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.

Negative Pressure Wound Therapy in Free Muscle Flaps-Risk or Benefit?

BACKGROUND: Application of negative pressure wound therapy (NPWT) on free flaps not only reduces edema but also increases the pressure from outside. The impact of these opposite effects on flap perfusion remains elusive. This study evaluates the NPWT system's influence on macro- and microcirculation of free flaps and edema reduction to better assess the clinical value of this therapy in microsurgical reconstructions. METHODS: In this open-label, prospective cohort study, a total of 26 patients with free gracilis muscle flaps for distal lower extremity reconstruction were included. Flaps were covered with an NPWT (13 patients) or a conventional, fatty gauze dressing (13 patients) for 5 postoperative days (PODs). Changes in flap perfusion were analyzed by laser Doppler flowmetry, remission spectroscopy, and an implanted Doppler probe. Flap volume as a surrogate parameter for flap edema was evaluated by three-dimensional (3D) scans. RESULTS: No flap showed clinical evidence of circulatory disturbances. The groups showed significant differences in the dynamic of macrocirculatory blood flow velocity with an increase in the NPWT group and a decelerated flow in the control group from PODs 0 to 3 and PODs 3 to 5. No significant differences in microcirculation parameters were observed. 3D scans for estimation of edema development demonstrated significant differences in volume dynamics between the groups. Flap volume of the controls increased, while the volume in the NPWT group decreased during the first 5 PODs. The volume of NPWT-treated flaps decreased even further after NPWT removal from PODs 5 to 14 and significantly more than the flap volume in the control group. CONCLUSION: NPWT is a safe form of dressing for free muscle flaps that enhances blood flow and results in a sustainable edema reduction. The use of NPWT dressings for free flaps should therefore be considered not only as a pure wound covering but also as a supportive therapy for free tissue transfer.

Global burn care and the ideal burn dressing reloaded - A survey of global experts.

PURPOSE: Burn care is a highly relevant medical specialty in every part of the world. Different infrastructure, healthcare systems and access to medical supplies lead to different needs, treatment strategies and outcomes. A fundamental tool in a burn care provider's armamentarium is the use of different dressings. Several studies have investigated the question of the ideal burn dressing, but none could achieve a proper global perspective. With advanced dressings being on the rise, we conducted this study to get a global understanding of the actual use and idea of the ideal burn dressing. OBJECTIVE: The objective of this study was to investigate the understanding of an 'ideal burn dressing' on a global scale. MATERIALS AND METHODS: A questionnaire about burn care and the ideal burn dressing has been created and translated to five of the most spoken languages world-wide (English, Spanish, French, Chinese, Indonesian). It has been uploaded to an online survey platform and sent out to burn experts worldwide. The voluntary participation was possible for a period of four weeks. RESULTS: In total, 196 respondents from 49 countries participated in the study, yielding a response rate of 24.5%. The most important burn dressing characteristics in a cumulative ranking were (1) lack of adhesion (80.54%), (2) pain-free dressing change (79.87%), (3) requirement of fewer dressing changes, while in a linear ranking they were (1) anti-infective (35.14% 1st), pain-reduction (24.14% 2nd), and high absorbency (23.49% 3rd). Silver-based dressings are the most used dressings for superficial (45.21%) and deep (52.78%). 94.81% believe that the choice of burn dressing affects the outcome. CONCLUSION: This investigation has delivered valuable insights into the global perspective of the ideal burn dressing. Yet, the question of the ideal burn dressing is still inconclusive. Wound dressing research is of fundamental interest for patients, healthcare providers and healthcare systems.

Less Is More? Impact of Single Venous Anastomosis on the Intrinsic Transit Time of Free Flaps.

Background The number of venous anastomoses advisable for a free flap continues to be controversial. Intrinsic transit time (ITT) is the time it takes dye during indocyanine green (ICG) microangiography to travel from the arterial to the venous anastomosis. ITT provides information on blood flow velocity and can predict postoperative circulatory complications. This study investigated the effect of the number of venous anastomoses on ITT. Methods The study enrolled 126 patients who had undergone microsurgical reconstruction and intraoperative ICG microangiography. Selection was limited to free gracilis and anterolateral thigh flaps as flaps with a single venous system. The retrospective assessment included reconstruction characteristics of the flaps, clinical outcome, ITT, and the number of venous anastomoses. Results The two groups were homogenous in terms of reconstruction characteristics. The single-venous anastomosis group (n = 75) had a reduced ITT (23.6 ± 11.7 vs. 43.8 ± 23.7 seconds; p < 0.001) compared with the double-anastomosis group (n = 51). A shorter ITT resulted in a significant reduction in the risk of reexploration for anastomotic thrombosis (OR 0.96; p = 0.024). Despite this, a higher reexploration rate tended to occur in the single-venous anastomosis group (9.3 vs. 7.8%; p = 1.0). Conclusion The results highlight the effect of shortening the ITT (thromboprotective blood flow acceleration) by using only one venous anastomosis. However, if the ITT is already at a low enough level with two veins, restriction to one vein does not appear to result in a reduced reexploration rate. For these flaps, the advantages of double-venous anastomosis prevail in terms of a backup drainage.

Perfusion Controlled Mobilization after Lower Extremity Free Flaps-Pushing the Limits of Time and Intensity.

Background The current standard to gradually adapt the fragile perfusion in lower extremity free flaps to an upright posture is the dangling maneuver. This type of flap training neither fits the orthostatic target load of an upright posture, nor does it assist in mobilizing the patients effectively. In this study, we quantitatively analyzed training effects of an early and full mobilization on flap perfusion. Methods A total of 15 patients with gracilis flaps for distal lower extremity reconstruction were included. Flap training was performed daily by mobilizing the patients on a tilt table into a fully upright posture for 5 minutes between the third and fifth postop days (PODs). Changes in micro- and macrocirculation were analyzed by laser Doppler flowmetry, remission spectroscopy, and an implanted Doppler probe. Results All flaps healed without complications. Yet, in three patients, the increased orthostatic load required an adjustment of the training duration due to a critical blood flow. The others showed an increasing compensation in the microcirculation. When tilting the patients, blood flow and oxygen saturation dropped significantly less on POD5 than on POD3. Furthermore, a significant increase of the blood flow was noted after an initial decrease during the mobilization on all days. An increasing compensation in the macrocirculation could not be determined. Conclusion Full mobilization of patients with lower extremity free flaps can be performed safely under perfusion monitoring, already starting on POD3. Additionally, monitoring allows a consideration of the individual orthostatic competence and therefore, exploitation of the maximum mobilization potential.