The mechanical problems in tumor and tumor microenvironment

肿瘤微环境包括肿瘤细胞、间质细胞、细胞外基质等.其在肿瘤的生长和发展过程中起着关键作用.肿瘤的微环境与正常组织的微环境有着显著的不同.肿瘤中的压应力对微环境有着多方面的影响, 例如, 可调控血管与淋巴管的功能, 造成代谢异常和间质高压, 压缩间隙基质, 增大药物输运的困难, 促进间质细胞变异并诱导肿瘤细胞转移. 因此, 肿瘤中的力学因素引起了广泛关注.本文总结了肿瘤及其微环境力学问题的研究进展, 讨论了肿瘤微环境中应力产生、药物输运、肿瘤转移等问题, 介绍了肿瘤微环境正常化的策略及其对肿瘤治疗的意义.     

肿瘤及其微环境的力学问题

肿瘤微环境包括肿瘤细胞、间质细胞、细胞外基质等.其在肿瘤的生长和发展过程中起着关键作用.肿瘤的微环境与正常组织的微环境有着显著的不同.肿瘤中的压应力对微环境有着多方面的影响,例如,可调控血管与淋巴管的功能,造成代谢异常和间质高压,压缩间隙基质,增大药物输运的困难,促进间质细胞变异并诱导肿瘤细胞转移.因此,肿瘤中的力学因素引起了广泛关注.本文总结了肿瘤及其微环境力学问题的研究进展,讨论了肿瘤微环境中应力产生、药物输运、肿瘤转移等问题,介绍了肿瘤微环境正常化的策略及其对肿瘤治疗的意义.     

利用血管生成模型计算实体肿瘤内的血液动力学

肿瘤血管生成(Tumor-induced Angiogenesis)是指在实体肿瘤细胞诱导下毛细血管的生长以及肿瘤中血液微循环的建立。肿瘤内血液、组织液等流体流动在肿瘤药物输运过程中扮演着重要作用,而这些流动受到肿瘤内微血管网络结构的直接影响。目前要获得精确的肿瘤内外的毛细血管拓扑结构存在一定困难,因此给肿瘤内的血液动力学研究带来困难。本文根据肿瘤内外的复杂生理特性,建立肿瘤内外血管生成的二维离散模型,在获得相对真实的毛细血管网络拓扑结构基础上对肿瘤内的血液动力学进行初步计算,数值计算的结果加深了对肿瘤的复杂生理特性的理解,同时也给肿瘤内的药物输运给予一定的提示。     

力敏感受体介导细胞功能调控的力学生物学研究

细胞膜是细胞与外部环境进行物质与能量交换的界面,是调节细胞正常生命活动的重要结构基础.细胞膜上力敏感受体可通过力学作用方式参与并影响细胞的力信号转导等功能.整合素和钙黏素是细胞膜上典型的力敏感受体,可介导细胞与细胞周围基质或邻近细胞发生力学作用,并将力学刺激信号转导为生化信号,进而激活细胞内一系列应答反应,最终影响细胞生长、分化、增殖、凋亡和迁移等功能.力敏感受体介导细胞功能调控研究已成为探索细胞主动响应外界复杂力学微环境的力学生物学机制的关键,为进一步深入认识生理和病理状态下细胞功能变化规律,为揭示疾病的发生、发展机制提供重要的力学生物学理论与实验依据.本文总结了力敏感受体介导细胞功能调控的国内外研究进展;介绍了黏附界面处典型力敏感受体的结构和功能;总结了这些力敏感受体参与的细胞力信号感知与响应的数理模型;概述了细胞通过力敏感受体进行力学信号转导的过程;介绍了黏附介导细胞功能调控的力学生物学过程和机制;简述了体外构建模拟细胞力学微环境中细胞-细胞外基质和细胞-细胞力学相互作用的技术;指出了力敏感受体介导细胞功能调控的力学生物学研究发展趋势和未来方向.     

CD44-配体相互作用的生物力学与功能调控

作为一种广谱表达的细胞粘附分子, I型跨膜糖蛋白CD44(cluster of differentiation 44)参与细胞增殖、分化、迁移, 血管生成等生物学过程,对于介导细胞信号转导, 调节组织稳态等功能具有关键作用. 特别地,CD44-选择素、CD44 -透明质酸相互作用介导的细胞粘附动力学在经典炎症反应、肿瘤转移或组织特异的肝脏免疫中具有重要作用.该综述分别从细胞层次粘附动力学、二维与三维条件下的分子层次反应动力学、原子层次微观结构以及胞内信号转导通路等方面综述了CD44 -选择素、CD44 -透明质酸相互作用的研究进展及尚待回答的生物力学问题.力学、物理因素对生命活动的不可或缺性逐渐被研究者们接受,力学医学、力学免疫学、力学组学等新概念相继提出. 生理、病理条件下,CD44 -配体相互作用介导的细胞粘附必将受到血流剪切、基底硬度等力学、物理微环境的调控,但是其调控机制还远不清楚. 基于此,本文就CD44 -配体相互作用相关的未来研究方向做出展望, 主要包括:力学、物理因素如何调控CD44 -配体相互作用介导的细胞粘附动力学及其内在机制;CD44 -配体相互作用反应动力学的力学调控规律及结构基础是什么;以及力学作用下CD44 -配体相互作用原子层次的微观结构如何发生动态演化.本文可为深入理解CD44 -配体相互作用的生物学功能及其结构功能关系提供线索.      

页岩气开采中的若干力学前沿问题

页岩气的开采涉及破裂和收集输运两个关键过程.如何实现2000,m以下、复杂地应力作用下、多相复杂介质组分的页岩层内网状裂纹的形成,同时将孔洞、缝隙中的游离、吸附气体进行高效收集,涉及到诸多的核心力学问题.这一工程过程涵盖了力学前沿研究的诸多领域:介质和裂纹从纳米尺度到千米尺度的空间跨越,游离、吸附气体输运过程中微秒以下的时间尺度事件到历经数年开采的时间尺度跨越,不同尺度上流体固体的相互作用,以及压裂过程中通过监测信息反演内部破坏状态等.针对近年来我们国家页岩气勘探开发工作所取得的成就及后续发展中面临的前沿力学问题,在综合介绍页岩气藏的基本特征和开发技术的基础上,以页岩气开采中的若干力学前沿问题为主线,从页岩力学性质及其表征方法、页岩气藏实验模拟技术、页岩气微观流动机制及流固耦合特征、水力压裂过程数值模拟方法、水力压裂过程微地震监测技术、高效环保的无水压裂技术等6个方面的最新研究进展进行了总结和展望,结合页岩气藏开发的工程实践, 深入探究了其中力学关键问题,以期对从事页岩气领域的开发和研究的从业人员提供理论基础, 同时,该方面的内容对力学学科、尤其是岩土力学领域的科研工作也具有重要指导价值.      

Mechanical frontiers in shale-gas development

页岩气的开采涉及破裂和收集输运两个关键过程.如何实现2000,m以下、复杂地应力作用下、多相复杂介质组分的页岩层内网状裂纹的形成,同时将孔洞、缝隙中的游离、吸附气体进行高效收集,涉及到诸多的核心力学问题.这一工程过程涵盖了力学前沿研究的诸多领域：介质和裂纹从纳米尺度到千米尺度的空间跨越,游离、吸附气体输运过程中微秒以下的时间尺度事件到历经数年开采的时间尺度跨越,不同尺度上流体固体的相互作用,以及压裂过程中通过监测信息反演内部破坏状态等.针对近年来我们国家页岩气勘探开发工作所取得的成就及后续发展中面临的前沿力学问题,在综合介绍页岩气藏的基本特征和开发技术的基础上,以页岩气开采中的若干力学前沿问题为主线,从页岩力学性质及其表征方法、页岩气藏实验模拟技术、页岩气微观流动机制及流固耦合特征、水力压裂过程数值模拟方法、水力压裂过程微地震监测技术、高效环保的无水压裂技术等6个方面的最新研究进展进行了总结和展望,结合页岩气藏开发的工程实践, 深入探究了其中力学关键问题,以期对从事页岩气领域的开发和研究的从业人员提供理论基础, 同时,该方面的内容对力学学科、尤其是岩土力学领域的科研工作也具有重要指导价值.     

非饱和土力学理论的研究进展

回顾了非饱和土有效应力的发展,目前普遍认同采用两个应力变量来建立本构模型,且对基质吸力中毛细和粘吸两部分作用进行了阐述。分析了非饱和土强度问题,包括抗剪强度和抗拉强度。讨论了非饱和土的本构模型问题,包括基于净应力和基质吸力的弹塑性模型,基于Bishop有效应力和基质吸力的水力力学耦合弹塑性模型,以及双孔隙结构的模型。最后探讨了热力学方法和多孔介质理论在非饱和土中的应用,基于多孔介质理论在多场耦合条件下土体复杂的行为是当前值得研究的问题。     

利用重正化群方法推导湍流二阶矩封闭模型

Rubinstein和Barton在他们的原始工作中，利用Yakhot-Orszag湍流重正化群方法对雷诺 应力输运方程中的速度-压力梯度项和各向同性回归过程进行了模拟. 文中分析了 其在理论推导过程中存在的数学物理上不自洽的问题及计算错误，并且利用重正化 群方法重新系统地对雷诺应力输运方程进行了模拟，计算得到的湍流常数理论值和 经验值相接近.     

汽车工程中的若干力学问题

汽车的设计、开发和使用离不开力学.简述汽车的发展历史、主要组成及其性能.介绍汽车工程中的几个关键力学问题,包括汽车轮胎力学、行驶稳定性分析、驱动与阻力、振动与噪声、碰撞力学与车身耐撞性、撞击损伤生物力学、行人保护力学等.展望了汽车工程中需要关注的力学问题.     

3D numerical study of tumor blood perfusion and oxygen transport during vascular normalization

The changes of blood perfusion and oxygen transport in tumors during tumor vascular normalization are studied with 3-dimensional mathematical modeling and numerical simulation. The models of tumor angiogenesis and vascular-disrupting are used to simulate "un-normalized" and "normalized" vasculatures. A new model combining tumor hemodynamics and oxygen transport is developed. In this model, the intravasculartransvascular-interstitial flow with red blood cell(RBC) delivery is tightly coupled, and the oxygen resource is produced by heterogeneous distribution of hematocrit from the flow simulation. The results show that both tumor blood perfusion and hematocrit in the vessels increase, and the hypoxia microenvironment in the tumor center is greatly improved during vascular normalization. The total oxygen content inside the tumor tissue increases by about 67%, 51%, and 95% for the three approaches of vascular normalization,respectively. The elevation of oxygen concentration in tumors can improve its metabolic environment, and consequently reduce malignancy of tumor cells. It can also enhance radiation and chemotherapeutics to tumors.     

Hybrid discrete-continuum model of tumor growth considering capillary points

A hybrid discrete-continuum model of tumor growth in the avascular phase considering capillary points is established. The influence of the position of capillary points on tumor growth is also studied by simulation. The results of the dynamic tumor growth and the distribution of oxygen, matrix-degrading enzymes, and extracellular matrixconcentration in the microenvironment with respect to time are shown by graphs. The relationships between different oxygenated environments and the numbers of surviving, dead, proliferative, and quiescent tumor cells are also investigated.     

Isolation of circulating tumor cells under hydrodynamic loading using microfluidic technology(基于微流控技术在流体动力载荷下分离循环肿瘤细胞)

在世界范围内, 癌症的死亡率仍在逐年上升. 循环肿瘤细胞(circulating tumor cells, CTCs) 是指从原发肿瘤脱落并进入血液循环系统的细胞, 可能引发肿瘤转移并入侵其他正常组织和器官. 因此, CTCs 的检测结果可以作为癌症病人疗效和预后的评价指标. 但是CTCs 的数量及其稀少, 使得CTCs 的检测尤为困难. 在癌症转移的病人中, 每毫升血液约含有10-100 个CTCs. 利用经生物活性材料表面修饰的微流控器件, 可以从血液中分离出CTCs. 这是一项跨学科的挑战, 需要来自不同学科背景的专家们共同参与, 如细胞生物学、表面化学、流体力学及微纳加工技术等. 该文首先介绍了CTCs 的细胞生物学基础, 然后总结了当前分离CTCs 的主要微流控技术, 包括基于细胞-- 配体作用、磁力作用和过滤等, 最后综述了基于微流控技术的CTC 检测和计数、在体CTC 成像等最新研究进展.      

Simulation of tumor microvasculature and microenvironment response to anti-angiogenic treatment by angiostatin and endostatin

The effects of anti-angiogenesis treatment by angiostatin and endostatin on normalization of tumor microvasculature and microenvironment are investigated, based on mathematical modeling and numerical simulation of tumor anti-angiogenesis and tumor haemodynamics. The results show that after anti-angiogenesis treatment: (i) the proliferation, growth, and branching of neo-vessels are effectively inhibited, and the extent of vascularization in tumors is accordingly reduced. (ii) the overall blood perfusion inside of tumor is declined, the plateau of tumor interstitial fluid pressure (IFP) is relieved, the interstitial fluid oozing out from the tumor periphery into the surrounding normal tissue is reduced, the reduction of overall extravasation across vasculature to tumor interstium is much less than the decreased overall blood perfusion, due to the decline of IFP, the intravasations is remarkablely effected by the change, in some cases there are no intravasation flow appear.     

Some basic questions on mechanosensing in cell–substrate interaction

Cells constantly probe their surrounding microenvironment by pushing and pulling on the extracellular matrix (ECM). While it is widely accepted that cell induced traction forces at the cell–matrix interface play essential roles in cell signaling, cell migration and tissue morphogenesis, a number of puzzling questions remain with respect to mechanosensing in cell–substrate interactions. Here we show that these open questions can be addressed by modeling the cell–substrate system as a pre-strained elastic disk attached to an elastic substrate via molecular bonds at the interface. Based on this model, we establish analytical and numerical solutions for the displacement and stress fields in both cell and substrate, as well as traction forces at the cell–substrate interface. We show that the cell traction generally increases with distance away from the cell center and that the traction-distance relationship changes from linear on soft substrates to exponential on stiff substrates. These results indicate that cell adhesion and migration behaviors can be regulated by cell shape and substrate stiffness. Our analysis also reveals that the cell traction increases linearly with substrate stiffness on soft substrates but then levels off to a constant value on stiff substrates. This biphasic behavior in the dependence of cell traction on substrate stiffness immediately sheds light on an existing debate on whether cells sense mechanical force or deformation when interacting with their surroundings. Finally, it is shown that the cell induced deformation field decays exponentially with distance away from the cell. The characteristic length of this decay is comparable to the cell size and provides a quantitative measure of how far cells feel into the ECM.     

Cell membrane-encapsulated nanoparticles for vaccines and immunotherapy

Functionalized nanoparticles are widely used in drug targeted delivery and immune microenvironment regulation. As a new type of biomaterial, cell-derived carriers are receiving considerable attention in clinical translation owing to their desirable biocompatibility and lower toxicity. Importantly, cell membrane-encapsulated nanoparticles can achieve specific biological effects from the benefit of their parent cell characteristics. In this review, we introduce the cell membrane coating technologies that are under extensive investigation, we also summarize various applications that have been developed for immunotherapy, and discuss the prospects in this field. With further understanding and integration with advanced biotechnology methods, it is believed that the continuing development of cell membrane-encapsulated nanoparticles will achieve promotion in clinical application.