Understanding Gas Transport in Polymer-Grafted Nanoparticle Assemblies.

We rationalize the unusual gas transport behavior of polymer-grafted nanoparticle (GNP) membranes. While gas permeabilities depend specifically on the chemistry of the polymers considered, we focus here on permeabilities relative to the corresponding pure polymer which show interesting, "universal" behavior. For a given NP radius, Rc, and for large enough areal grafting densities, σ, to be in the dense brush regime we find that gas permeability enhancements display a maximum as a function of the graft chain molecular weight, Mn. Based on a recently proposed theory for the structure of a spherical brush in a melt of GNPs, we conjecture that this peak permeability occurs when the densely grafted polymer brush has the highest, packing-induced extension free energy per chain. The corresponding brush thickness is predicted to be h max = 3 R c , independent of chain chemistry and σ, i.e., at an apparently universal value of the NP volume fraction (or loading), ϕNP, ϕNP,max = [Rc/(Rc + hmax)]3 ≈ 0.049. Motivated by this conclusion, we measured CO-2 and CH4 permeability enhancements across a variety of Rc, Mn and σ, and find that they behave in a similar manner when considered as a function of ϕNP, with a peak in the near vicinity of the predicted ϕNP,max. Thus, the chain length dependent extension free energy appears to be the critical variable in determining the gas permeability for these hybrid materials. The emerging picture is that these curved polymer brushes, at high enough σ behave akin to a two-layer transport medium - the region in the near vicinity of the NP surface is comprised of extended polymer chains which speed-up gas transport relative to the unperturbed melt. The chain extension free energy increases with increasing chain length, up to a maximum, and apparently leads to an increasing gas permeability. For long enough grafts, there is an outer region of chain segments that is akin to an unperturbed melt with slow gas transport. The permeability maximum and decreasing permeability with increasing chain length then follow naturally.

Fibrous hydrogels under biaxial confinement.

Confinement of fibrous hydrogels in narrow capillaries is of great importance in biological and biomedical systems. Stretching and uniaxial compression of fibrous hydrogels have been extensively studied; however, their response to biaxial confinement in capillaries remains unexplored. Here, we show experimentally and theoretically that due to the asymmetry in the mechanical properties of the constituent filaments that are soft upon compression and stiff upon extension, filamentous gels respond to confinement in a qualitatively different manner than flexible-strand gels. Under strong confinement, fibrous gels exhibit a weak elongation and an asymptotic decrease to zero of their biaxial Poisson's ratio, which results in strong gel densification and a weak flux of liquid through the gel. These results shed light on the resistance of strained occlusive clots to lysis with therapeutic agents and stimulate the development of effective endovascular plugs from gels with fibrous structures for stopping vascular bleeding or suppressing blood supply to tumors.

Mucus concentration-dependent biophysical abnormalities unify submucosal gland and superficial airway dysfunction in cystic fibrosis.

Cystic fibrosis (CF) is characterized by abnormal transepithelial ion transport. However, a description of CF lung disease pathophysiology unifying superficial epithelial and submucosal gland (SMG) dysfunctions has remained elusive. We hypothesized that biophysical abnormalities associated with CF mucus hyperconcentration provide a unifying mechanism. Studies of the anion secretion-inhibited pig airway model of CF revealed elevated SMG mucus concentrations, osmotic pressures, and SMG mucus accumulation. Human airway studies revealed hyperconcentrated CF SMG mucus with raised osmotic pressures and cohesive forces predicted to limit SMG mucus secretion/release. Using proline-rich protein 4 (PRR4) as a biomarker of SMG secretion, CF sputum proteomics analyses revealed markedly lower PRR4 levels compared to healthy and bronchiectasis controls, consistent with a failure of CF SMGs to secrete mucus onto airway surfaces. Raised mucus osmotic/cohesive forces, reflecting mucus hyperconcentration, provide a unifying mechanism that describes disease-initiating mucus accumulation on airway surfaces and in SMGs of the CF lung.

Physiology and pathophysiology of human airway mucus.

The mucus clearance system is the dominant mechanical host defense system of the human lung. Mucus is cleared from the lung by cilia and airflow, including both two-phase gas-liquid pumping and cough-dependent mechanisms, and mucus transport rates are heavily dependent on mucus concentration. Importantly, mucus transport rates are accurately predicted by the gel-on-brush model of the mucociliary apparatus from the relative osmotic moduli of the mucus and periciliary-glycocalyceal (PCL-G) layers. The fluid available to hydrate mucus is generated by transepithelial fluid transport. Feedback interactions between mucus concentrations and cilia beating, via purinergic signaling, coordinate Na+ absorptive vs Cl- secretory rates to maintain mucus hydration in health. In disease, mucus becomes hyperconcentrated (dehydrated). Multiple mechanisms derange the ion transport pathways that normally hydrate mucus in muco-obstructive lung diseases, e.g., cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), non-CF bronchiectasis (NCFB), and primary ciliary dyskinesia (PCD). A key step in muco-obstructive disease pathogenesis is the osmotic compression of the mucus layer onto the airway surface with the formation of adherent mucus plaques and plugs, particularly in distal airways. Mucus plaques create locally hypoxic conditions and produce airflow obstruction, inflammation, infection, and, ultimately, airway wall damage. Therapies to clear adherent mucus with hydrating and mucolytic agents are rational, and strategies to develop these agents are reviewed.

Gas Transport in Interacting Planar Brushes.

Recent experiments on melts of spherical nanoparticles (NPs) densely grafted with polymer chains show enhanced gas transport relative to the neat polymer (without NPs). As a means of understanding this unexpected behavior, we consider here the simpler case of two interacting planar brushes, under conditions representing a polymer melt far below its critical point (i.e., where the "free volume" or holes act akin to a poor solvent). Computer simulations illustrate, in agreement with mean-field ideas, that the density profile far away from the walls is flat but with a value that is marginally larger than the corresponding polymer melt under identical state conditions. We find that tracer particles, which represent the gas of interest, segregate preferentially to the grafting surface, with this result being relatively insensitive to the nature of polymer-surface interactions. These brush layers therefore correspond to heterogeneous transport media: the gas molecules near the grafting surface have accelerated dynamics (presumably parallel to the wall) relative to the corresponding polymer melt, but they have slower dynamics in the central region of the brush. We therefore find that gas molecules perform hop-like motions - they spend a significant part of their time in the regions of fast transport, separated by motions where they "hop" from one surface to the other. These phenomena in combination lead to an overall speedup in gas dynamics in these brush layers relative to a polymer melt, in good agreement with the experimental data.

Tuning Selectivities in Gas Separation Membranes Based on Polymer-Grafted Nanoparticles.

Polymer membranes are critical to many sustainability applications that require the size-based separation of gas mixtures. Despite their ubiquity, there is a continuing need to selectively affect the transport of different mixture components while enhancing mechanical strength and hindering aging. Polymer-grafted nanoparticles (GNPs) have recently been explored in the context of gas separations. Membranes made from pure GNPs have higher gas permeability and lower selectivity relative to the neat polymer because they have increased mean free volume. Going beyond this ability to manipulate the mean free volume by grafting chains to a nanoparticle, the conceptual advance of the present work is our finding that GNPs are spatially heterogeneous transport media, with this free volume distribution being easily manipulated by the addition of free polymer. In particular, adding a small amount of appropriately chosen free polymer can increase the membrane gas selectivity by up to two orders of magnitude while only moderately reducing small gas permeability. Added short free chains, which are homogeneously distributed in the polymer layer of the GNP, reduce the permeability of all gases but yield no dramatic increases in selectivity. In contrast, free chains with length comparable to the grafts, which populate the interstitial pockets between GNPs, preferentially hinder the transport of the larger gas and thus result in large selectivity increases. This work thus establishes that we can favorably manipulate the selective gas transport properties of GNP membranes through the entropic effects associated with the addition of free chains.

Understanding Factors Governing Distribution Volume of Ethyl Cellulose-Ethanol to Optimize Ablative Therapy in the Liver.

OBJECTIVE: Ethanol ablation, the injection of ethanol to induce necrosis, was originally used to treat hepatocellular carcinoma, with survival rates comparable to surgery. However, efficacy is limited due to leakage into surrounding tissue. To reduce leakage, we previously reported incorporating ethyl cellulose (EC) with ethanol as this mixture forms a gel when injected into tissue. To further develop EC-ethanol injection as an ablative therapy, the present study evaluates the extent to which salient injection parameters govern the injected fluid distribution. METHODS: Utilizing ex vivo swine liver, injection parameters (infusion rate, EC%, infusion volume) were examined with fluorescein added to each solution. After injection, tissue samples were frozen, sectioned, and imaged. RESULTS: While leakage was higher for ethanol and 3%EC-ethanol at a rate of 10 mL/hr compared to 1 mL/hr, leakage remained low for 6%EC-ethanol regardless of infusion rate. The impact of infusion volume and pressure were also investigated first in tissue-mimicking surrogates and then in tissue. Results indicated that there is a critical infusion pressure beyond which crack formation occurs leading to fluid leakage. At a rate of 10 mL/hr, a volume of 50 µL remained below the critical pressure. CONCLUSIONS: Although increasing the infusion rate increases stress on the tissue and the risk of crack formation, injections of 6%EC-ethanol were localized regardless of infusion rate. To further limit leakage, multiple low-volume infusions may be employed. SIGNIFICANCE: These results, and the experimental framework developed to obtain them, can inform optimizing EC-ethanol to treat a range of medical conditions.

Roles of mucus adhesion and cohesion in cough clearance.

Clearance of intrapulmonary mucus by the high-velocity airflow generated by cough is the major rescue clearance mechanism in subjects with mucoobstructive diseases and failed cilial-dependent mucus clearance, e.g., subjects with cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD). Previous studies have investigated the mechanical forces generated at airway surfaces by cough but have not considered the effects of mucus biophysical properties on cough efficacy. Theoretically, mucus can be cleared by cough from the lung by an adhesive failure, i.e., breaking mucus-cell surface adhesive bonds and/or by cohesive failure, i.e., directly fracturing mucus. Utilizing peel-testing technologies, mucus-epithelial surface adhesive and mucus cohesive strengths were measured. Because both mucus concentration and pH have been reported to alter mucus biophysical properties in disease, the effects of mucus concentration and pH on adhesion and cohesion were compared. Both adhesive and cohesive strengths depended on mucus concentration, but neither on physiologically relevant changes in pH nor bicarbonate concentration. Mucus from bronchial epithelial cultures and patient sputum samples exhibited similar adhesive and cohesive properties. Notably, the magnitudes of both adhesive and cohesive strength exhibited similar velocity and concentration dependencies, suggesting that viscous dissipation of energy within mucus during cough determines the efficiency of cough clearance of diseased, hyperconcentrated, mucus. Calculations of airflow-induced shear forces on airway mucus related to mucus concentration predicted substantially reduced cough clearance in small versus large airways. Studies designed to improve cough clearance in subjects with mucoobstructive diseases identified reductions of mucus concentration and viscous dissipation as key therapeutic strategies.

Strong, Tough, Stretchable, and Self-Adhesive Hydrogels from Intrinsically Unstructured Proteins.

Strong, tough, stretchable, and self-adhesive hydrogels are designed with intrinsically unstructured proteins. The extraordinary mechanical properties exhibited by these materials are enabled by an integration of toughening mechanisms that maintain high elasticity and dissipate mechanical energy within the protein networks.

Universal behavior of hydrogels confined to narrow capillaries.

Flow of soft matter objects through one-dimensional environments is important in industrial, biological and biomedical systems. Establishing the underlying principles of the behavior of soft matter in confinement can shed light on its performance in many man-made and biological systems. Here, we report an experimental and theoretical study of translocation of micrometer-size hydrogels (microgels) through microfluidic channels with a diameter smaller than an unperturbed microgel size. For microgels with different dimensions and mechanical properties, under a range of applied pressures, we established the universal principles of microgel entrance and passage through microchannels with different geometries, as well as the reduction in microgel volume in confinement. We also show a non-monotonic change in the flow rate of liquid through the constrained microgel, governed by its progressive confinement. The experimental results were in agreement with the theory developed for non-linear biaxial deformation of unentangled polymer gels. Our work has implications for a broad range of phenomena, including occlusion of blood vessels by thrombi and needle-assisted hydrogel injection in tissue engineering.

The Relationship of Mucus Concentration (Hydration) to Mucus Osmotic Pressure and Transport in Chronic Bronchitis.

RATIONALE: Chronic bronchitis (CB) is characterized by persistent cough and sputum production. Studies were performed to test whether mucus hyperconcentration and increased partial osmotic pressure, in part caused by abnormal purine nucleotide regulation of ion transport, contribute to the pathogenesis of CB. OBJECTIVES: We tested the hypothesis that CB is characterized by mucus hyperconcentration, increased mucus partial osmotic pressures, and reduced mucus clearance. METHODS: We measured in subjects with CB as compared with normal and asymptomatic smoking control subjects indices of mucus concentration (hydration; i.e., percentage solids) and sputum adenine nucleotide/nucleoside concentrations. In addition, sputum partial osmotic pressures and mucus transport rates were measured in subjects with CB. MEASUREMENTS AND RESULTS: CB secretions were hyperconcentrated as indexed by an increase in percentage solids and total mucins, in part reflecting decreased extracellular nucleotide/nucleoside concentrations. CB mucus generated concentration-dependent increases in partial osmotic pressures into ranges predicted to reduce mucus transport. Mucociliary clearance (MCC) in subjects with CB was negatively correlated with mucus concentration (percentage solids). As a test of relationships between mucus concentration and disease, mucus concentrations and MCC were compared with FEV1, and both were significantly correlated. CONCLUSIONS: Abnormal regulation of airway surface hydration may slow MCC in CB and contribute to disease pathogenesis.

Elastin-like Polypeptide Diblock Copolymers Self-Assemble into Weak Micelles.

The self-assembly of synthetic diblock copolymers has been extensively studied experimentally and theoretically. In contrast, self-assembly of polypeptide diblock copolymers has so far been mostly studied experimentally. We discovered that the theory developed for synthetic diblock copolymer does not fully explain the self-assembly of elastin-like polypeptide diblock copolymers, leading us to generalize the theory to make it applicable for these polypeptides. We demonstrated that elastin-like polypeptide diblocks self-assemble into weak micelles with dense cores and almost unstretched coronas, a state not previously observed for synthetic diblock copolymers. Weak micelles form if the surface tension at the core-corona interface is low compared to that expected of a micelle with a dense core. The predictions of the theory of weak micelles for the critical micelle temperature, hydrodynamic radius, and aggregation number of elastin-like polypeptide diblocks are in reasonable agreement with the experimentally measured values. The unique and unprecedented control of amphiphilicity in these recombinant peptide polymers reveals a new micellar state that has not been previously observed in synthetic diblock copolymer systems.

Microfluidic fabrication of stable gas-filled microcapsules for acoustic contrast enhancement.

We introduce a facile approach for the production of gas-filled microcapsules designed to withstand high pressures. We exploit microfluidics to fabricate water-filled microcapsules that are then externally triggered to become gas-filled, thus making them more echogenic. In addition, the gas-filled microcapsules have a solid polymer shell making them resistant to pressure-induced buckling, which makes them more mechanically robust than traditional prestabilized microbubbles; this should increase the potential of their utility for acoustic imaging of porous media with high hydrostatic pressures such as oil reservoirs.

A physical linkage between cystic fibrosis airway surface dehydration and Pseudomonas aeruginosa biofilms.

A vexing problem in cystic fibrosis (CF) pathogenesis has been to explain the high prevalence of Pseudomonas aeruginosa biofilms in CF airways. We speculated that airway surface liquid (ASL) hyperabsorption generates a concentrated airway mucus that interacts with P. aeruginosa to promote biofilms. To model CF vs. normal airway infections, normal (2.5% solids) and CF-like concentrated (8% solids) mucus were prepared, placed in flat chambers, and infected with an approximately 5 x 10(3) strain PAO1 P. aeruginosa. Although bacteria grew to 10(10) cfu/ml in both mucus concentrations, macrocolony formation was detected only in the CF-like (8% solids) mucus. Biophysical and functional measurements revealed that concentrated mucus exhibited properties that restrict bacterial motility and small molecule diffusion, resulting in high local bacterial densities with high autoinducer concentrations. These properties also rendered secondary forms of antimicrobial defense, e.g., lactoferrin, ineffective in preventing biofilm formation in a CF-like mucus environment. These data link airway surface liquid hyperabsorption to the high incidence of P. aeruginosa biofilms in CF via changes in the hydration-dependent physical-chemical properties of mucus and suggest that the thickened mucus gel model will be useful to develop therapies of P. aeruginosa biofilms in CF airways.

Adherence to imaging protocol and impact of training on the interpretation of CEA-Scan® (arcitumomab) imaging for colorectal cancer

Purpose: To determine if imaging with arcitumomab (immunoscintigraphy) is sensitive to technical and interpretative techniques that must be mastered in order to obtain reliable results. We studied the impact of training to reduce the learning curve. Methods: 1) Evaluate the performance of an experienced Nuclear Medicine Physicians (Team A) un-blinded with their initial series of patients, compared to the conclusions of Experts (Team B) blinded from any clinical information; 2) Training of Team A is by the expert team on image acquisition, processing and interpretation techniques as well as using all clinical information and anatomic studies for comparison; 3) Assess the performance of the Team A on a second series of patients. 4) Questionnaires were sent to 65 consecutive physicians trained by experts to determine if the learned techniques improved interpretation of immunoscintigrams. Results: Twenty three (23) patients with CRC were included, 13 pre and 10 for the post teaching phase with a total of 30 clinically confirmed lesions (pathologically proven or demonstrated on follow-up). The clinically confirmed lesions include: 8 primary, 12 pelvic recurrences and 10 metastatic sites. On the pre-teaching series, Team A correctly identified only 6/19 lesions (32 percent). On the post teaching series, Team A found 8/11 lesions (73 percent) including 4/5 pelvic recurrence (80 percent), all 3 primary lesions, and 1/3 metastasis which compares favorably to published results. To determine the effect of blinded reading of immunoscintigrams, Team B reviews the first 13 studies without any clinical information or CT for comparison. Team B found 10/19 lesions (53 percent) with 4 false positive. Questionnaires were mailed to 65 trained physicians (54 returned), 67 percent of responders found that training improved their results, 22 percent experienced mixed results and 11 percent did not notice any improvement. Conclusion: The lower than expected sensitivity by the blinde...