0.0852、0.0851、0.0850 respectively.
2)The rat 3-D FE model simulates the CCI animal experiment process well in the different impacted depth. The highest value of von Mises stress 0.57064Mpa, 0.64684Mpa, 3.0449Mpa were respectively in the different vimpacted depths. When the impactor reachs the maximum depth, the area under the impactor has the largest deformations, and decrease in the radial directions, the deep part structure has the relative small deformations. And the highest value of strain in increased impacted depths were 1.1179,1.2535 and 1.5571. In 3.2mm depth the high peak of strain continued until the computer simulation analysis ended. In the four interest regions, the hightest MPS value occurred on the cortex in impacted side. All highest values in different groups were present within the foreset analysis time. In 2.4mm and 3.2mm depths simulation, the surface cortex was present the higher value than subcortex, it was 1.2%and 11.1%respectively. In the another depth the subcortex was 4.4%higher than surface cortex. The lateral ventricles had the lower change range in MPS. In 2.4mm and 2.8mm depths groups, the hippocampus was taken the higher MPS than lateral ventricles. In the another group the ventricle was taken more higher. The differences were 29.2%,40.8%and 27.8%. The initial research in linear regression between the MPSs predicted by the FE model and the neuron injury of cortex in animals experiment. The correlation coefficient R~2 were 0.9953 and 0.9685.
Conclusion:
1)The analysis result is more exactly and the analysis time is more longer when the mesh density decreases. The mesh density in 0.3mm is good for the precision and reasonable computing time. The decay constant in 20ms has little influence in our study.
2)In the simulation of the CCI animal model, the different brain tissues have the complicated stress, strain and deformation relationship when the cortex has been impacted. The differences in the biomechanics responses induce the different levels of the TBIs in the primary injury and secondly injury. In the initial study the MPS can be the parameter that predicts the neurons injury in TBIs. More animals experiments and more different pre-processing conditions FE models should be developed to implore the feasibility of MPS acted as the quantitate parameter of cortical neuron injury in TBI.
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