Grand Challenges at the Interface of Engineering and Medicine.

Over the past two decades Biomedical Engineering has emerged as a major discipline that bridges societal needs of human health care with the development of novel technologies. Every medical institution is now equipped at varying degrees of sophistication with the ability to monitor human health in both non-invasive and invasive modes. The multiple scales at which human physiology can be interrogated provide a profound perspective on health and disease.

Self-assembly pathways and polymorphism in peptide-based nanostructures.

Dipeptide derivative molecules can self-assemble into space-filling nanofiber networks at low volume fractions (<1%), allowing the formation of molecular gels with tunable mechanical properties. The self-assembly of dipeptide-based molecules is reminiscent of pathological amyloid fibril formation by naturally occurring polypeptides. Fluorenylmethoxycarbonyl-diphenylalanine (Fmoc-FF) is the most widely studied such molecule, but the thermodynamic and kinetic phenomena giving rise to Fmoc-FF gel formation remain poorly understood.

Intrinsic nonlinearities in the mechanics of hard sphere suspensions.

The onset of nonlinear responses in near hard sphere suspensions is characterized as a function of oscillatory frequency and strain amplitude. At low frequencies where the viscous behavior dominates, the onset of nonlinearities is driven by increases in rate of strain. At high deformation frequency, where suspension mechanics is dominated by an elastic response, the nonlinear responses occur when deformation exceeds a characteristic strain.

Gelation of Fmoc-diphenylalanine is a first order phase transition.

We explore the gel transition of the aromatic dipeptide derivative molecule fluorenylmethoxycarbonyl-diphenylalanine (Fmoc-FF). The addition of water to a solution of Fmoc-FF in dimethyl sulfoxide (DMSO) results in increased attractions leading to self-assembly of Fmoc-FF molecules into a space-filling fibrous network. We provide evidence that gel formation is associated with a first order phase transition resulting in nucleation and growth of strongly anisotropic crystals with high aspect ratios.

Impact of small changes in particle surface chemistry for unentangled polymer nanocomposites.

We report microstructural and rheological consequences of altering silica particle surface chemistry when the particles are suspended in unentangled polyethylene glycol with a molecular weight of 400. The particle surfaces are altered by reacting them with isobutyltrimethyoxysilane. Levels of silanization are chosen so that the particles remain dispersed in the polymer at all volume fractions studied.

Nanoscale dynamics and aging of fibrous peptide-based gels.

Solutions of the aromatic dipeptide derivative molecule fluorenylmethoxycarbonyl-diphenylalanine (Fmoc-FF) in dimethyl sulfoxide produce fibrous gels when mixed with water. We study the evolution of density fluctuations of this three-component system using X-ray photon correlation spectroscopy (XPCS) and compare these results to the macroscopic rheology of the gels and optical observations of the microstructure evolution. At the investigated scattering angles, the intensity autocorrelation functions do not follow behavior expected for simple diffusion of individual Fmoc-FF molecules localized within cages of nearest neighbors.

Evidence for equilibrium gels of valence-limited particles.

We explore the formation and structure of gels produced from solutions of the aromatic dipeptide derivative molecule fluorenylmethoxycarbonyl-diphenylalanine (Fmoc-FF) in dimethyl sulfoxide (DMSO). Mixing these solutions with water results in the self-assembly of Fmoc-FF molecules into space-filling fibrous networks, exhibiting mechanical properties characteristic of gels. Using confocal fluorescence microscopy, we observe the gel transition in situ and find that, upon the addition of water, the solution undergoes a rapid transition to a non-equilibrium state forming ∼ 2 μm spheres, followed by the formation of fibers 5-10 nm in diameter, nucleating at a sphere surface and expanding into the solution as the remaining spheres dissolve, extending the network.

Binary diamondoid building blocks for molecular gels.

Adamantane is a type of diamondoid molecules that has a cage or globular shape with a diameter of 6.34 ± 0.04 Å.

Mechanical properties of self-assembled Fmoc-diphenylalanine molecular gels.

We explore the phase diagram and mechanical properties of molecular gels produced from mixing water with a dimethyl sulfoxide (DMSO) solution of the aromatic dipeptide derivative fluorenylmethoxycarbonyl-diphenylalanine (Fmoc-FF). Highly soluble in DMSO, Fmoc-FF assembles into fibrous networks that form gels upon addition of water. At high water concentrations, rigid gels can be formed at Fmoc-FF concentrations as low as 0.

Rheology of dense suspensions of shape anisotropic particles designed to show pH-sensitive anisotropic pair potentials.

Here we investigate the flow properties of suspensions of dicolloidal particles composed of interpenetrating spheres where one sphere is rich in polystyrene and the second is rich in poly 2-vinyl pyridine. The synthesis method is designed to create both anisotropic shape and anisotropic interaction potentials that should lead to head to tail clustering. These particles are referred to as copolymer dicolloids (CDCs).

Synthesis of pH-responsive particles with shape anisotropy.

Seeded emulsion polymerization is used to produce large quantities of shape anisotropic, amphoteric particles in a size range of about 1 μm. Copolymer dicolloids (CDCs) containing pyridine groups are synthesized by swelling spherical, lightly cross-linked polystyrene seeds with a mixture of styrene and pH-responsive monomer 2-vinyl pyridine followed by secondary polymerization to contrast with their analogue homopolymer dicolloids (HDCs) where the swelling step is carried out with styrene alone. After the particles are coated with a nonionic surfactant to minimize van der Waals attractions, surface potentials and aggregation properties of dilute suspensions are studied as functions of pH and ionic strength.

Effect of the range of repulsions on the existence of a stable liquid phase.

Experimental and theoretical results have established that the range of the attraction plays a critical role in determining whether a particle system exhibits a stable liquid phase. Changes to the range of the repulsions can similarly affect the existence of a stable liquid phase; however, these effects have not been clearly elucidated. We demonstrate that an increase in the range of repulsions can either enhance or decrease the stability of the liquid phase, depending on the form of the interaction potential.

Multiscale structure, interfacial cohesion, adsorbed layers, and thermodynamics in dense polymer-nanoparticle mixtures.

We establish the existence and size of adsorbed polymer layers in miscible dense nanocomposites and their consequences on microstructure and the bulk modulus. Using contrast-matching small-angle neutron scattering to characterize all partial collective structure factors of polymers, particles, and their interface, we demonstrate qualitative failure of the random phase approximation, accuracy of the polymer reference site interaction model theory, ability to deduce the adsorbed polymer layer thickness, and high sensitivity of the nanocomposite bulk modulus to interfacial cohesion.

A microfluidic platform for pharmaceutical salt screening.

We describe a microfluidic platform comprised of 48 wells to screen for pharmaceutical salts. Solutions of pharmaceutical parent compounds (PCs) and salt formers (SFs) are mixed on-chip in a combinatorial fashion in arrays of 87.5-nanolitre wells, which constitutes a drastic reduction of the volume of PC solution needed per condition screened compared to typical high throughput pharmaceutical screening approaches.

Role of polymer segment-particle surface interactions in controlling nanoparticle dispersions in concentrated polymer solutions.

The microstructure of particles suspended in concentrated polymer solutions is examined with small-angle X-ray scattering and small-angle neutron scattering. Of interest are changes to long wavelength particle density fluctuations in ternary mixtures of silica nanoparticles suspended in concentrated solutions of poly(ethylene glycol). The results are understood in terms of application of the pseudo-two-component polymer reference interaction site model (PRISM) theory modified to account for solvent addition via effective contact strength of interfacial attraction, ε(pc), in an implicit manner.

Effect of particle size on the glass transition.

The glass transition temperature of a broad class of molecules is shown to depend on molecular size. This dependency results from the size dependence of the pair potential. A generalized equation of state is used to estimate how the volume fraction at the glass transition depends on the size of the molecule, for rigid molecule glass-formers.

Particle restabilization in silica/PEG/ethanol suspensions: how strongly do polymers need to adsorb to stabilize against aggregation?

We study the effects of increasing the concentration of a low molecular weight polyethylene glycol on the stability of 44 nm diameter silica nanoparticles suspended in ethanol. Polymer concentration, c(p), is increased from zero to that characterizing the polymer melt. Particle stability is accessed through measurement of the particle second-virial coefficient, B(2), performed by light scattering and ultrasmall angle X-ray scattering (USAXS).

Molecular mixture as an effective single-component system.

Colloidal systems exhibit a dramatic slowdown in particle dynamics at high concentrations. The study of the concentration-induced glass transition in these systems has been greatly simplified by treating the colloidal phase as an effective single component in a viscous continuum. We seek to apply an effective single-component approach to molecular systems by investigating a material that also exhibits a dramatic slowdown as the relative concentration of two components change.

Yielding in dense suspensions: cage, bond, and rotational confinements.

The effect of weak particle anisotropy on the onset of fluidity in dense suspensions of glasses of repulsive, weakly attractive and strongly attractive spherical and dumbbell shaped particles is explored. Yield stresses are found to scale with volume fraction showing a divergence at random close packing for all systems. However the onsets of yielding in suspensions of spherical and dumbbell shaped particles are shown to display qualitatively different behaviors.

Re-entrant kinetic arrest and elasticity of concentrated suspensions of spherical and nonspherical repulsive and attractive colloids.

We have designed and studied a new experimental colloidal system to probe how the weak shape anisotropy of uniaxial particles and variable repulsive (Coulombic) and attractive (van der Waals) forces influence slow dynamics, shear elasticity, and kinetic vitrification in dense suspensions. The introduction of shape anisotropy dramatically delays kinetic vitrification and reduces the shear elastic modulus of colloidal diatomics relative to their chemically identical spherical analogs. Tuning the interparticle interaction from repulsive, to nearly hard, to attractive by increasing suspension ionic strength reveals a nonmonotonic re-entrant dynamical phase behavior (glass-fluid-gel) and a rich variation of the shear modulus.

A Stochastic Model for Nucleation Kinetics Determination in Droplet-Based Microfluidic Systems.

The measured induction times in droplet-based microfluidic systems are stochastic and are not described by the deterministic population balances or moment equations commonly used to model the crystallization of amino acids, proteins, and active pharmaceutical ingredients. A stochastic model in the form of a Master equation is formulated for crystal nucleation in droplet-based microfluidic systems for any form of nucleation rate expression under conditions of time-varying supersaturation. An analytical solution is provided to describe the (1) time evolution of the probability of crystal nucleation, (2) the average number of crystals that will form at time t for a large number of droplets, (3) the induction time distribution, and (4) the mean, most likely, and median induction times.

Glass formation and shear elasticity in dense suspensions of repulsive anisotropic particles.

Kinetic vitrification, shear elasticity, and the approach to jamming are investigated for repulsive nonspherical colloids and contrasted with their spherical analog. Particle anisotropy dramatically increases the volume fraction for kinetic arrest. The shear modulus of all systems increases roughly exponentially with volume fraction, and a universal collapse is achieved based on either the dynamic crossover or random close packing volume fraction as the key nondimensionalizing quantity.

Emulsion polymerization routes to chemically anisotropic particles.

Methods are presented to synthesize suspensions of chemically and shape anisotropic colloids on submicrometer length scales. Particles are synthesized through seeded emulsion polymerization where a weakly cross-linked seed is swollen with monomer that phase separates at the reaction temperature resulting in a protrusion. The final particles can be considered to be composed of interpenetrating spheres.

Elasticity of dilatant particle suspensions during flow.

Dense suspensions under sufficiently high shear stress can exhibit a dramatic transition to a solidlike state. This is known as extreme shear thickening and is sometimes accompanied by dilatancy. This behavior is contradictory; the material is solidlike but only when flowing.

Determination of the phase diagram for soluble and membrane proteins.

Methods to efficiently determine the phase behavior of novel proteins have the potential to significantly benefit structural biology efforts. Here, we present protocols to determine both the solubility boundary and the supersolubility boundary for protein/precipitant systems using an evaporation-based crystallization platform. This strategy takes advantage of the well-defined rates of evaporation that occur in this platform to determine the state of the droplet at any point in time without relying on an equilibrium-based end point.