【作者】 吴洁；

【导师】 许世雄；

【作者基本信息】 复旦大学 ， 生物力学， 2009， 博士

【摘要】 肿瘤血管靶向治疗(tumor vascular-targeted therapy)是当今世界医学界最新的癌症治疗方案之一。根据作用机理不同,血管靶向治疗分为抗血管生成疗法(anti-angiogenesis therapy)和血管阻断疗法(vascular-disrupting therapy)。前者旨在抑制血管新生,后者则选择性地损坏或阻断已有血管。临床研究发现,单纯的血管靶向治疗的疗效并不确定,但将其与化疗或放疗序贯地联合应用,可以明显提高临床疗效。最新观点认为,血管靶向治疗可促使肿瘤血管及微环境由原来的结构及功能的异常状态向正常状态转变,从而消除肿瘤内药物传递屏障,增强对放、化疗的敏感性。基于此,本文以数值模拟为研究手段,针对肿瘤血管靶向治疗的特点和途径,研究各种治疗方案对肿瘤血液动力学的影响,探讨血管靶向治疗对肿瘤微环境流动状态正常化的生物力学机制,为制定更合理的抗肿瘤治疗策略提供理论依据及参考信息。本文主要工作1.深化拓展实体肿瘤血管生成的数值模拟综合考虑血管芽尖内皮细胞在肿瘤组织和宿主组织不同力学环境影响下的随机、趋化和趋触性运动,同时考虑血管分叉级数、血管管径变化等因素;对模拟生成的血管网进行连通性检验,以确保微循环网络结构的完整有效;对部分模型参数进行灵敏度分析,以考察模拟结果的可调控性;为减少由数值网络引起的血液流动几何阻力的增量,提出对血管网采取后期平滑处理的观点,并进行了实际处理。模拟结果与真实的肿瘤微血管网几何形态特征基本一致,可为肿瘤血液动力学、药物输运等理论研究提供较接近实际的微血管网络模型。2.实体肿瘤血液动力学多尺度耦合的数值模拟真正意义上耦合肿瘤微血管网内——跨血管壁——组织间质内的多尺度流动,同时考虑血管顺应性、血液流变性、微血管比面的空间异构性、宿主组织淋巴系统吸收等因素;建立以迭代计算为基础的数值求解方法,对流动进行严格地耦合求解;分析肿瘤血管管壁渗透率、间质水力传导系数、宿主组织淋巴系统吸收能力等生理参数的改变对肿瘤微环境流动状态的影响作用。模拟结果不仅能体现实体肿瘤内异常血液灌注及微环境的基本特征,而且还反映了跨壁渗漏在决定整个流动状态、影响肿瘤内部环境以及促进肿瘤细胞转移中所起的重要作用,这些结果是之前的非耦合和半耦合模型无法得到的。3.肿瘤血管靶向治疗的血液动力学数值研究将上述模型及相应的模拟手段应用到肿瘤血管靶向治疗的血液动力学数值研究中。比较分析各表征流动状态的重要指标值的相对变化,考察各治疗方案对肿瘤微环境正常化的作用。(1)抗血管生成疗法:根据前期工作中建立的肿瘤抗血管生成模型,模拟肿瘤在血管抑素和内皮抑素以不同联合方式作用下的血管网生成,并在此基础上进行血液动力学数值模拟。(2)血管阻断疗法:根据肿瘤血管网异常特征,设计四种血管阻断方案——随机阻断、根据血管异常形态阻断、根据血管成熟度阻断、根据血管内血液流量阻断,并在经阻断处理后的血管网上进行流动模拟。研究表明,血管靶向疗法可一定程度地改善肿瘤内异常的微环境流动,有效缓解药物传递屏障,消除肿瘤细胞转移的动力因素;抗血管生成并非抑制血管越多疗效就越好,血管数过量减少不利于微环境的正常化;针对性地阻断某几类血管能得到较好疗效,如阻断血管内血液流量较低的血管可整体改善流动状态;阻断成熟度较低的血管对促进血管内物质的跨壁传递效果明显。◆本文主要创新点1.肿瘤血管数值生成是国际上广泛研究的课题,本文在以下几方面拓展深入:建立肿瘤血管生成三维模型,根据肿瘤血管管径特点,定义血管分叉级数及初始管径;对血管网采取连通性检验,确保微循环流动有效进行;提出并实施血管网后期平滑处理,以减少数值网络引起的流动几何阻力增量。2.真正意义上实现肿瘤内多尺度耦合流动的数值模拟,同时耦合血管顺应性、血液流变性、微血管比面空间异构性、宿主组织淋巴系统吸收等因素;建立以迭代计算为基础的数值求解方法,进行严格地耦合求解。3.目前肿瘤血管靶向治疗主要以实验及临床研究为主。本文基于模拟生成的微血管网,数值研究了抗血管生成及血管阻断作用下的肿瘤血液动力学,比较分析各治疗方案对肿瘤微环境流动状态的改善效果。上述研究目前尚未见报道。更多还原

【Abstract】 Tumor vascular-targeted therapy is one of the latest treatments for cancers in the world at present. According to the different therapeutic mechanisms, vascular-targeted therapy is divided to two groups: anti-angiogenesis approaches, aim at inhibiting new vessels formation; and vascular-disrupting approaches, designed to selectively damage or disrupt the established vessels. Clinical studies have indicated that the effect of single vascular-targeted therapy is uncertain, but combined with sequential chemotherapy or radiotherapy can significantly improve the clinical efficacy. The current view is, vascular-targeted agents can normalize tumor vasculature and microenvironment of abnormal structure or function, consequently eliminate drug barrier and enhance sensitivity to radiotherapy and chemotherapy. The main purpose of this study is to generate a simulation tool able to investigate the effects on tumor hemodynamics of anti-angiogenesis and vascular-disrupting treatments, based on the respetive characteristics and approaches, accordingly, to study the biomechanical mechanism of tumor microenvironment normalization by vascular-targeted therapy. The findings may provide theoretical basis and reference information for designing a more effective treatment strategy of solid tumors.◆Main works of the dissertation1. Extension of modeling and simulation of tumor angiogenesisThe present model incorporated the migration of endothelial cells on vessel sprout through random motility, chemotaxis and haptotaxis under the influence of different mechanical environments inside of tumor and host tissues. Additionally, the branching generations of vessels and the heterogeneous distribution of vessel diameters were taken into account. The examination of vessel connectivity was carried out to guarantee the efficiency of blood circulation through the network. The sensitivities of network structures to the changes of some model parameters were studied, to investigate the flexibility and controllability of the model results. With a view to reducing the additional geometric resistance to blood flow caused by the numerical networks, the view of post-processing smoothing of networks was proposed, and practiced in the present work.The network structure from simulation is consistent with the basic features of real tumor microvasculature, which could provide a relatively actual vascular network for numerical research of hemodynamics and drug delivery in solid tumors.2. Multi-scale coupled simulation of tumor hemodynamicsThe flow model completely coupled intravascular blood flow, transvascular leakiness and interstitial fluid movement of tumor hemodynamics, furthermore, vessel compliance, blood rheology, lymphatic absorption in host tissue and heterogeneity of vessel surface area per unit tissue volume were also considered. To solve the coupling of the multi-scale flows, a specific computational procedure was built on the basis of iterative algorithms. The sensitivities of the flows to the changes of some key physiological parameters were analyzed, such as hydraulic permeability of tumor vessels; hydraulic conductivity of tumor interstitium; absorption capacity of lymphatic system.The model could not only predict the basic features and characteristics of abnormal microcirculation and microenvironment in solid tumors, but also present the important role of transvascular leakiness in governing the systemic flowing pattern, influencing the tumor internal environment and contributing to the metastasis of tumor cells, which could not be presented by the previous uncoupled or half-coupled models.3. Numerical study of tumor hemodynamics after vascular-targeted threapyTumor hemodynmaics after the vascular-targeted treatments were studied numerically, by the above mathematical models and the corresponding simulation techniques. Through comparing and analyzing the relative changes of some key indicators of the flows, the effects of different treatments on tumor microenvironment normalization were investigated.(1) Anti-angiogenesis therapy Generation of tumor angiogenic microvasculature under the synthetic effects of angiogenic inhibitors Angiostatin and Endostatin, used by the model of tumor anti-angiogenesis developed previously. Simulation of hemodynamics based on the anti-angiogenic networks.(2) Vascular-disrupting therapyDesignment of four approaches of vascular disrupting, in accordance with the abnormalities of tumor vessels: disrupt randomly; disrupt according to network structure; disrupt according to vessel maturity; disrupt according to blood flowrate. Simulation and investigation of hemodynamics based on the disrupted networks.The results showed that, vascular-targeted therapies could improve tumor microenvironmental flows, eliminate drug barrier and inhibit tumor metastasis to some extent; for anti-angiogenesis treatments, not more vessels inhibited, the better of the effects; decreasing too much vessels may go against normalization of microenvironment; disrupting certain types of vessels may get better effects, e.g. discrupting the vessels of lower blood flowrate could improve the whole flowing state; disrupting the vessels of lower maturity could effectively enhance the extravastions.◆Innovations of the study1. Numerical simulation of tumor angiogenesis is one hot topic extensively researched in the world. In the present dissertation, a further study was made in the following aspects: development of 3D model of tumor angiogenesis, considering branching generations of vessels and various diameter of branching vessels according to physiological feature of tumor vasculature; examination of vessel connectivity to guarantee the efficiency of blood circulation through the network; post-processing of network smoothing with a view to reducing the additional geometric resistance to blood flow caused by the numerical networks.2. Real coupling simulations of multi-scale flows in solid tumors were carried out, which included intravascular blood flow, transvascular leakiness and interstitial fluid movement, and also combined vessel compliance, blood rheology, lymphatic absorption in host tissue and heterogeneity of vessel surface area per unit tissue volume as well. Based on the iterative algorithms, one specific computational procedure was built to solve the coupled flow rigidly.3. Recent studies of tumor vascular-targeted therapy mainly focus on experiments and clinical researches. In this dissertation, through developing a simulation method, the effects on tumor hemodynamics and microenvironment normalization of the various vascular-targeted treatments (anti-angiogenesis and vascular-disrupting therapies) were investigated, based on the microvascular networks generated numerically.The above studies haven’t been reported yet.更多还原