In vitro three-dimensional cancer metastasis modeling:Past,present, and future

Metastasis is the leading cause of most cancer deaths, as opposed to dysregulated cell growth of the primary tumor.Molecular mechanisms of metastasis have been studied for decades and the findings have evolved our understanding of the progression of malignancy. However, most of the molecular mechanisms fail to address the causes of cancer and its evolutionary origin, demonstrating an inability to find a solution for complete cure of cancer. After being a neglected area of tumor biology for quite some time, recently several studies have focused on the impact of the tumor microenvironment on cancer growth. The importance of the tumor microenvironment is gradually gaining attention, particularly from the perspective of biophysics. In vitro three-dimensional(3-D) metastatic models are an indispensable platform for investigating the tumor microenvironment, as they mimic the in vivo tumor tissue. In 3-D metastatic in vitro models, static factors such as the mechanical properties, biochemical factors, as well as dynamic factors such as cell–cell, cell–ECM interactions, and fluid shear stress can be studied quantitatively. With increasing focus on basic cancer research and drug development, the in vitro 3-D models offer unique advantages in fundamental and clinical biomedical studies.     

肿瘤物理学——探索癌症的新思路

<正>目前全球每年约有700万人死于癌症,而到2030年将可能超过1310万。在过去的几十年里,尽管癌症研究不断出现新进展,但研究成果不甚显著,最直接的证明便是死亡率无明显下降。癌症研究进展迟缓,可以说处于探索时期。这让越来越多的研究人员开始怀疑,用经典的生物学或医学思路研究癌症是否存在策略上的缺陷?——译者注     

三维微纳米制造技术在癌症生物物理研究中的应用

癌症致命的主要原因是癌细胞在临床上的转移性. 癌细胞的侵袭和转移是一个非常复杂的三维过程, 但现有的癌症研究在活体上有诸多观测和操作上的困难. 而体外实验又通常在培养皿中进行, 其二维的生长环境已完全不能满足对癌细胞空间转移性的深入研究, 故在活体外构建出癌细胞侵袭和转移的三维物理模型具有十分重要的意义. 然而如何在体外尽可能真实地模拟体内癌细胞的生长微环境一直是困扰科学家的难题. 本文系统介绍了三维微纳米制造的几种主流技术, 探讨了它们在癌症生物物理研究中的应用和发展. 在此基础上为了在未来实现对体外三维模型的制造、观测和精确操作, 文章还创新性地提出了一种结合紫外线固化生物型水凝胶的三维成型技术、光片三维成像技术以及微纳米探针控制技术的一体化研究平台. 这些先进的技术和理念, 势必会逐步升级现有传统的癌症研究手段, 为未来理解和治疗癌症揭开全新的篇章.     

Biophysical model for high-throughput tumor and epithelial cell co-culture in complex biochemical microenvironments

The in vivo tumor microenvironment is a complex niche that includes heterogeneous physical structures,unique biochemical gradients and multiple cell interactions.Its high-fidelity in vitro reconstruction is of fundamental importance to improve current understandings of cell behavior,efficacy predictions and drug safety.In this study,we have developed a high-throughput biochip with hundreds of composite extracellular matrix(ECM)microchambers to co-culture invasive breast cancer cells(MDA-MB-231-RFP)and normal breast epithelial cells(MCF-10 A-GFP).The composite ECM is composed of type I collagen and Matrigel which provides a heterogeneous microenvironment that is similar to that of in vivo cell growth.Additionally,the growth factors and drug gradients that involve human epidermal growth factor(EGF),discoidin domain receptor 1(DDR1)inhibitor 7 rh and matrix metalloproteinase inhibitor batimastat allow for the mimicking of the complex in vivo biochemical microenvironment to investigate their effect on the spatial-temporal dynamics of cell growth.Our results demonstrate that the MDA-MB-231-RFP cells and MCF-10 A-GFP cells exhibit different spatial proliferation behaviors under the combination of growth factors and drugs.Basing on the experimental data,we have also developed a cellular automata(CA)model that incorporated drug diffusion to describe the experimental phenomenon,as well as employed Shannon entropy(SE)to explore the effect of the drug diffusion coefficient on the spatial-temporal dynamics of cell growth.The results indicate that the uniform cell growth is related to the drug diffusion coefficient,which reveals that the pore size of the ECM plays a key role in the formation of complex biochemical gradients.Therefore,our integrated,biomimetic and high-throughput co-culture platforms,as well as the computational model can be used as an effective tool for investigating cancer pathogenesis and drug development.     

微流体芯片中的癌症生物物理研究

文章从生物物理的新角度出发,介绍了如何利用微流体技术研究癌症的一系列重大问题,其中包括:构建三维微型结构体,用于在体外模拟和研究肿瘤细胞侵袭组织的细胞生物行为;开发新型微流体芯片,以检测血液中循环肿瘤细胞,并分析将其应用于临床中的可能性。文章还展望了飞秒激光三维直写技术构建肿瘤细胞转移模型的应用前景。     

Electrical field-driven ripening profiles of colloidal suspensions

Electrorheological(ER) fluid is a type of smart fluid whose shear yield stress relies on the external electrical field strength. The transition of ER fluid microstructure driven by the electrical field is the reason why viscosity changes.Experimentally, the transparent electrodes are used to investigate the column size distribution where an external electric field is applied to a colloidal suspension, i.e., ER fluid is increased. The coarsening profile of ER suspensions is strongly related to electrical field strength, but it is insensitive to particle size. In addition, in a low field range the shear stress corresponding to the mean column diameter is studied and they are found to satisfy a power law. However, this dependence is invalid when the field strength surpasses a threshold value.     

Drop impact on substrates with heterogeneous stiffness

Previous studies of drop impact mainly focus on homogeneous substrates while heterogeneous substrates remain largely unexplored. A convenient preparation strategy of stiff heterogeneous substrates is presented in this work, and the drop impact on such a stiffness-patterned substrate consisting of soft spirals surrounded by a rigid region is systematically investigated. The results show that the splash behavior of a drop on a stiffness-patterned substrate exhibits distinct characteristics from those on a homogeneous substrate. Prompt splash is more likely to occur on the substrate with the greater heterogeneity of stiffness, which is reflected in the lower critical impact velocity. Moreover, the splash velocity of emitted droplet is significantly larger on the heterogeneous substrate than that on a corresponding homogeneous substrate, especially at a higher impact velocity of the drop, indicating a stronger splash intensity on the heterogeneous substrate. The difference in drop splashing between homogeneous substrate and heterogeneous substrate is largely due to the stiffness heterogeneity, rather than the variation of overall stiffness of the substrate. The use of spiral shape provides a feasible solution for introducing stiffness heterogeneity of substrate. This study is conducive to the understanding of drop impact research beyond uniform substrates, reveals the potential of using stiffness-patterned substrates to control splash, and may find useful applications in industries related to drop impact and splash.     

Motile parameters of cell migration in anisotropic environment derived by speed power spectrum fitting with double exponential decay

Cell migration through anisotropic microenvironment is critical to a wide variety of physiological and pathological processes.However,adequate analytical tools to derive motile parameters to characterize the anisotropic migration are lacking.Here,we proposed a method to obtain the four motile parameters of migration cells based on the anisotropic persistent random walk model which is described by two persistence times and two migration speeds at perpendicular directions.The key process is to calculate the velocity power spectra of cell migration along intrinsically perpendicular directions respectively,then to apply maximum likelihood estimation to derive the motile parameters from the power spectra fitting with double exponential decay.The simulation results show that the averaged persistence times and the corrected migration speeds can be good estimations for motile parameters of cell migration.     

Derivation of persistent time for anisotropic migration of cells

Cell migration plays an essential role in a wide variety of physiological and pathological processes. In this paper we numerically discuss the properties of an anisotropic persistent random walk(APRW) model, in which two different and independent persistent times are assumed for cell migrations in the x-and y-axis directions. An intrinsic orthogonal coordinates with the primary and non-primary directions can be defined for each migration trajectory based on the singular vector decomposition method. Our simulation results show that the decay time of single exponential distribution of velocity auto-correlation function(VACF) in the primary direction is actually the large persistent time of the APRW model, and the small decay time of double exponential VACF in the non-primary direction equals the small persistent time of the APRW model. Thus, we propose that the two persistent times of anisotropic migration of cells can be properly estimated by discussing the VACFs of trajectory projected to the primary and non-primary directions.     

Bio-inspired environmental adaptability of swarm active matter

How biologically active matters survive adaptively in complex and changeable environments is a common concern of scientists. Genetics, evolution and natural selection are vital factors in the process of biological evolution and are also the key to survival in harsh environments. However, it is challenging to intuitively and accurately reproduce such longterm adaptive survival processes in the laboratory. Although simulation experiments are intuitive and efficient, they lack fidelity. Therefore, ...