Mechanical models for malaria infected erythtocytes 7

Chapter Conclusions and Future Work Chapter Conclusions and Future Work This thesis focused on the modeling of malaria (P.f) infected erythrocytes. One of the main objectives was to propose computational models for the malaria (P.f) infected erythrocytes at their different stages of parasite maturation, in particular at the mid and late stages, for which no accurate models had been proposed currently. The other was to relate the loss of cell deformability to the change in mechanical properties of the cell membrane and structural changes occurred within the cell. 7.1 Conclusions The major contributions and findings of this thesis are summarized as follows: 1. A two-component model was developed to study the malaria (P.f.) infected erythrocyte deformation. Finite element analysis was done to simulate the cell deformation in micropipette aspiration and optical tweezers stretching. The simulation was done using finite element program ABAQUS. The model was able to predict the cell deformation in both of these two experiments. 2. The effect of initial membrane shear modulus µ on the malaria (P.f.) infected erythrocyte deformability was studied using the two-component model. The values of initial membrane shear modulus were obtained by comparing the finite element simulation result with that of experiments. Considering the decreasing cell sizes and data deviation, the analysis 140 Chapter Conclusions and Future Work provided the range of initial membrane shear modulus for each parasite maturation stage. The increase in membrane shear modulus with the progression of disease state was quantified. 3. The effect of bending stiffness on the cell deformability was studied by simulating the cell deformation in both micropipette aspiration and optical tweezers stretching. Parametric studies were done by varying the initial bending stiffness D0 in the range of 3.3 x 10 -20 J to 1.5 x 10 -18 J. The bending stiffness was found to have little effect on the cell deformation. 4. The hemispherical cap model was commonly used for analyzing cell deformation in micropipette aspiration, due to its simplicity in calculating membrane shear modulus. However, with the wide range of micropipette sizes used in the experiments, this model may not be valid for all pipette sizes. The model and method proposed in this thesis allowed us to test the validity of hemispherical cap model by applying the model to analyze the simulation curves with known values of membrane shear modulus. Using this method, the range of 0.1 ≤ Rp Rcell ≤ 0.4 was proved valid for using hemispherical cap model in micropipette aspiration. For cells that can be assumed as a liquid enclosed by incompressible membrane, it is easier to apply hemispherical cap model due to its simplicity in calculation, and the results will be valid as long as 0.1 ≤ Rp Rcell ≤ 0.4. 5. It may not be suitable to use hemispherical cap model and two-component model to analyze the infected cells in the middle to late stages, since the parasite occupies more than 40% of the host cell’s volume. An advanced 141 Chapter Conclusions and Future Work multi-component model was developed to study the effect of parasite inclusion on the host cell deformation. Finite element simulations were done using ABAQUS to simulate the deformation in both micropipette aspiration and optical tweezers stretching. This advanced model was able to simulate mechanical probing at the different locations of the host cell and explain the difference in shear modulus given by hemispherical cap model for the same cell. The multi-component model also allowed us to quantify the effect of PVM stiffness and sizes. 6. Using the multi-component model, it was found that compared to the PVM sizes and the stiffness of PVM and host cell membrane, the interaction between PVM and host cell membrane did not significantly play an important role in the cell deformation induced by optical tweezers. Even if they were stuck to each other after contact, it would not affect the cell deformation as much as the change in membrane stiffness, PVM sizes and PVM stiffness would. 7.2 Future Works The work in this thesis indicated interesting directions of studying the malaria infected erythrocytes. The future work can include the following: 1. The current multi-component model can be further developed to include not only the hemoglobin but also the food vacuole and the parasite itself within the parasitophorous vacuole membrane (PVM). If the experimental techniques allow us to probe the PVM and its internal structure directly, a 142 Chapter Conclusions and Future Work more complete model can be established. If the current experimental techniques are not able to probe them directly, a more complex multicomponent model is still a good tool to analyze the heterogeneity within the host cell. 2. These models can also be used in studying the mechanical properties of malaria P.vivax, which is believed to become softer instead of stiffer with the progression of infection stage. Due to the limitation of culturing techniques, we cannot conduct micropipette aspiration and optical tweezers stretching on P.vivax in our lab. If the experiment data of these two experiments are available for P.vivax cells, the models used in this thesis can be applied in studying their mechanical properties. 3. These models proposed in this thesis may also be used to evaluate the drug treatments on the mechanical properties of the cells. 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Lim, Computational Modeling of the Micropipette Aspiration of Malaria Infected Erythrocytes, IFMBE Proceedings, Vol. 23, 1788-1791 (2009) G. Y. Jiao, K. S. W. Tan, C. H. Sow, Ming Dao, Subra Suresh, C. T. Lim, A Multicomponent Model for Malaria Infected Erythrocytes (Manuscript in preparation) A. Li, U. Lek-Uthai, S.W. Tan, R. Suwanarusk, G.Y. Jiao, G. Snounou, L. Renia, B. Russell and C.T. Lim, Nanomorphological changes to the surface of Plasmodium vivax infected erythrocytes (Manuscript in preparation) Conference Presentations G. Y. Jiao, K. S. W. Tan, C. H. Sow, Ming Dao, Subra Suresh, C. T. Lim, Modeling of Malaria Infected Red Blood Cells Using ABAQUS, at South East Asia Abaqus Regional Users’ Conference (Thailand) 2008 G. Y. Jiao, K. S. W. Tan, C. H. Sow, Ming Dao, Subra Suresh, C. T. Lim, Computational Mechanical Models for Malaria Infected Erythrocytes, at SingaporeMIT Alliance for Research and Technology ID-IRG (Singapore) 2009 150 [...]... Aspiration of Malaria Infected Erythrocytes, IFMBE Proceedings, Vol 23, 178 8- 179 1 (2009) G Y Jiao, K S W Tan, C H Sow, Ming Dao, Subra Suresh, C T Lim, A Multicomponent Model for Malaria Infected Erythrocytes (Manuscript in preparation) A Li, U Lek-Uthai, S.W Tan, R Suwanarusk, G.Y Jiao, G Snounou, L Renia, B Russell and C.T Lim, Nanomorphological changes to the surface of Plasmodium vivax infected erythrocytes... K S W Tan, C H Sow, Ming Dao, Subra Suresh, C T Lim, Modeling of Malaria Infected Red Blood Cells Using ABAQUS, at South East Asia Abaqus Regional Users’ Conference (Thailand) 2008 G Y Jiao, K S W Tan, C H Sow, Ming Dao, Subra Suresh, C T Lim, Computational Mechanical Models for Malaria Infected Erythrocytes, at SingaporeMIT Alliance for Research and Technology ID-IRG (Singapore) 2009 150 . of Malaria Infected Erythrocytes, IFMBE Proceedings, Vol. 23, 178 8- 179 1 (2009) G. Y. Jiao, K. S. W. Tan, C. H. Sow, Ming Dao, Subra Suresh, C. T. 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