Yeng-Long Chen

Clusters of circulating tumor cells traverse capillary-sized vessels.

Significance Metastasis is responsible for 90% of cancer-related deaths and is driven by tumor cells circulating in blood. However, it is believed that only individual tumor cells can reach distant organs because multicellular clusters are too large to pass through narrow capillaries. Here, we collected evidence by examining clusters in microscale devices, computational simulations, and animals, which suggest that this assumption is incorrect, and that clusters may transit through capillaries by unfolding into single-file chains. This previously unidentified cell behavior may explain why previous experiments reported that clusters were more efficient at seeding metastases than equal numbers of single tumor cells, and has led to a strategy that, if applied clinically, may reduce the incidence of metastasis in patients. Multicellular aggregates of circulating tumor cells (CTC clusters) are potent initiators of distant organ metastasis. However, it is currently assumed that CTC clusters are too large to pass through narrow vessels to reach these organs. Here, we present evidence that challenges this assumption through the use of microfluidic devices designed to mimic human capillary constrictions and CTC clusters obtained from patient and cancer cell origins. Over 90% of clusters containing up to 20 cells successfully traversed 5- to 10-μm constrictions even in whole blood. Clusters rapidly and reversibly reorganized into single-file chain-like geometries that substantially reduced their hydrodynamic resistances. Xenotransplantation of human CTC clusters into zebrafish showed similar reorganization and transit through capillary-sized vessels in vivo. Preliminary experiments demonstrated that clusters could be disrupted during transit using drugs that affected cellular interaction energies. These findings suggest that CTC clusters may contribute a greater role to tumor dissemination than previously believed and may point to strategies for combating CTC cluster-initiated metastasis.

Viscoelasticity and rheology of depletion flocculated gels and fluids

The flow properties of high volume fraction hard sphere colloid–polymer suspensions are studied as a function of polymer concentration, depletion attraction range, and solvent quality up to, and well beyond, the gelation boundary. As the gel boundary is approached, the shear viscosity tends to diverge in a critical power law manner at a polymer concentration that is a function of the polymer radius of gyration and solvency condition. The shear viscosity for different polymer size suspensions can be collapsed onto a master curve motivated by mode coupling theory (MCT). The low frequency elastic modulus grows rapidly with increasing depletion attraction near the gel boundary, but becomes a dramatically weaker function of polymer concentration as the gel state is more deeply entered. A simplified version of MCT with accurate, no adjustable parameter polymer reference interaction site model (PRISM) theory structural input has been applied to predict the gelation boundaries and elastic shear moduli. The calcul...

Phase behavior and concentration fluctuations in suspensions of hard spheres and nearly ideal polymers

The phase behavior and concentration fluctuations in suspensions of hard sphere colloids and nonadsorbing polymers under nearly ideal solvent conditions is studied experimentally. A remarkably different qualitative behavior compared to the athermal solvent case is observed for the dependence on polymer/particle size asymmetry of both the gelation and fluid–fluid phase separation boundaries. Near the theta state the effect of increasing the range of depletion attractions leads to a weak monotonic destabilization of the homogeneous phase at high particle volume fractions, with a reversal of the trend at lower volume fractions. In stark contrast to athermal solvent behavior, this nonmonotonic behavior results in multiple “curve crossings” of gel and phase separation boundaries as the polymer/particle size ratio is varied. Quantitative comparisons with no adjustable parameter PRISM integral equation theory for the fluid–fluid spinodals and osmotic compressibilities show good qualitative or semiquantitative ag...

Entropy-Driven Single Molecule Tug-of-War of DNA at Micro−Nanofluidic Interfaces

Entropy-driven polymer dynamics at the nanoscale is fundamentally important in biological systems but the dependence of the entropic force on the nanoconfinement remains elusive. Here, we established an entropy-driven single molecule tug-of-war (TOW) at two micro-nanofluidic interfaces bridged by a nanoslit, performed the force analysis from a modified wormlike chain in the TOW scenario and the entropic recoiling process, and determined the associated scalings on the nanoconfinement. Our results provide a direct experimental evidence that the entropic forces in these two regimes, though unequal, are essentially constant at defined slit heights, irrespective of the slit lengths and the DNA segments within. Our findings have the implications to polymer transport at the nanoscale, device design for single molecule analysis, and biotechnological applications.

Potential of mean force between two nanometer-scale particles in a polymer solution

Expanded ensemble density-of-states simulations and a connectivity altering algorithm are used to investigate the effective interactions that arise between nanoparticles suspended in polymer solutions. Our calculations with systems of long polymeric chains reveal oscillations in the effective polymer-induced interactions between the particles, even at low concentrations. The range of these interactions is considerably longer than originally anticipated, and their origin is traced back to the chain-end effects and density fluctuations that were absent in previous treatments of these systems.

Microstructure of dense colloid–polymer suspensions and gels

A systematic experimental study of polymer-induced changes of the collective structure of model hard-sphere nanocolloids in the fluid and gel states has been carried out using ultra-small-angle x-ray scattering. The focus is on small, non-adsorbing polymer depletants where a direct transition from the homogeneous fluid phase to a nonequilibrium gel state occurs with increasing polymer additions. As the polymer concentration is increased in the homogeneous fluid phase, the low angle concentration fluctuations monotonically increase, the characteristic interparticle separation decreases and tends to saturate, and the intensity of the cage order peak varies in a non-monotonic manner. These equilibrium structural changes depend in a systematic fashion on colloid volume fraction and polymer–colloid size asymmetry, and are in near quantitative agreement with the parameter-free polymer reference interaction site model theory calculations. By combining the accurate equilibrium theory with experimental observations, the loss of ergodicity and nonequilibrium structure formation in the gel state can be deduced. Abrupt departures between theory and experiment on the ~2–3 particle diameter and greater length scales are observed as the gel boundary is traversed. The liquid-like local cage structure is arrested. Intermediate scale fluctuations are suppressed suggesting the formation of small, compact clusters. Large amplitude, Porod-like fluctuations emerge on large length scales due to quenched heterogeneities which are analysed using a random two-phase composite model. By combining the results of all the scattering experiments and theoretical calculations a qualitative real space picture of the gel microstructure is constructed, and its mechanical consequences are qualitatively discussed.

Electro-entropic excluded volume effects on DNA looping and relaxation in nanochannels

We investigate the fluctuation-relaxation dynamics of entropically restricted DNA molecules in square nanochannels ranging from 0.09 to 19.9 times the persistence length. In nanochannels smaller than the persistence length, the chain relaxation time is found to have cubic dependence on the channel size. It is found that the effective polymer width significantly alter the chain conformation and relaxation time in strong confinement. For thinner chains, looped chain configurations are found in channels with height comparable to the persistence length, with very slow relaxation compared to un-looped chains. Larger effective chain widths inhibit the formation of hairpin loops.

Mass detection by means of the vibrating nanomechanical resonators

We present a theoretical analysis of the vibrating resonator in cantilever and bridge configurations operating as ultrasensitive mass sensors. An exact solution of the problem has been obtained. For the small mass ratio, the asymptotic solutions (which relate the frequency shift, mass ratio, and position of the attached particle) have been derived. It has been shown that the mass and position of the attached particle for the cantilever configuration can be unambiguously resolved by the use of three consecutive resonant frequencies. For the bridge configuration, the particle mass can be deduced by using only two measured resonant frequencies.

Phase separation in suspensions of colloids, polymers and nanoparticles : role of solvent quality, physical mesh, and nonlocal entropic repulsion

Analytic and numerical microscopic integral equation theory for polymer–particle suspensions is employed to investigate the dependence of fluid–fluid phase separation on size asymmetry, solvent quality, and higher order polymer–polymer interactions. For athermal good solvents, our prior novel prediction of enhanced miscibility with increasing (decreasing) polymer (particle) size is found not to be fundamentally tied to physical mesh formation or strong polymer-induced colloid clustering. Rather, the key is a proper treatment of the polymer second virial coefficient, which is sensitive to how chains organize in the empty space between particles. The origin of the qualitative error made by classic mean-field theories for the shifting of phase boundaries with size asymmetry is established. The phase separation behavior predicted by integral equation theory for ideal polymers is completely different than the athermal case for all size asymmetries and particle volume fractions, thereby establishing the remarka...

Depletion interactions in suspensions of spheres and rod-polymers

Liquid-state integral equation methods are employed to study the thermodynamic and structural properties of ideal and repelling rigid rods mixed with hard spheres in the limits when one of the species is dilute. The role of rod aspect ratio and sphere/rod size asymmetry is explored over a wide range of system parameters encompassing the colloid, nanoparticle, and crossover regimes. Novel predictions are found for the polymer (sphere) mediated depletion potentials and second virial coefficients of particles (rods) in dense polymer (sphere) suspensions. The adequacy of the closure approximations employed is tested by comparison with available numerical calculations and more rigorous theories in special limits. The liquid-state theory appears to be accurate for all properties in the nanoparticle regime and for the insertion chemical potential of needles and spherocylinders. However, it significantly underestimates depletion attractions effects in the colloidal regime of short rods and large spheres due to no...