Numerical Study Of Tumor Hemodynamics For Vascular-targeted Therapy

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.â—†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.â—†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.