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BACKGROUND: Inhaled drug delivery can be limited by heterogeneous dose distribution. An additive that would disperse drug over the internal surfaces of the lung after aerosol deposition could improve dosing uniformity and increase the treated area. Our previous studies demonstrated that surfactant additives can produce surface tension-driven (Marangoni) flows that effectively dispersed aerosol-delivered drugs over mucus surfaces. Here we sought to determine whether the addition of a surfactant would increase transport of an aerosol between lung regions and also improve dosing uniformity in human lungs. METHODS: We compared the deposition and postdeposition dispersion of surfactant (10 mg/mL dipalmitoylphosphatidylcholine; DPPC) and saline-based liquid aerosols, admixed with Technetium 99m (Tc99m) diethylenetriaminepentaacetic acid, using gamma scintigraphy. Deposition images were obtained ex vivo in eight pairs of ventilated human lungs. The trachea was intubated and the mainstem bronchi were alternately clamped so that saline was delivered to one lung and then DPPC to the other (sides alternated). The lungs were continually imaged for 15 minutes during delivery. We assessed transport of the deposited aerosol by quantifying the percentage of Tc99m in each of four lung quadrants over time. We quantified dose uniformity within each lung quadrant by measuring the coefficient of variation (CV = standard deviation of the pixel associated radioactive counts/mean of the counts within each quadrant). RESULTS: There was no change in the percentage of Tc99m in each quadrant over time, indicating no improvement in transport with the addition of the surfactant. The addition of surfactant was associated with a statistically significant decrease in CV in the lower inner lung quadrant at each of the three time points, indicating an improvement in dosing uniformity. CONCLUSION: These preliminary results indicate the possible utility of adding surfactant to aerosols to improve drug distribution uniformity to lower inner lung regions.

BACKGROUND: Although mucus plugging is a well-reported feature of asthma, whether asthma and type 2 inflammation affect mucociliary clearance (MCC) is unknown. RESEARCH QUESTION: Does type 2 inflammation influence mucus clearance rates in patients with mild asthma who are not receiving corticosteroids? STUDY DESIGN AND METHODS: The clearance rates of inhaled radiolabeled particles were compared between patients with mild asthma with low (n = 17) and high (n = 18) levels of T2 inflammation. Fraction exhaled nitric oxide (Feno) was used to prospectively segregate subjects into T2 Lo (Feno < 25 ppb) and T2 Hi (Feno > 35 ppb) cohorts. Bronchial brush samples were collected with fiber-optic bronchoscopy, and quantitative polymerase chain reaction was performed to measure expression of genes associated with T2 asthma. MCC rate comparisons were also made with a historical group of healthy control subjects (HCs, n = 12). RESULTS: The T2 Lo cohort demonstrated increased MCC when compared with both T2 Hi and historic HCs. MCC within the T2 Hi group varied significantly, with some subjects having low or zero clearance. MCC decreased with increasing expression of several markers of T2 airway inflammation (CCL26, NOS2, and POSTN) and with Feno. MUC5AC and FOXJ1 expression was similar between the T2Lo and T2Hi cohorts. INTERPRETATION: Increasing T2 inflammation was associated with decreasing MCC. High rates of MCC in T2 Lo subjects may indicate a compensatory mechanism present in mild disease but lost with high levels of inflammation. Future studies are required to better understand mechanisms and whether impairments in MCC in more severe asthma drive worse clinical outcomes.

Aim: Inhaled hypertonic saline increases mucociliary clearance, improves pulmonary function, and decreases exacerbations in cystic fibrosis (CF) but contributes to the already significant treatment burden of CF. Overnight delivery of inhaled medications via a specially designed nasal cannula-aerosol device (Trans-nasal Pulmonary Aerosol Delivery [tPAD]) is an alternative approach. Here, we test whether overnight inhalation of hypertonic saline via tPAD improves mucociliary clearance and assess the tolerability of the device. Method: In this study, 12 CF subjects inhaled 7% hypertonic saline (HS) for 8 h overnight using the tPAD system. Safety and tolerability were assessed and measurements of mucociliary and absorptive clearance (MCC/ABS) were performed after the treatment. Comparisons were made versus sham treatment where the same subjects wore the nasal cannula overnight but did not receive aerosol. Results: Both the HS and sham treatments were well-tolerated. Only one subject did not complete the overnight HS treatment. There were no significant differences in MCC associated with HS inhalation at any time point (90 min, 3 h, 6 h) in any lung zone. Changes in FEV1 on both study days were similar. There were no differences in quality of sleep between HS and sham nights as assessed with the modified Leeds Sleep Evaluation Questionnaire (mLSEQ). Sino-Nasal Outcome Test (SNOT-14) questionnaires demonstrated significant increases (worsening) in 2/14 symptom categories with HS. Conclusions: The most likely cause for the failure to accelerate MCC was under-dosing of HS relative to the active transport of salt from the airways.

New measures are needed to rapidly assess emerging treatments for cystic fibrosis (CF) lung disease. Using an imaging approach, we evaluated the absorptive clearance of the radiolabeled small molecule probe diethylene triamine penta-acetic acid (DTPA) as an in vivo indicator of changes in airway liquid absorption. DTPA absorption and mucociliary clearance rates were measured in 21 patients with CF (12 adults and nine children) and nine adult controls using nuclear imaging. The effect of hypertonic saline on DTPA absorption was also studied. In addition, in vitro studies were conducted to identify the determinants of transepithelial DTPA absorption. CF patients had significantly increased rates of DTPA absorption compared with control subjects but had similar mucociliary clearance rates. Treatment with hypertonic saline resulted in a decrease in DTPA absorption and an increase in mucociliary clearance in 11 out of 11 adult CF patients compared with treatment with isotonic saline. In vitro studies revealed that ∼ 50% of DTPA absorption can be attributed to transepithelial fluid transport. Apically applied mucus impedes liquid and DTPA absorption. However, mucus effects become negligible in the presence of an osmotic stimulus. Functional imaging of DTPA absorption provides a quantifiable marker of immediate response to treatments that promote airway surface liquid hydration.

Airway surface liquid hyperabsorption and mucus accumulation are key elements of cystic fibrosis lung disease that can be assessed in vivo using functional imaging methods. In this study we evaluated experimental factors affecting measurements of mucociliary clearance (MCC) and small-molecule absorption (ABS) and patient factors associated with abnormal absorption and mucus clearance.Our imaging technique utilises two radiopharmaceutical probes delivered by inhalation. Measurement repeatability was assessed in 10 adult cystic fibrosis subjects. Experimental factors were assessed in 29 adult and paediatric cystic fibrosis subjects (51 scans). Patient factors were assessed in a subgroup with optimal aerosol deposition (37 scans; 24 subjects). Paediatric subjects (n=9) underwent initial and 2-year follow-up scans. Control subjects from a previously reported study are included for comparison.High rates of central aerosol deposition influenced measurements of ABS and, to a lesser extent, MCC. Depressed MCC in cystic fibrosis was only detectable in subjects with previous Pseudomonas aeruginosa infection. Cystic fibrosis subjects without P. aeruginosa had similar MCC to control subjects. Cystic fibrosis subjects had consistently higher ABS rates.We conclude that the primary experimental factor affecting MCC/ABS measurements is central deposition percentage. Depressed MCC in cystic fibrosis is associated with P. aeruginosa infection. ABS is consistently increased in cystic fibrosis.

Biomarkers providing in vivo quantification of the basic elements of cystic fibrosis (CF) lung disease are needed. A study was performed to determine whether the absorption of a small radiolabelled hydrophilic molecule (Indium-111 (In-)DTPA) would be increased in CF airways. DTPA clearance has been used previously to assess epithelial permeability and may also be useful for quantifying liquid absorption. The absorptive clearance rate of DTPA was quantified in 10 CF and 11 control subjects using a novel aerosol technique. Subjects inhaled an aerosol containing nonabsorbable technetium-99m sulfur colloid (Tc-SC) particles and In-DTPA. Tc-SC clearance from the lung is exclusively mucociliary, while In-DTPA is cleared by both absorption and mucociliary clearance. The difference between the In-DTPA and Tc-SC clearance rates estimates In-DTPA absorption. Tc-SC (mucociliary) clearance was similar in central and peripheral zones in CF and non-CF lungs. Total In-DTPA clearance was increased in both zones in CF lungs. The absorptive component of In-DTPA clearance was increased in the airway-dominated central lung zones in CF (42% x h( -1) versus 32% x h(-1), p = 0.03). The absorption of In-DTPA is increased in the CF airway. Further study is needed to understand the relative roles of fluid absorption, inflammation and other mechanisms potentially affecting epithelial permeability and DTPA absorption.

Tendon ruptures are common injuries that are often treated surgically. Growth Differentiation Factor-5 (GDF-5) has been shown to accelerate tendon healing with varying degrees of success. We used a novel technique to apply recombinant human GDF-5 (rhGDF-5) to suture and hypothesized that controlled, local delivery of rhGDF-5 can be used to enhance tendon repair. Tendons of 92 rats were transected and repaired with sutures. All researchers were blinded to the following treatment groups (24 rats in each group): 0 rhGDF (control), 24 ng/cm rhGDF, 55 ng/cm rhGDF, and 556 ng/cm rhGDF. Rats were euthanized at 3 weeks (n = 48) and at 6 weeks (n = 48). Sutures were coated with rhGDF-5 using a novel dip-coat technique. Enzyme-linked immunosorbent assay confirmed consistent and reproducible delivery of rhGDF-5. Within each group, 8 were tested biomechanically, and 4 were assessed histologically. Histologic grading at 3 weeks showed improved healing in tendons repaired with coated suture versus controls. By 6 weeks, there were no significant differences. At 3 weeks, minimal isolated cartilage formation was observed; 6-week samples showed more extensive presence, typically surrounding suture fibers. At 3 weeks, tendons repaired with rhGDF-5-coated sutures resulted in significantly higher ultimate tensile load and stiffness compared with control sutures (P < .05) At 6 weeks, there were no significant differences in the mechanical properties of repaired tendons. At 3 weeks, rhGDF-5 induced significant tendon hypertrophy that was more pronounced than at 6 weeks. In addition, tendons repaired with rhGDF-5 showed an increased rate of healing versus control repairs at 3 weeks. This study showed that a novel dip-coating technique can be used to deliver growth factors in varying concentrations to local repair sites to accelerate tendon healing.

Sodium polyphosphate-modified Class F fly ash/calcium aluminate blend (SFCB) cements were prepared at room temperature and their resistance to hot acid erosion was evaluated by submerging them in H2SO4 solution (pH 1.6) at 90°C. Sodium polyphosphate preferentially reacted with calcium aluminate cement (CAC) to form amorphous Ca(HPO4).xH2O and Al2O3.xH2O gel, rather than fly ash. These amorphous reaction products, which bound the partially reacted and unreacted CAC and fly ash particles into a coherent mass, were responsible for strengthening and densifying the SFCB specimens at room temperature, playing an essential role in mitigating their acid erosion. In these cements, the extent of acid erosion depended primarily on the ratio of fly ash/CAC; namely, those with a higher ratio underwent a severe erosion. This effect was due to the formation of a porous structure, which allowed acid to permeate the cement easily, diminishing the protective activity of Ca(HPO4).xH2O and Al2O3.xH2O gel against H2SO4.

A survey of cement manufacturers in the Asia Pacific Region revealed that only five companies produce a certified API Class G cement. Because of this, certain countries have been forced to import cement and in many cases ship it great distances. In some situations, API Class G cement can cost three times more than local construction cement. While the authors believe that the API Monogram is an excellent benchmark for oilwell cement, the question is – is it necessary to preclude good local cements from use simply because they are not certified. After all, the key issues for oilwell cement are predictability and performance, not certification In the absence of local API Class G cement, the authors propose two ways to use local cement in oilwell applications. First, work with existing construction cement companies to develop cements that consistently meet specifications of the desired API Class and use it in the field. Second, when and where it is applicable, use construction cement for oilwell cementing. The authors are implementing both techniques successfully in parts of South East Asia. This paper presents historical and technical background as well as laboratory data to support the use of local cements as an alternative to imported API Class G cement. Also, presented are several case studies on the use of local cement in oilwell applications as a means to save drilling costs.

Abstract For effective zonal isolation, drill cuttings and gelled, dehydrated drilling fluid (GDDF) should be removed from the wellbore before a cement job, but such removal can be a challenge when the wellbore is deviated and the casing is not centered. This paper discusses simulated wellbore experiments that investigated the effect of different factors on the removal of drill cuttings and GDDF from a horizontal well bore. The parameters studied included eccentricity, flow rate, hole size, casing size, fluids pumped as flush/spacer, and pipe movement. The results showed that below a certain flow rate, the drill cuttings and GDDF could not be dislodged from the wellbore. In field applications, this flow rate must be known so that job designers can selectively design flushes that will effectively dislodge the drill cuttings and GDDF. As expected, eccentricity also alters the velocity profile in the narrow side of the annulus, and geometry was also a factor in removal efficiency. The experimental setup, procedure, and results are discussed in detail. Flow rates needed to dislodge the drill cuttings and GDDF are also discussed, A numerical analysis of the fluid flow in wide and narrow annuli was also performed. Introduction Cement operators should always use the following guidelines to obtain a successful cementing job.Remove the drill cuttings.Remove the gelled and partially dehydrated drilling fluid. In some cases. this fluid will have the consistency of a paste. Hereafter, it will be referred to as partially dehydrated paste (PDP).Design the cement slurry to meet properties such as pumping time, fluid loss, gas migration, etc. In addition, design the density, rheology, and other placement parameters so that the cement slurry will displace the fluid ahead of it and seal the entire annulus. The cement formulation should also provide zonal isolation over the life of the well. The removal of drill cuttings and PDP are influenced by the following:–properties of drilling fluid, fluid loss, plastic viscosity etc, a temperature, pressure, differential pressure across the formation–shutdown period–drilling fluid formulation–wellbore details–casing/drillpipe size–hole size–standoff/eccentricity–pore pressure–fracture gradient For successful PDP removal, the downhole forces in both the narrow and wide sides of the annulus must exceed the yield stress of the PDP under downhole conditions. The force exerted could depend on the following factors:–flow rate of fluid–standoff/eccentricity–properties of fluid–pipe movement–wellbore geometry–scratchers Although the general effect of these parameters on a cement job is well known, the designer must quantify the effect of each factor to optimize the design of each individual well. For a wellbore with a certain drilling fluid, geometry and standoff, it may be difficult to generate needed forces by hydraulic means only. In such cases, ways to reduce the downhole forces should be explored. P. 347