Simulated Mucus Research Articles

Impact of Nebulized BromAc® on Mucus Plug Clearance in a Mechanically Ventilated Ex Vivo Ovine Lung Model of Obstructive Respiratory Conditions.

Mucus plugging of the respiratory tract occurs in airway diseases, including asthma, chronic obstructive pulmonary disease, and cystic fibrosis. It can cause blockage of the airways, leading to breathlessness and lung failure. Here, we used a ventilatory setup to demonstrate the effect of BromAc® in dissolving mucus plugs in a novel ex vivo ovine obstructive lung model. Mucus simulant was filled into the trachea of freshly slaughtered ovine lungs and ventilated via an endotracheal tube (ETT) using Continuous Mandatory Ventilation. Predetermined single or repeated doses of Bromelain, Acetylcysteine (Ac), BromAc®, and saline control were administered via an Aerogen® vibrating nebulizer and ventilated for 30 or 60 min. Ventilatory recording of resistance, compliance, and tidal volume was conducted, and rheology pre- and post-treatment were measured. A significant decline in airway resistance (p < 0.0001) compared to the saline control was observed when treated with Bromelain, Ac, and BromAc®, with the latter showing a stronger mucolytic effect than single agents. The decline in resistance was also effective in shorter time points (p < 0.05) at lower doses of the drugs. Changes in compliance, peak pressure, and tidal volume were not observed after administration of the drugs. Rheology measurements revealed that BromAc®TM significantly reduced the viscosity of the mucin at the end of 30 min and 60 min time points (p < 0.001) compared to the saline control. BromAc® showed complete dissolution of the respiratory mucus simulant and improved ventilatory airflow parameters in the ex vivo ovine model.

Integration of mucus and its impact within in vitro setups for inhaled drugs and formulations: Identifying the limits of simple vs. complex methodologies when studying drug dissolution and permeability

Traditionally, developing inhaled drug formulations relied on trial and error, yet recent technological advancements have deepened the understanding of ‘inhalation biopharmaceutics’ i.e. the processes that occur to influence the rate and extent of drug exposure in the lungs. This knowledge has led to the development of new in vitro models that predict the in vivo behavior of drugs, facilitating the enhancement of existing formulation and the development of novel ones. Our prior research examined how simulated lung fluid (SLF) affects the solubility of inhaled drugs. Building on this, we aimed to explore drug dissolution and permeability in lung mucosa models containing mucus. Thus, the permeation of four active pharmaceutical ingredients (APIs), salbutamol sulphate (SS), tiotropium bromide (TioBr), formoterol fumarate (FF) and budesonide (BUD), was assayed in porcine mucus covered Calu-3 cell layers, cultivated at an air liquid interface (ALI) or submerged in a liquid covered (LC) culture system. Further analysis on BUD and FF involved their transport in a mucus-covered PAMPA system. Finally, their dissolution post-aerosolization from Symbicort® was compared using ‘simple’ Transwell and complex DissolvIt® apparatuses, alone or in presence of porcine mucus or polymer-lipid mucus simulant. The presence of porcine mucus impacted both permeability and dissolution of inhaled drugs. For instance, permeability of SS was reduced by a factor of ten in the Calu-3 ALI model while the permeability of BUD was reduced by factor of two in LC and ALI setups. The comparison of dissolution methodologies indicated that drug dissolution performance was highly dependent on the setup, observing decreased release efficiency and higher variability in Transwell system compared to DissolvIt®. Overall, results demonstrate that relatively simple methodologies can be used to discriminate between formulations in early phase drug product development. However, for more advanced stages complex methods are required. Crucially, it was clear that the impact of mucus and selection of its composition in in vitro testing of dissolution and permeability should not be neglected when developing drugs and formulations intended for inhalation.

Low yield stress measurements with a microfluidic rheometer.

Yield stress, τy, is a key rheological property of complex materials such as gels, dense suspensions, and dense emulsions. While there is a range of established techniques to measure τy in the order of tens to thousands of pascals, the measurement of low τy, specifically below 1 Pa, remains underexplored. In this article, we present the measurement of low apparent τy using a Hele-Shaw microfluidic extensional flow device (MEFD). Using the MEFD, we observe a gradient in shear stress, τ, such that τ is lower near the center or stagnation point, and higher away from the stagnation point. For a yield stress fluid, we observe that, below a certain flow rate, τ exceeds τy only in the outer region, leading to stagnation or unyielding of the fluid in the inner region. We use scaling analysis based on a Hele-Shaw linear extensional flow to deduce τy by measuring the size of the unyielded region, S. We validate this scaling relationship using Carbopol solutions with concentrations ranging between 0.015 to 0.3%, measuring τy as low as ∼10 mPa to ∼1 Pa, and comparing it with τy measured using a standard rheometer. While the experimental lower limit of our technique is 5 mPa, modifying the geometry or improving the image analysis can reduce this limit to the order of 10-4 Pa. The MEFD facilitates rapid measurement of τy, allowing for its real-time assessment. We further report τy of human blood samples between 30 to 80 mPa with their hematocrit ranging between 14 to 63%. Additionally, we determine τy for a mucus simulant (∼0.7 Pa), and lactic drink (∼7 mPa) to demonstrate the versatility of the MEFD technique.

Bionic Snail Robot Enhanced by Poroelastic Foams Crawls Using Direct and Retrograde Waves.

Snails employ a distinctive crawling mechanism in which the pedal waves travel along the foot and interact with the mucus to promote efficient movement on various substrates. Inspired by the concavities on the pedal wave, we develop a new bionic snail robot that introduces transverse patterns in a longitudinal wave to periodically change the friction. The poroelastic foam serves as flexible constraint and fills the robot's internal cavity. It contributes to the bending action, and maintains the thinness and softness of the robot. Then, the model of the robot's single segment is built utilizing the Euler-Bernoulli beam theory. The model aligns well with the experimental data, thereby confirming the effectiveness of soft constraints. The evaluation of pedal wave is conducted, which further guides the optimization of the control sequence. The experiments demonstrated the robot performing retrograde wave locomotion on dry substrates. Notably, shear-thickening fluids were found to be suitable for this particular crawling pattern compared with other mucus simulants, resulting in direct wave locomotion with a 49% increase in speed and a 33% reduction in energy usage. The load capacity of the soft snail robot was also enhanced, enabling it to carry loads up to 2.84 times its own weight. The use of mucus in crawling also brings valuable insights for the enhancement of other biomimetic robots.

Gels That Serve as Mucus Simulants: A Review.

Mucus is a critical part of the human body's immune system that traps and carries away various particulates such as anthropogenic pollutants, pollen, viruses, etc. Various synthetic hydrogels have been developed to mimic mucus, using different polymers as their backbones. Common to these simulants is a three-dimensional gel network that is physically crosslinked and is capable of loosely entrapping water within. Two of the challenges in mimicking mucus using synthetic hydrogels include the need to mimic the rheological properties of the mucus and its ability to capture particulates (its adhesion mechanism). In this paper, we review the existing mucus simulants and discuss their rheological, adhesive, and tribological properties. We show that most, but not all, simulants indeed mimic the rheological properties of the mucus; like mucus, most hydrogel mucus simulants reviewed here demonstrated a higher storage modulus than its loss modulus, and their values are in the range of that found in mucus. However, only one mimics the adhesive properties of the mucus (which are critical for the ability of mucus to capture particulates), Polyvinyl alcohol-Borax hydrogel.

Demonstration of mucus simulant clearance in a Bench-Model using acoustic Field-Integrated Intrapulmonary Percussive ventilation

Intrapulmonary Percussive Ventilation (IPV) is a high-frequency airway clearance technique used to help in mucus transport for mechanically ventilated and unventilated patients. Despite the many years of usage, this technique does not provide clear evidence of its intended efficacy. This is mainly attributable to the lack of in vitro observations that show “mucokinesis” towards the direction of the mouth. In the current manuscript, we demonstrate and subsequently propose a mechanism that details the movement of a mucus simulant in the proximal (towards the mouthpiece) direction. Towards this end, a novel method utilizing a high-frequency acoustic field in addition to the conventional air pulsations brought forth by traditional IPV is proposed. Under these conditions, at certain parameter settings, it is shown that the simulant is broken down into much smaller parts and subsequently pushed in the upstream direction gradually over a period of half-hour.

Effects of Mechanical Insufflation-Exsufflation With Different Pressure Settings on Respiratory Mucus Displacement During Invasive Ventilation.

Mechanical insufflation-exsufflation (MI-E) has been proposed as a potential strategy to generate high expiratory flows and simulate cough in the critically ill. However, efficacy and safety of MI-E during invasive mechanical ventilation are still to be fully elucidated. This study in intubated and mechanically ventilated pigs aimed to evaluate the effects of 8 combinations of insufflation-exsufflation pressures during MI-E on mucus displacement, respiratory flows, as well as respiratory mechanics and hemodynamics. Six healthy Landrace-Large White female pigs were orotracheally intubated, anesthetized, and invasively ventilated for up to 72 h. Eight combinations of insufflation-exsufflation pressures (+40/-40, +40/-50, +40/-60, +40/-70, +50/-40, +50/-50, +50/-60, +50/-70 cm H2O) were applied in a randomized order. The MI-E device was set to automatic mode, medium inspiratory flow, and an inspiratory-expiratory time 3 and 2 s, respectively, with a 1-s pause between cycles. We performed 4 series of 5 insufflation-exsufflation cycles for each combination of pressures. Velocity and direction of movement of a mucus simulant containing radio-opaque markers were assessed through sequential lateral fluoroscopic images of the trachea. We also evaluated respiratory flows, respiratory mechanics, and hemodynamics before, during, and after each combination of pressures. In 3 of the animals, experiments were conducted twice; and for the remaining 3, they were conducted once. In comparison to baseline mucus movement (2.85 ± 2.06 mm/min), all insufflation-exsufflation pressure combinations significantly increased mucus velocity (P = .01). Particularly, +40/-70 cm H2O was the most effective combination, increasing mucus movement velocity by up to 4.8-fold (P < .001). Insufflation pressure of +50 cm H2O resulted in higher peak inspiratory flows (P = .004) and inspiratory transpulmonary pressure (P < .001) than +40 cm H2O. MI-E appeared to be an efficient strategy to improve mucus displacement during invasive ventilation, particularly when set at +40/-70 cm H2O. No safety concerns were identified although a transient significant increase of transpulmonary pressure was observed.

Rapid Viscoelastic Characterization of Airway Mucus Using a Benchtop Rheometer.

In muco-obstructive lung diseases (e.g., asthma, chronic obstructive pulmonary disease, cystic fibrosis) and other respiratory conditions (e.g., viral/bacterial infections), mucus biophysical properties are altered by goblet cell hypersecretion, airway dehydration, oxidative stress, and the presence of extracellular DNA. Previous studies showed that sputum viscoelasticity correlated with pulmonary function and that treatments affecting sputum rheology (e.g., mucolytics) can result in remarkable clinical benefits. In general, rheological measurements of non-Newtonian fluids employ elaborate, time-consuming approaches (e.g., parallel/cone-plate rheometers and/or microbead particle tracking) that require extensive training to perform the assay and interpret the data. This study tested the reliability, reproducibility, and sensitivity of Rheomuco, a user-friendly benchtop device that is designed to perform rapid measurements using dynamic oscillation with a shear-strain sweep to provide linear viscoelastic moduli (G', G", G*, and tan δ) and gel point characteristics (γcand σc) for clinical samples within 5 min. Device performance was validated using different concentrations of a mucus simulant, 8 MDa polyethylene oxide (PEO), and against traditional bulk rheology measurements. A clinical isolate harvested from an intubated patient with status asthmaticus (SA) was then assessed in triplicate measurements and the coefficient of variation between measurements is <10%. Ex vivo use of a potent mucus reducing agent, TCEP, on SA mucus resulted in a five-fold decrease in elastic modulus and a change toward a more "liquid-like" behavior overall (e.g., higher tan δ). Together, these results demonstrate that the tested benchtop rheometer can make reliable measures of mucus viscoelasticity in clinical and research settings. In summary, the described protocol could be used to explore the effects of mucoactive drugs (e.g., rhDNase, N-acetyl cysteine) onsite to adapt treatment on a case-by-case basis, or in preclinical studies of novel compounds.

A Cranberry Concentrate Decreases Adhesion and Invasion of Escherichia coli (AIEC) LF82 In Vitro.

While many beneficial host–microbiota interactions have been described, imbalanced microbiota in the gut is speculated to contribute to the progression and recurrence of chronic inflammatory diseases such as Crohn’s disease (CD). This in vitro study evaluated the impact of a cranberry concentrate Type M (CTM) on adherent-invasive Escherichia coli (AIEC) LF82, a pathobiont associated with CD. Different stages of pathogenic infection were investigated: (i) colonization of the mucus layer, and (ii) adhesion to and (iii) invasion of the epithelial cells. Following 48 h of fecal batch incubation, 0.5 and 1 mM of CTM significantly altered AIEC LF82 levels in a simulated mucus layer, resulting in a decrease of 50.5% in the untreated blank, down to 43.0% and 11.4%, respectively. At 1 mM of CTM, the significant decrease in the levels of AIEC LF82 coincided with a stimulation of the metabolic activity of the background microbiota. The increased levels of health-associated acetate (+7.9 mM) and propionate levels (+3.5 mM) suggested selective utilization of CTM by host microorganisms. Furthermore, 1 mM of both fermented and unfermented CTM decreased the adhesion and invasion of human-derived epithelial Caco-2 cells by AIEC LF82. Altogether, this exploratory in vitro study demonstrates the prebiotic potential of CTM and supports its antipathogenic effects through direct and/or indirect modulation of the gut microbiome.

In vitro–in vivo Validation of Stimulatory Effect of Oat Ingredients on Lactobacilli

The prebiotic activity of a commercially available oat product and a novel oat ingredient, at similar β-glucan loads, was tested using a validated in vitro gut model (M-SHIME®). The novel oat ingredient was tested further at lower β-glucan loads in vitro, while the commercially available oat product was assessed in a randomised, single-blind, placebo-controlled, and cross-over human study. Both approaches focused on healthy individuals with mild hypercholesterolemia. In vitro analysis revealed that both oat products strongly stimulated Lactobacillaceae and Bifidobacteriaceae in the intestinal lumen and the simulated mucus layer, and corresponded with enhanced levels of acetate and lactate with cross-feeding interactions leading to an associated increase in propionate and butyrate production. The in vitro prebiotic activity of the novel oat ingredient remained at lower β-glucan levels, indicating the prebiotic potential of the novel oat product. Finally, the stimulation of Lactobacillus spp. was confirmed during the in vivo trial, where lactobacilli abundance significantly increased in the overall population at the end of the intervention period with the commercially available oat product relative to the control product, indicating the power of in vitro gut models in predicting in vivo response of the microbial community to dietary modulation.

Enhancing Mucus Clearance by Cough Through Repeated Pulses

AbstractThe aim of this study is to investigate the potential increase in the efficiency of the mucus clearance by repeated pulses of the same maximum speed and total air volume compared to single pulse simulated cough and to explore the effect of mucus simulant rheology and duration between repeated pulses on it. Experiments are conducted to study the behavior and clearance of a mucus simulant through a D-shaped rigid plexiglass horizontal tracheal model by approximately rectangular pulses. Mucus simulants with viscoelastic properties like mucus of patients with chronic obstructive pulmonary disease (COPD) or similar illnesses, a moderate increase in elastic modulus, and a sharp decrease in viscosity with increasing frequency were prepared by locust bean gum and borax-de-ionized water solutions (Ragavan, A. J., Evrensel, C. A., and Krumpe, P., 2010, “Interactions of Airflow Oscillation, Tracheal Inclination, and Mucus Elasticity Significantly Improve Simulated Cough Clearance,” Chest, 137(2), pp. 355–361). Displacement of 0.3 ml mucus simulant aliquot is measured during single or repeated airflow pulses with a total air volume of about 1.1 L and the same maximum velocity. The desired flow pattern is generated by a compressor set at 4.5 bar and a computer-controlled on–off valve. Displacement of the same volume of mucus aliquot increases with the increasing number of pulses with the same total volume of air and maximum velocity and increasing of elasticity of mucus simulants. The increased maximum airflow velocity of repeated pulses affects the displacement of mucus aliquot positively. Moreover, when the duration length between the repeated pulses increased up to 100 ms, the displacement of aliquot increased up to but after 100 ms to 150 ms started to decrease.

Size effect of curcumin nanocrystals on dissolution, airway mucosa penetration, lung tissue distribution and absorption by pulmonary delivery

Nanocrystals (NCs) have been introduced for use in pulmonary delivery in recent decades. Although the deposition and bioavailability have been extensively studied, little is known about the biofate, which influences the drug release and absorption process of NCs. In this study, we fabricated three different sized curcumin NCs by adjusting the parameters of mill machine using a wet milling method and studied the size effect on pulmonary absorption. The small nanocrystals (NC-S, 246.16 ± 21.98 nm) exhibited a faster dissolution rate and higher diffusion percentage in vitro compared with middle (NC-M, 535.26 ± 50.33 nm) and large nanocrystals (NC-L, 1089.53 ± 194.34 nm). Multiple particle tracking experiments revealed that NC-S had larger mean squared displacement during diffusion in simulated mucus of 0.5% hydroxyethyl cellulose solution. Moreover, enhanced cellular uptake and transport efficiency were achieved by NC-S in Calu-3 cells and an air-liquid interface culturing model. NCs were mainly absorbed in the dissolved drug form, as assessed by using the Förster resonance energy transfer (FRET) technique. In vivo lung retention and distribution revealed that few smaller sized nanocrystals were retained in the lung after intratracheal administration. The pharmacokinetic study showed that the AUC(0-t) values of small sized nanocrystals were 1.75- and 3.32-fold greater than NC-M and NC-L, respectively. In conclusion, this study demonstrated that smaller sized nanocrystals were more easily absorbed into the blood system by increasing the dissolution rate.

Time-controlled adaptive ventilation (TCAV) accelerates simulated mucus clearance via increased expiratory flow rate

BackgroundVentilator-associated pneumonia (VAP) is the most common nosocomial infection in intensive care units. Distal airway mucus clearance has been shown to reduce VAP incidence. Studies suggest that mucus clearance is enhanced when the rate of expiratory flow is greater than inspiratory flow. The time-controlled adaptive ventilation (TCAV) protocol using the airway pressure release ventilation (APRV) mode has a significantly increased expiratory relative to inspiratory flow rate, as compared with the Acute Respiratory Distress Syndrome Network (ARDSnet) protocol using the conventional ventilation mode of volume assist control (VAC). We hypothesized the TCAV protocol would be superior to the ARDSnet protocol at clearing mucus by a mechanism of net flow in the expiratory direction.MethodsPreserved pig lungs fitted with an endotracheal tube (ETT) were used as a model to study the effect of multiple combinations of peak inspiratory (IPF) and peak expiratory flow rate (EPF) on simulated mucus movement within the ETT. Mechanical ventilation was randomized into 6 groups (n = 10 runs/group): group 1—TCAV protocol settings with an end-expiratory pressure (PLow) of 0 cmH2O and PHigh 25 cmH2O, group 2—modified TCAV protocol with increased PLow 5 cmH2O and PHigh 25 cmH2O, group 3—modified TCAV with PLow 10 cmH2O and PHigh 25 cmH2O, group 4—ARDSnet protocol using low tidal volume (LTV) and PEEP 0 cmH2O, group 5—ARDSnet protocol using LTV and PEEP 10 cmH2O, and group 6—ARDSnet protocol using LTV and PEEP 20 cmH2O. PEEP of ARDSnet is analogous to PLow of TCAV. Proximal (towards the ventilator) mucus movement distance was recorded after 1 min of ventilation in each group.ResultsThe TCAV protocol groups 1, 2, and 3 generated significantly greater peak expiratory flow (EPF 51.3 L/min, 46.8 L/min, 36.8 L/min, respectively) as compared to the ARDSnet protocol groups 4, 5, and 6 (32.9 L/min, 23.5 L/min, and 23.2 L/min, respectively) (p < 0.001). The TCAV groups also demonstrated the greatest proximal mucus movement (7.95 cm/min, 5.8 cm/min, 1.9 cm/min) (p < 0.01). All ARDSnet protocol groups (4–6) had zero proximal mucus movement (0 cm/min).ConclusionsThe TCAV protocol groups promoted the greatest proximal movement of simulated mucus as compared to the ARDSnet protocol groups in this excised lung model. The TCAV protocol settings resulted in the highest EPF and the greatest proximal movement of mucus. Increasing PLow reduced proximal mucus movement. We speculate that proximal mucus movement is driven by EPF when EPF is greater than IPF, creating a net force in the proximal direction.

In vitro dissolution testing of respirable size anti-tubercular drug particles using a small volume dissolution apparatus

A dissolution apparatus that uses a small volume of stationary medium (25 μL) has been developed for in vitro dissolution testing of respirable drug particles and used to evaluate the dissolution of two anti-tubercular drugs, moxifloxacin and ethionamide. Solubilities of moxifloxacin and ethionamide in phosphate buffered saline (PBS, pH 7.4) were 17.68 ± 0.85 mg mL−1 and 0.46 ± 0.02 mg mL−1 whereas in the presence of lung surfactant (0.4% w/v Curosurf® in PBS) solubilities were 20.76 ± 0.35 mg mL−1 and 0.56 ± 0.03 mg mL−1, respectively. A fine particle dose (∼50 µg) of aerodynamically separated moxifloxacin or ethionamide particles (<6.4 µm) was collected onto a glass coverslip using a modified Twin Stage Impinger. The dissolution behaviour of the fine particle dose was evaluated at various perfusate flow rates (0.2, 0.4 and 0.8 mL min−1 of PBS), mucus simulant concentrations (1.0, 1.5 and 2.0% w/v polyethylene oxide in PBS), and in the presence of lung surfactant. The dissolution behaviour of the respirable size particles was observed under an optical microscope and the dissolved drug that diffused into the perfusate was quantified by HPLC. The moxifloxacin particles disappeared quickly and showed faster permeation (<30 min) compared to the ethionamide particles at all the dissolution conditions evaluated. This study demonstrated the differences in the dissolution rates of moxifloxacin and ethionamide particles and may be useful to estimate the residence time of the inhaled dry powder particles in the lungs.

Effects of manual hyperinflation, clinical practice versus expert recommendation, on displacement of mucus simulant: A laboratory study.

IntroductionManual hyperinflation (MH), a maneuver applied in mechanically ventilated patients to facilitate secretion removal, has large variation in its performance. Effectiveness of MH is usually evaluated by its capacity to generate an expiratory flow bias. The aim of this study was to compare the effects of MH—and its resulting flow bias—applied according to clinical practice versus according to expert recommendation on mucus movement in a lung model simulating a mechanically ventilated patient.MethodsTwelve physiotherapists were asked to apply MH, using a self-inflating manual resuscitator, to a test lung as if to remove secretions under two conditions: according to their usual clinical practice (pre-instruction phase) and after verbal instruction to perform MH according to expert recommendation was given (post-instruction phase). Mucus simulant movement was measured with a photodensitometric technique. Peak inspiratory flow (PIF), peak inspiratory pressure (PIP), inspiratory time (TINSP), tidal volume (VT) and peak expiratory flow (PEF) were measured continuously.ResultsIt was found that MH performed post-instruction delivered a smaller VT (643.1 ± 57.8 ml) at a lower PIP (15.0 ± 1.5 cmH2O), lower PIF (38.0 ± 9.6 L/min), longer TINSP (1.84 ±0.54 s) and lower PEF (65.4 ± 6.7L/min) compared to MH pre-instruction. In the pre-instruction phase, MH resulted in a mean PIF/PEF ratio of 1.73 ± 0.38 and mean PEF-PIF difference of -54.6 ± 28.3 L/min, both out of the range for secretion removal. In the post-instruction phase both indexes were in the adequate range. Consequently, the mucus simulant was moved outward when MH was applied according to expert recommendation and towards the test lung when it was applied according to clinical practice.ConclusionsPerformance of MH during clinical practice with PIF higher than PEF was ineffective to clear secretion in a lung model simulating a mechanically ventilated patient. In order to remove secretion, MH should result in an adequate expiratory flow bias.

Rheological properties of synthetic mucus for airway clearance.

In this work, a complete rheological characterization of bronchial mucus simulants based on the composition proposed by Zahm et al. (Eur Respir J 1991; 4:311-315) is presented. Dynamic small amplitude oscillatory shear (SAOS) experiments, steady state (SS) flow measurements and three intervals thixotropy tests (3ITT), are carried out to investigate the global rheological complexities of simulants (viscoelasticity, viscoplasticity, shear-thinning, and thixotropy) as a function of scleroglucan concentrations (0.5-2 wt %) and under temperatures of 20 and 37°C. SAOS measurements show that the limit of the linear viscoelastic range as well as the elasticity both increase with increasing sclerogucan concentrations. Depending on the sollicitation frequency, the 0.5 wt % gel response is either liquid-like or solid-like, whereas more concentrated gels show a solid-like response over the whole frequency range. The temperature dependence of gels response is negligible in the 20-37°C range. The Herschel-Bulkley (HB) model is chosen to fit the SS flow curve of simulants. The evolution of HB parameters versus polymer concentration show that both shear-thinning and viscoplasticity increase with increasing concentrations. 3ITTs allow calculation of recovery thixotropic times after shearings at 100 or 1.6 s-1 . Empiric correlations are proposed to quantify the effect of polymer concentration on rheological parameters of mucus simulants. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 386-396, 2018.

Thermo-physical properties of synthetic mucus for the study of airway clearance.

In this article, dynamic viscosity, surface tension, density, heat capacity and thermal conductivity, of a bronchial mucus simulant proposed by Zahm et al., Eur Respir J 1991; 4: 311-315 were experiementally determined. This simulant is mainly composed of a galactomannan gum and a scleroglucan. It was shown that thermophysical properties of synthetic mucus are dependant of scleroglucan concentrations. More importantly and for some scleroglucan concentrations, the syntetic mucus, exhibits, somehow, comparable thermophysical properties to real bronchial mucus. An insight on the microstructure of this simulant is proposed and the different properties enounced previously have been measured for various scleroglucan concentrations and over a certain range of operating temperatures. This synthetic mucus is found to mimic well the rheological behavior and the surface tension of real mucus for different pathologies. Density and thermal properties have been measured for the first time. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3025-3033, 2017.

DissolvIt: An In Vitro Method for Simulating the Dissolution and Absorption of Inhaled Dry Powder Drugs in the Lungs.

The main purpose of this work was to develop an in vitro method for simulating the dissolution and absorption of inhaled dry powder drugs that also mimics systemic pharmacokinetic data. A second purpose was to evaluate this method. DissolvIt® was developed as a simulation of the air-blood barrier of the upper airways, constituting: "airborne" particles deposited on a glass cover slip, a mucus simulant, a polycarbonate (basal) membrane, and a pumped albumin buffer simulating the pulmonary blood flow. The PreciseInhale® exposure system was used to aerosolize and deposit test formulations onto cover slips. The particle dissolution was observed by optical microscopy as particle disappearance, and it was started directly when the particles came into contact with the mucus simulant. Solute from the dissolving particles diffused through the barrier and was absorbed into the perfusate. The drug concentration in the perfusate over time and the remaining drug in the barrier at the end of the experiment were quantitated by using liquid chromatography-tandem mass spectrometry. Budesonide and fluticasone propionate generated different pharmacokinetic dissolution/absorption profiles in DissolvIt. This study indicates that DissolvIt simulates dissolution and absorption of drugs in the lung, and that DissolvIt also mimics pharmacokinetic profiles and parameters.

Effects of intrapulmonary percussive ventilation on airway mucus clearance: A bench model.

AIMTo determine the ability of intrapulmonary percussive ventilation (IPV) to promote airway clearance in spontaneously breathing patients and those on mechanical ventilation.METHODSAn artificial lung was used to simulate a spontaneously breathing patient (Group 1), and was then connected to a mechanical ventilator to simulate a patient on mechanical ventilation (Group 2). An 8.5 mm endotracheal tube (ETT) connected to the test lung, simulated the patient airway. Artificial mucus was instilled into the mid-portion of the ETT. A filter was attached at both ends of the ETT to collect the mucus displaced proximally (mouth-piece filter) and distally (lung filter). The IPV machine was attached to the proximal end of the ETT and was applied for 10-min each to Group 1 and 2. After each experiment, the weight of the various circuit components were determined and compared to their dry weights to calculate the weight of the displaced mucus.RESULTSIn Group 1 (spontaneously breathing model), 26.8% ± 3.1% of the simulated mucus was displaced proximally, compared to 0% in Group 2 (the mechanically ventilated model) with a P-value of < 0.01. In fact, 17% ± 1.5% of the mucus in Group 2 remained in the mid-portion of the ETT where it was initially instilled and 80% ± 4.2% was displaced distally back towards the lung (P < 0.01). There was an overall statistically significant amount of mucus movement proximally towards the mouth-piece in the spontaneously breathing (SB) patient. There was also an overall statistically significant amount of mucus movement distally back towards the lung in the mechanically ventilated (MV) model. In the mechanically ventilated model, no mucus was observed to move towards the proximal/mouth piece section of the ETT.CONCLUSIONThis bench model suggests that IPV is associated with displacement of mucus towards the proximal mouthpiece in the SB patient, and distally in the MV model.

Estimation of Mucus Clearance in Pulmonary Airways by Means of a Regression Model

In this study, a multivariate regression analysis was performed on a dataset obtained from experimental tracheal model for mucus clearance in pulmonary airways. Several simulations have been done to verify the validity of the generated regression model. In general, the clearance of mucus in the airways is achieved by the beating action of cilia inside the serous layer which is the primary means of removing inhaled particulates and airway debris from airways in healthy people. In this study, two types of mucus simulants are used in the experimental setup. Clearance distances of a teardrop shape simulant are measured for different velocities, slope angles and surfaces properties. On the obtained data by applying several genuine transformations we developed a multiple regression model that is able to predict clearance up to 86% accuracy. Simulations revealed several important data like direct relation between velocity and clearance and indirect relation between angle and clearance.