Thickened Liquids Using Pureed Foods for Children with Dysphagia: IDDSI and Rheology Measurements.

Children with dysphagia, or swallowing disorder, are at an increased risk for developing respiratory compromise, failure to thrive, and aversion. Thickened liquids can be recommended for children with dysphagia, if shown to be effective on instrumental examination and if strategies/interventions with thin liquids are not successful. Thickened liquids have many benefits, including creating a more cohesive bolus, slowing oropharyngeal transit time, and reducing aspiration. However, preparing thickened liquids with commercially available thickeners can result in poor compliance due to concerns regarding taste, texture, accessibility, cost, thickness variability, and potential negative impact of these substances on a child's immature digestive tract. The purpose of this study was to determine if liquids could be successfully thickened with widely available, commercial pureed foods, and to assess how these mixtures compare to starch and gum based thickening agents. The International Dysphagia Diet Standardisation Initiative (IDDSI) flow test was performed for each sample of puree thickened liquids, gum based thickened water, and cornstarch based thickened water. In addition, rheology testing was performed on each category of the samples to measure viscosity at various shear rates and temperatures, and to assess the presence of yield stress. Results revealed that liquids thickened with smooth textured purees were comparable to commercial starch and gum based thickeners, and may be offered as a viable alternative.

Synergistic Reinforcement of Composite Hydrogels with Nanofiber Mixtures of Cellulose Nanocrystals and Chitin Nanofibers.

Simultaneous incorporation of cellulose nanocrystals (CNCs) and chitin nanofibers (ChNFs) into a polyvinyl alcohol (PVA) matrix opens possibilities for customization of more environmentally friendly composite materials. When used in tricomponent composite hydrogels, the opposite surface charges on CNCs and ChNFs lead to the construction of beneficial nanofiber structures. In this work, composite hydrogels containing CNCs, ChNFs, or their mixtures are produced using cyclic freeze-thaw (FT) treatments. When considering different compositions and FT cycling, tricomponent composite hydrogels containing a specific ratio of CNCs/ChNFs are shown to have promising mechanical performance in comparison to other samples. These results together with results from water absorption, rheological, and light scattering studies suggest that the CNC/ChNF structures produced property improvement by concurrently accessing the stronger interfacial interactions between CNCs and PVA and the longer lengths of the ChNFs for load transfer. Overall, these results provide insight into using electrostatically driven nanofiber structures in nanocomposites.

Rheology finds distinct glass and jamming transitions in emulsions.

We study the rheology of monodisperse and bidisperse emulsions with various droplet sizes (1-2 µm diameter). Above a critical volume fraction φc, these systems exhibit solid-like behavior and a yield stress can be detected. Previous experiments suggest that for small thermal particles, rheology will see a glass transition at φc = φg ≈ 0.58; for large athermal systems, rheology will see a jamming transition at φc = φJ ≈ 0.64. However, simulations point out that at the crossover of thermal and athermal regimes, the glass and jamming transitions may both be observed in the same sample. Here we conduct an experiment by shearing four oil-in-water emulsions with a rheometer. We observe both a glass and a jamming transition for our smaller diameter droplets, and only a jamming transition for our larger diameter droplets. The bidisperse sample behaves similarly to the small droplet sample, with two transitions observed. Our rheology data are well-fit by both the Herschel-Bulkley model and the three component model. Based on the fitting parameters, our raw rheological data would not collapse onto a master curve. Our results show that liquid-solid transitions in dispersions are not universal, but depend on particle size.

Solution-Based 3D Printing of Polymers of Intrinsic Microporosity.

Current additive manufacturing methods have significant limitations in the classes of compatible polymers. Many polymers of significant technological interest cannot currently be 3D printed. Here, a generalizable method for 3D printing of viscous tenary polymer solutions (polymer/solvent/nonsolvent) is applied to both "intrinsically porous" (a polymer of intrinsic microporosity, PIM-1) and "intrinsically nonporous" (cellulose acetate) polymers. Successful ternary ink formulations require balancing of solution thermodynamics (phase separation), mass transfer (solvent evaporation), and rheology. As a demonstration, a microporous polymer (PIM-1) incompatible with current additive manufacturing technologies is 3D printed into a high-efficiency mass transfer contactor exhibiting hierarchical porosity ranging from sub-nanometer to millimeter pores. Short contactors (1.27 cm) can fully purify (<1 ppm) toluene vapor (1000 ppm) in N2 gas for 1.7 h, which is six times longer than PIM-1 in traditional structures, and more than 4000 times the residence time of gas in the contactor. This solution-based additive manufacturing approach greatly extends the range of 3D-printable materials.

Dual-purpose linker for alpha helix stabilization and imaging agent conjugation to glucagon-like peptide-1 receptor ligands.

Peptides display many characteristics of efficient imaging agents such as rapid targeting, fast background clearance, and low non-specific cellular uptake. However, poor stability, low affinity, and loss of binding after labeling often preclude their use in vivo. Using glucagon-like peptide-1 receptor (GLP-1R) ligands exendin and GLP-1 as a model system, we designed a novel α-helix-stabilizing linker to simultaneously address these limitations. The stabilized and labeled peptides showed an increase in helicity, improved protease resistance, negligible loss or an improvement in binding affinity, and excellent in vivo targeting. The ease of incorporating azidohomoalanine in peptides and efficient reaction with the dialkyne linker enable this technique to potentially be used as a general method for labeling α helices. This strategy should be useful for imaging beta cells in diabetes research and in developing and testing other peptide targeting agents.

Oral and Subcutaneous Administration of a Near-Infrared Fluorescent Molecular Imaging Agent Detects Inflammation in a Mouse Model of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that causes irreversible damage to the joints. However, effective drugs exist that can stop disease progression, leading to intense interest in early detection and treatment monitoring to improve patient outcomes. Imaging approaches have the potential for early detection, but current methods lack sensitivity and/or are time-consuming and expensive. We examined potential routes for self-administration of molecular imaging agents in the form of subcutaneous and oral delivery of an integrin binding near-infrared (NIR) fluorescent imaging agent in an animal model of RA with the long-term goal of increasing safety and patient compliance for screening. NIR imaging has relatively low cost, uses non-ionizing radiation, and provides minimally invasive spatial and molecular information. This proof-of-principle study shows significant uptake of an IRDye800CW agent in inflamed joints of a collagen antibody induced arthritis (CAIA) mouse model compared to healthy joints, irrespective of the method of administration. The imaging results were extrapolated to clinical depths in silico using a 3D COMSOL model of NIR fluorescence imaging in a human hand to examine imaging feasability. With target to background concentration ratios greater than 5.5, which are achieved in the mouse model, these probes have the potential to identify arthritic joints following oral delivery at clinically relevant depths.

Multiscale Modeling of Antibody-Drug Conjugates: Connecting Tissue and Cellular Distribution to Whole Animal Pharmacokinetics and Potential Implications for Efficacy.

Antibody-drug conjugates exhibit complex pharmacokinetics due to their combination of macromolecular and small molecule properties. These issues range from systemic concerns, such as deconjugation of the small molecule drug during the long antibody circulation time or rapid clearance from nonspecific interactions, to local tumor tissue heterogeneity, cell bystander effects, and endosomal escape. Mathematical models can be used to study the impact of these processes on overall distribution in an efficient manner, and several types of models have been used to analyze varying aspects of antibody distribution including physiologically based pharmacokinetic (PBPK) models and tissue-level simulations. However, these processes are quantitative in nature and cannot be handled qualitatively in isolation. For example, free antibody from deconjugation of the small molecule will impact the distribution of conjugated antibodies within the tumor. To incorporate these effects into a unified framework, we have coupled the systemic and organ-level distribution of a PBPK model with the tissue-level detail of a distributed parameter tumor model. We used this mathematical model to analyze new experimental results on the distribution of the clinical antibody-drug conjugate Kadcyla in HER2-positive mouse xenografts. This model is able to capture the impact of the drug-antibody ratio (DAR) on tumor penetration, the net result of drug deconjugation, and the effect of using unconjugated antibody to drive ADC penetration deeper into the tumor tissue. This modeling approach will provide quantitative and mechanistic support to experimental studies trying to parse the impact of multiple mechanisms of action for these complex drugs.

Residualization Rates of Near-Infrared Dyes for the Rational Design of Molecular Imaging Agents.

PURPOSE: Near-infrared (NIR) fluorescence imaging is widely used for tracking antibodies and biomolecules in vivo. Clinical and preclinical applications include intraoperative imaging, tracking therapeutics, and fluorescent labeling as a surrogate for subsequent radiolabeling. Despite their extensive use, one of the fundamental properties of NIR dyes, the residualization rate within cells following internalization, has not been systematically studied. This rate is required for the rational design of probes and proper interpretation of in vivo results. PROCEDURES: In this brief report, we measure the cellular residualization rate of eight commonly used dyes encompassing three core structures (cyanine, boron-dipyrromethene (BODIPY), and oxazine/thiazine/carbopyronin). RESULTS: We identify residualizing (half-life >24 h) and non-residualizing (half-life <24 h) dyes in both the far-red (~650-680 nm) and near-infrared (~740-800 nm) regions. CONCLUSIONS: This data will allow researchers to independently and rationally select the wavelength and residualizing nature of dyes for molecular imaging agent design.

Multichannel imaging to quantify four classes of pharmacokinetic distribution in tumors.

Low and heterogeneous delivery of drugs and imaging agents to tumors results in decreased efficacy and poor imaging results. Systemic delivery involves a complex interplay of drug properties and physiological factors, and heterogeneity in the tumor microenvironment makes predicting and overcoming these limitations exceptionally difficult. Theoretical models have indicated that there are four different classes of pharmacokinetic behavior in tissue, depending on the fundamental steps in distribution. In order to study these limiting behaviors, we used multichannel fluorescence microscopy and stitching of high-resolution images to examine the distribution of four agents in the same tumor microenvironment. A validated generic partial differential equation model with a graphical user interface was used to select fluorescent agents exhibiting these four classes of behavior, and the imaging results agreed with predictions. BODIPY-FL exhibited higher concentrations in tissue with high blood flow, cetuximab gave perivascular distribution limited by permeability, high plasma protein and target binding resulted in diffusion-limited distribution for Hoechst 33342, and Integrisense 680 was limited by the number of binding sites in the tissue. Together, the probes and simulations can be used to investigate distribution in other tumor models, predict tumor drug distribution profiles, and design and interpret in vivo experiments.