(4bq) Dynamics of Cells, Multicellular Organisms, and Flowing Sand Grains

What do single cells, multicellular organisms, and flowing sand grains have in common? They are all highly dynamic materials that can display a variety of complex behaviors  including collective motion with patterns of extended spatiotemporal coherence, anomalous diffusion, active migration, and morphogenesis. Developing a deeper understanding of dynamics in these complex systems has the potential to lead to considerable engineering breakthroughs. For example, investigating tumor cell transport in the microcirculation can lead to improvements in disease diagnosis and prognosis; quantifying the stereotypical motions of important multicellular biological organisms can provide information on how genes and drugs regulate locomotion; and research into bulk grain transport under flow can have considerable implications for the pharmaceutical, agricultural, and energy production industries. My contributions to date in these areas are described below. In the future, I plan to integrate my expertise on biological soft matter, microfluidics, and novel imaging techniques to advance both fundamental science and engineering applications in these areas.

(i) Cancer cell mechanics and metastasis

Alterations in the mechanical properties of cells have been implicated in several pathologies and diseases, such as cancer metastasis, where studies have indicated that cancer cells have distinct mechanical properties compared to healthy cells.  I am currently investigating the potential of cell mechanics as a biophysical marker for cancer diagnosis using a microfluidic device that contains a narrow micrometer-scale pore. Fluid flow is used to drive cells into the pore mimicking the flow-induced passage of circulating tumor cells through the vasculature at a hemodynamic range of shear stresses. By integrating high speed imaging, the device allows for the simultaneous characterization of five different parameters including the blockage pressure, cell velocity, cell size, elongation and the entry time into the pore.

I have tested a variety of in vitro cell lines, including brain and prostate cancer cell lines, and have found that the entry time and blockage pressure are the most sensitive measurements capable of differentiating between cell lines with differing invasiveness¹. By characterizing this device with simple model systems including viscous drops and soft elastic particles, I have found that the blockage pressure and entry times show no apparent dependence on elastic modulus or drop interfacial tension, but depend significantly on drop internal viscosity. Thus, our findings suggest that in the hemodynamic range of shear stresses the metastatic potential of circulating cells can be characterized by an internal viscosity². This result has important implications for not only high throughput mechanical phenotying of tumor cells, but also on how circulating tumor cells are transported in microcapillaries.

I intend to continue investigating cancer cell mechanics using novel microfluidic devices. My future focus will be directed towards determining how the nucleus, nuclear structural proteins, and chemotherapy drugs affect cancer cell invasiveness and deformability. My proposed research will advance scientific understanding of cancer cell migration, metastasis, and drug efficacy, and will lead to new engineering tools for clinical diagnostics of cancer.

(ii) Behavior and locomotion of C. elegans

I am currently involved in a multi-group collaboration investigating the relationships between genetics, environmental cues and locomotion in the soil-dwelling nematode C. elegans. C. elegans is an important model animal in biology and medicine due to its simple nervous system, short life span and availability of tools to manipulate its genome. Not surprisingly, these attributes have made C. elegans the center of three Nobel prize winning investigations.

The main phenotype of this animal is locomotion, that is often used in genetic and drug screens. While the crawling motion of this simple animal has been widely studied, the details of the animal's swimming motion has not been quantitatively explored in the context of increasing the mechanical load or stimulation. Currently I am investigating the effects of varying the mechanical load of the environment on the animal’s locomotion using a principal component analysis of its swimming body shape³. I intend to utilize the techniques that we are developing⁴ to further investigate the effects of chemical and physical stimulation on this model creature. Thus, my efforts will lead to fundamental understanding of how the mechanical environment and physiochemical stimuli affect the locomotion of this important model organism. It may also provide the biomedical community new tools to better quantify the effects of gene expression and chemicals on its locomotion.

(iii) Dynamics of granular flows

Granular systems display a variety of complex behaviors including spontaneous pattern formation and anomalous diffusion. Granular materials are also the second most handled material in industry, the first being water. Indeed, granular materials are notoriously difficult to mix efficiently, and it has been estimated that nearly 10 percent of the world’s energy each year is spent processing granular materials. Much of my previous research focused on a system frequently used to investigate granular flows: the rotating drum apparatus.

An interesting phenomenon is often observed when one attempts to mix grains of different sizes, densities, or surface roughness in a rotating drum; instead of mixing, the grains separate partially or completely. After hundreds of drum rotations an initially mixed binary distribution of different-sized grains sorts itself into almost periodic bands along the axis of the drum. These bands are threaded by a radial core of the smaller grains that develops prior to axial band formation⁵. Using surface imaging techniques I have discovered that the mixing of grains in a rotating drum can be subdiffusive⁶. I have also investigated single-particle dynamics of tracer particles imaged using bulk synchrotron radioscopy imaging, and have found that while the standard measure of diffusive behavior, the slope of the mean-squared displacement, is close to that expected from diffusive transport, more detailed analyses indicate anomalous transport⁷. My future research interests include investigating the connection between the occurrence of pattern formation and the presence of dynamical heterogeneities that appear under flow, and investigating how the presence of an attractive force introduced by wetting the grains⁸ alters the dynamical features, when compared with the dry non-cohesive case. The understanding gained from these studies may provide insight into industrial grain-mixing procedures.

1. Z. S. Khan & S. A. Vanapalli, Biomicrofluidics 7, 011806 (2013).

2. Z. S. Khan, N. Kamyabi & S. A. Vanapalli, manuscript in preparation.

3. Z. S. Khan, F. Van Bussel, M. Rahman, J. Blawzdziewicz & S. A. Vanapalli, manuscript in preparation.

4. V. Padmanabhan, Z. S. Khan, D. E. Solomon, A. Armstrong, K. P. Rumbaugh, S. A. Vanapalli & J. Blawzdziewicz, PLoS ONE 7, e40121 (2012).

5. Z. S. Khan, W. A. Tokaruk and S. W. Morris, Europhysics Letters 66, 212 (2004).

6. Z. S. Khan and S. W. Morris, Physical Review Letters 94, 048002 (2005).

7. Z. S. Khan, F. Van Bussel, M. Schaber, R. Seemann, M. Scheel and M. DiMichiel, New Journal of Physics 13, 105005 (2011).

8. Z. S. Khan, A. Steinberger, R. Seemann, and S. Herminghaus, New Journal of Physics 13, 053041 (2011).