SISTEMAS DE INFORMAÇÃO EM SAÚDE
 

Computational Biofluidics for Cell Dynamics: Development of innovative techniques for modeling and simulation of the cell constituents and of microfluidic devices for the manipulation and testing.

The micromechanical behavior of living cells is strongly linked with their function within the organ or tissue, which depends on the mechanical response. The motion of cells is also affected by the ambient fluids, which transport and deform them. Research in Cell Mechanics thus makes use of microscopic testing arrays by which the cells are subject to forces and other stimuli, to measure their response. Such is the case of microfluidic devices such as micropipettes, and of optical tweezers, which have enough resolution and stability to manipulate and deform one single cell membrane. They allow for the measurement of forces (in the picoNewton range) and displacements (in the nano-micrometer range). Single-cell experiments have huge potential for the discovery of new biological and medical phenomena, and have been seldom studied due to the complexity and novelty of the technology involved. Simulation software is essential to the development of this field, in the same way as it has become essential in day-to-day macroscopic Mechanics. The first applications that would be considered in this project is that of phospholipid vesicles and other simple structures made of phospholipid bilayers. The ability of simulating phospholipid bilayers is crucial for simulating bacteria, eukaryotic cells, and even intra-cellular organelles such as mitochondria.

There exist, however, practically no scientific computing methods for cell simulation with the generality and robustness needed to mimic state-of-the-art experiments. Our proposal is to build such methods based on existing physical/mathematical models for phospholipid bilayers, some of which were introduced by the ICMC group in recent years. The overall goal is to foster Computational Biofluidics to reach the degree of sophistication currently available in Experimental Biofluidics. The models will be improved and generalized incrementally all along the project. They will consider membrane-cytoskeleton interactions, layer-to-layer slippage, membrane-protein interaction, deformation of ion channels, etc., and whatever relevant phenomenon is identified in the international literature.

Activities

  1. Review, development and implementation of advanced cell membrane models based on phospholipid bilayer mechanics. These bilayers constitute the basic building block of cell structures. Different models and behaviors need to be considered, governed by tangential elasticity/viscosity and curvature-dependent energies.
  2. Incorporation of models of biological membranes into three-dimensional CFD formulations of the adjacent fluids. Imposition of constraints such as inextensibility (area preservation) and, for closed membranes, of osmotic interactions through the surface. Incorporation of selective adhesion models.
  3. Theoretical-computational study of the formation of cylindrical elongations (tethers) by the application of external forces on small membrane parcels. This application is most important because tethering is a fundamental experiment for shedding light into membrane behavior.
  4. Review, development and implementation of curvature effects in membranes with boundary. This model is needed for the study of structural transitions in HDL cholesterol particles. To the classical Canham-Helfrich energy a quadratic term in the total curvature of the boundary curve must be added, modeling the bending of the apolipoprotein that supports the bilayer.
  5. Incorporation of thermal effects to the membrane model, to compare with optical interferometry methods that allow for accurate determination of red blood cell fluctuations. The envisaged application is to simulate oxygen transport as related to morphological changes in red blood cells.
  6. Development of the set of computational tools necessary for the implementation of a virtual laboratory dedicated to cell bio-chemical mechanics. Current virtual experiments in biochemistry are available at the molecular level (Molecular Dynamics techniques), but is restricted to nanometric sizes and to microsecond-long processes. Extending MD to the scale of a whole cell evolving over milliseconds is unforeseeable in the next decade. Cell-size virtual experiments must thus rely on continuum or quasi-continuum models, which are in incipient state and constitute the focus of this project.

Goals

  1. Until the end of 2017. Development of computational methods for the simulation of lipidic bilayers, including membrane visco-elasticity and bending rigidity. Incorporation of interaction with CFD model for outer and inner fluids, accounting for inextensibility and osmotic restrictions.
  2. Until the end of 2019. Development of coupled models for lipidic bilayers together with the cytoskeleton, considering layer-to-layer slippage.
  3. Until the end of 2019. Theoretical and computational study of the formation of tethers in microorganisms. Calibration of the theoretical model by comparison against experimental data on tethering by micropipettes and optical tweezers.
  4. Until the end of 2019. Development of mathematical and computational methods for the simulation of lipidic bilayers with boundary, and application to HDL cholesterol particles.
  5. Until the end of 2019. Implementation of thermal fluctuation models. Calibration against optical interferometry results.
  6. Until the end of 2021. Characterization of morphological transitions as induced by constitutive changes in bilayers, and of the dynamics thereof.
  7. Until the end of 2021. Design, development and implementation of a theoretical/computational package for virtual cell experimentation. Documentation and publication.
  8. Until the end of 2021. Finalization of the theoretical/computational package for virtual cell experimentation. Tranfer to partners.

Impacts

  • Experiment optimization and parameter identification will become feasible upon completion of this project, in what regards illnesses related to the cell membrane, such as malaria, sickle cell anemia, etc.
  • Models will be developed applicable also to liposomes and other synthetic particles, which are widely used for drug testing and delivery.
  • Models will be developed that will shed light on the dynamics of high-density protein vesicles (HDL), with potential impact on several vascular illnesses.