下權谷 祐児

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博士学位論文の要旨及び審査結果の要旨 (Summary of Thesis(DR))othe

下權谷, 祐児

Tohoku University Repository (TOUR) / 東北大学機関リポジトリ

Computational Biomechanical Study on theInitiation and Growth of Cerebral Aneurysm (脳動脈瘤の発生と成長に関する計算バイオメカニクス的研究)著者 下權谷 祐児号 53学位授与番号 4175URL http://hdl.handle.net/10097/42589しも こん や ゆう じ氏 名 下 權 谷 祐 児授 与 学 位 博士(工学)学 位 授 与 年 月 日 平成21年3月25日学位授与の根拠法規 学fSIIiiifi!Silij第4条第1項研究科,専 攻の名称 東北大学大学院工学研究科(博士課程)バイオロボテイクス専攻学 位 論 文 題 目ComputationalBiomecha皿icalStudyon七heInitiationandGroWthofCerebraIAneurysm(脳動脈瘤の発生と成長に関する計算バイオメカニクス的研究)指 導 教 員 東北大学教授 山口 隆美論 文 審 査 委 員 主査 東北大学教授 山口 隆美 東北大学教授 佐藤 正明東北大学教授 早瀬 敏幸 東北大学准教授 石川 拓司東北大学准教授 太田 信論 文 内 容 要 旨Cerebral neurysm, which is an abnormal expansion ofthe cerebral  rterial wall, is a serious pathological condition because the rupture of an aneurysm is the most common cause of subarachnoid hemorrhage, well known for its very high mortality. It has been reported that between 16 and 6% of the population have cerebral neurysms before rupture (called  unruptured cerebral aneurysms). Recent advances inmedical imaging techniques, such as computed tomography (CT) and  magnetic resonance imaging (MRI) have increased the rate of detecting  uruuptured cerebral neurysms. Surgery with clipping and endovascular  treatment with coiling are the effective  treatment options currently available for  unruptured aneurysms. However, the  morbidity of such treatments is not trivial. In contrast, the reported annual risk of the rupture of cerebral neurysms is only about  1.9%. Consequently, determining whether a patient with an  unruptured cerebral aneurysm, when it is detected, should undergo surgery or endovascular treatment is still difficult. To resolve this issue, one must better understand how cerebral neurysms initiate and grow, as this may lead to the prevention f cerebral neurysms or to other treatment options.    Cerebral aneurysms develop in several stages; initiation, growth, and rupture. It is widely accepted that blood flow-induced mechanical forces acting on the vessel wall, i.e. hemodynamics, plays a vital role at all the stages of the cerebral aneurysm  development. To date, many animal models have been developed to investigate the initiation and growth of cerebral aneurysms. These xperimental studies reported that he initiation ofcerebral neurysms was a result of the interaction between  hemodynamics and structural degeneration of the arterial wall. A number of specific hemodynamic fa tors, uch as wall shear  stress (WSS), pressure and related mural stress, impingement force, flow rate, and residence time, have been proposed as candidates responsible for the pathogenesis of cerebral neurysms. Among these several hemodynamic fa tors, however, WSS is the one which has received special ttention i  aneurysm studies, like  hemodynamic studies on arteriosclerosis from the late —  774  —1960s onward. On the other hand, some studies recently focused on other hemodynamic factors uch as spatial wall shear stress gradient (SWSSG), which is a  hemodynamic quantity representing spatial nonuniformity of WSS, and some possible flow-related factors derived from disturbed  flow. Although these studies regarding WSS, SWSSG, and other hemodynamic factors have provided useful insights into the initiation of cerebral  neurysms, the specific hemodynamic insults that lead to the arterial degeneration has not been clarified yet. Identification f specific  hemodynamic fa tors responsible for aneurysm initiation may lead to the prevention f cerebral neurysms.   Although the exact cause for the growth of cerebral aneurysms remains unclear, hemodynamics i  believed to play a key  role in the aneurysm growth as well and many experimental studies have been reported. These studies have provided useful information about the underlying mechanics. However, the growth of cerebral aneurysms i  essentially a remodeling process that involves the arterial wall components. Thus, to better understand the growth of cerebral aneurysms, it is needed to address not only hemodynamics, but also the biological behavior of the arterial wall. Very few computational studies have focused on the growth of cerebral aneurysms. Although the results obtained from these computational studies was suggestive, the resultant aneurysms were  fusiform, while most cerebral aneurysms are  saccular. Thus, some other mechanism should be considered to represent saccular cerebral aneurysms. The development of a computational model for simulating the growth of saccular cerebral aneurysms can further our understanding in the mechanism of aneurysm growth, and this may lead to the prevention of aneurysm rupture or to advances in treatment of cerebral  aneurysms.    To date, the bulk of investigations into aneurysm  hemodynamics have been  conducted in animal experiments and in vitro experiments. Although these experimental studies have provided valuable insights, each approach has some serious limitations. Computational biomechanics provide effective means for  overcoming limitations in the biomechanical experiments, and it is appropriate for testing various hypotheses on biological events in the aneurysmal wall. That enables us to tackle the initiation and growth of cerebral aneurysms with a powerful tool.   With these backgrounds, the objectives ofthis thesis are summarized as follows: (1) to develop a computational model that can be used to test various hypothesis on the growth of saccular aneurysms, and to perform the simulation of saccular aneurysm formation based on a hemodynamic hypothesis, (2) to propose a novel possible hemodynamic fa tor esponsible for the initiation of cerebral neurysms, and (3) to demonstrate a realistic simulation of saccular cerebral neurysm formation based on the distribution  the proposed hemodynamic index. In Chapter 2, a computational model for the growth of saccular cerebral aneurysms was developed. This computational— 775 —model was designed to be able to take into account an arterial biological process, uch as the cellular and  extracellular matrix production  ofthe wall. Using this model, we performed numerical simulations to examine saccular cerebral neurysm  growth at the outer curve of a bent  artery. A U-shaped arterial geometry with torsion, which was modeled on part of the human internal carotid artery (ICA), was employed. The cellular and extracellular matrix production of the arterial wall was modeled by surface area expansion i  high wall shear stress (WSS) region. Based on WSS distribution the artery model, we  investigated aneurysm formation for the following three conditions: (a) strength degradation of the wall, (b) cellular and extracellular matrix production ofthe wall, and (c) both strength  degradation a d cellular and extracellular matrix production f the wall. A  saccular aneurysm shape was not observed when considering only arterial wall degradation upto 90%. However, the  saccular shape formed when cellular and extracellular matrix production of  the arterial wall was also taken into consideration. The resultant shape was consistent with clinical observations. From these results, it can be concluded that he strength degradation f the arterial wall is not sufficient to explain the  formation of saccular cerebral neurysms and the arterial wall growth due to biological process may play a vital role in the saccular shape formation.    In Chapter 3, a novel possible hemodynamic index, the gradient oscillatory number  (GON), for the initiation of  cerebral aneurysms was proposed. The  GON was designed to  quantify the temporal fluctuations of hemodynamic tension/compression forces  acting on  endothelial cells, specifically temporal fluctuations of the spatial wall shear stress gradient (SWSSG) vector on the arterial wall. A  patient-specific geometry ofa human ICA with an aneurysm was employed. Based on this  patient  specific geometry, we constructed anartery model without the aneurysm inthe following manner to investigate the blood flow before aneurysm formation.  First, we removed the segment of the parent artery near the aneurysm.  Then, using the data for center positions and the mean diameters atseveral cross ections extracted from the original geometry, we roughly  reconstructed he parent artery from both remaining parts. Finally, the wall was smoothed so that he elastic  energy calculated by the spring network model was minimized. In this way the artery model of the ICA before aneurysm formation was successfully reconstructed. Wecalculated the proposed hemodynamic index and six  other hemodynamic indices (WSS at peak systole, time-averaged WSS, oscillatory shear index (OSI), potential neurysm formation i dicator (AFI), SWSSG at peak systole, and time-averaged SWSSG) for the geometry before aneurysm formation using a computational fluid dynamics technique. By comparing the distribution f each index at the location of aneurysm formation, we discussed the validity of each. The results showed that only the proposed hemodynamic index had a significant  correlation with the location of aneurysm formation. We investigated the sensitivity of the proposed hemodynamic index to the reconstructed surface geometry by performing additional flow calculations for other two different surface geometry. The result showed  the similar distributions of the  GON index among all cases. The GON was the highest at the location of aneurysm formation i all cases, and the differences of the maximum value was less than 5%. The influence of the inlet flow rate waveform on the  GON was also discussed by— 776 —performing an additional flow calculation with a physiological inlet waveform. Again, the result showed the similar distribution of the GON index to the original case. These results have suggested that the proposed index, GON, may be useful as a hemodynamic index for the initiation of cerebral aneurysms.    In Chapter 4, we examined whether a saccular aneurysm could form in our  aneurysm growth model for actual cerebral arterial  geometry. Using aneurysm growth model in which the cellular and extracellular matrix production of the arterial  wall was hypothesized, we performed an aneurysm formation analysis based on the  GON index distribution for the patientspecific ICA  geometry. It should be noted that, based on the  findings in Chapter 3,  the  GON was taken to be a possible trigger to the aneurysm growth in Chapter 4. The result showed that a saccular cerebral aneurysm could appear based on our hypothesis for an actual cerebral arterial  geometry.  While a saccular aneurysm was not observed when assuming only strength degradation of the wall as with the result in Chapter 2, a realistic simulation of saccular cerebral aneurysm formation was successfully demonstrated when considering the cellular and extracellular matrix production of the  wall.    In  conclusion, it has been suggested that the formation of saccular cerebral aneurysms may require at least following two mechanisms: aneurysm initiation accompanied by arterial degenerative change due to  hemodynamic stress, which would be marked by the high-GON index; and the subsequent aneurysmal wall remodeling and growth, specifically the arterial expansion due to persistent production of cellular and extracellular matrix of the wall, which can be modeled well by the growth model developed in this thesis. —  777  —論文審査結果の要旨脳動脈瘤の発生 と成長のメカニズムの理解は,瘤の予防や新 しい治療選択肢の提供 にっながる重要な研究課題である。本論文では第一に,血 管壁の生物学的反応を考慮 した脳動脈瘤の成長に対す る計算モデルを構築 してい る。第二に,血 流が及ぼす血管壁への力学的負荷 の時間変動 について考察 し,瘤の発生 リスクを評価す るための新 しい血行力学的指標 を提案 している。第三に,これ らを統合することにより,脳動脈実形状 にお ける瘤のリア リステ ィックな形成シミュレーシ ョンに成功 している。本論文は,これ らの研究成果 をま とめたものであ り,全編5章 からなる。第1章 は緒論であ り,本研究の背景,目 的お よび構成を述べている。第2章 では,壁 の生物学的反応を考慮 した脳動脈瘤 の成長に対す る計算モデルを構築 してい る。当該成長モデルをヒ ト内頸動脈の走行 を模擬 したモデル形状に対 して適用 し,臨床で観察され る脳動脈瘤の形態的特徴(嚢 形状)を 極めてよく再現す ることに成功 している。 これは初の成功例であ り,瘤の成長メカニズムの解明 に資す る成果である。第3章 では,血 流が及ぼす血管壁への力学的負荷の時間変動について考察 し,瘤の発生 リスクを評価す るための新 しい血行力学的指標 を定式化 している。また、瘤を発症 した実際の患者の3次 元脳動脈モデルか ら瘤発生前の脳動脈形状を再構築す るアル ゴリズムを開発 している。再構築 された脳動脈実形状において,脈 動する血流の解析を行 うことによ り、前述の血行力学的指標が瘤 の発生箇所 と強い相関を有することを明 らかにしている。 これは,独 創的かつ重要な成果である。第4章 では,第2章 にお ける成長モデルおよび第3章 における血行力学的指標 に関す る研究を統合 している。脳動脈実形状における提案指標の分布 に対して,生 物学的反応 を考慮 した成長モデルを適用することで,瘤 の リア リスティックな形成シ ミュレーションに成功 している。さらに,従 来言われてきたよ うな血管壁の強度低下による受動的拡張だけでは,嚢形状の形成 を説明できないこ とを示 し,瘤の成長において壁の生物学的反応が重要な役割を果たすことを明 らかに している。 これ らは,脳 動脈瘤の形成メカニズムの解 明のために有用である。第5章 は結論である。以上要するに本論文は,脳 動脈瘤の発生 と成長に関して計算バイオメカニクスの手法 を用いて独創的な研究を行ったものであり,バイオロボティクスお よび生体力学の発展 に寄与するところが少 なくない。よって,本 論文 は博士(工学)の学位論文 として合格 と認める。778

Computational Biomechanical Study on the Initiation and Growth of Cerebral Aneurysm (脳動脈瘤の発生と成長に関する計算バイオメカニクス的研究)

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Computational Biomechanical Study on the Initiation and Growth of Cerebral Aneurysm (脳動脈瘤の発生と成長に関する計算バイオメカニクス的研究)

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