Recent Developments in Aerosol Pulmonary Drug Delivery: New Technologies, New Cargos, and New Targets.

There is nothing like a global pandemic to motivate the need for improved respiratory treatments and mucosal vaccines. Stimulated by the COVID-19 pandemic, pulmonary aerosol drug delivery has seen a flourish of activity, building on the prior decades of innovation in particle engineering, inhaler device technologies, and clinical understanding. As such, the field has expanded into new directions and is working toward the efficient delivery of increasingly complex cargos to address a wider range of respiratory diseases. This review seeks to highlight recent innovations in approaches to personalize inhalation drug delivery, deliver complex cargos, and diversify the targets treated and prevented through pulmonary drug delivery. We aim to inform readers of the emerging efforts within the field and predict where future breakthroughs are expected to impact the treatment of respiratory diseases.

A Pediatric Upper Airway Library to Evaluate Interpatient Variability of In Silico Aerosol Deposition.

The airway of pediatric patients' changes through development, presenting a challenge in developing pediatric-specific aerosol therapeutics. Our work aims to quantify geometric variations and aerosol deposition patterns during upper airway development in subjects between 3.5 months-6.9 years old using a library of 24 pediatric models and 4 adult models. Computational fluid-particle dynamics was performed with varying particle size (0.1-10 µm) and flow rate (10-120 Lpm), which was rigorously analyzed to compare anatomical metrics (epiglottis angle (θE), glottis to cricoid ring ratio (GC-ratio), and pediatric to adult trachea ratio (H-ratio)), inhaler metrics (particle diameter, [Formula: see text], and flow rate, Q), and clinical metrics (age, sex, height, and weight) against aerosol deposition. Multivariate non-linear regression indicated that all metrics were all significantly influential on resultant deposition, with varying influence of individual parameters. Additionally, principal component analysis was employed, indicating that [Formula: see text], Q, GC-ratio, θE, and sex accounted for 90% of variability between subject-specific deposition. Notably, age was not statistically significant among pediatric subjects but was influential in comparing adult subjects. Inhaler design metrics were hugely influential, thus supporting the critical need for pediatric-specific inhalable approaches. This work not only improves accuracy in prescribing inhalable therapeutics and informing pediatric aerosol optimization, but also provides a framework for future aerosol studies to continue to strive toward optimized and personalized pediatric medicine.

Spatial aerosol deposition correlated to anatomic feature development in 6-year-old upper airway computational models.

The upper airways of children undergo developmental changes around age 6, yielding differences between adult and pediatric anatomies. These differences include the cricoid ring area shape, the location of narrowest constriction, and the angle of the epiglottis, all of which are expected to alter local fluid dynamic profiles and subsequent upper airway deposition and downstream aerosol delivery of inhaled therapeutics. In this work, we quantify "pediatric"-like and "adult"-like geometric and fluid dynamic features of two computed tomography (CT)-scan derived models of 6-year-old upper airways in healthy subjects and compare to an idealized model. The two CT-scan models had a mixture of "adult"- and "pediatric"-like anatomic features, with Subject B exhibiting more "pediatric"-like features than Subject A, while the idealized model exhibited entirely "adult"-like features. By computational fluid-particle dynamics, these differences in anatomical features yielded distinct local fluid profiles with altered aerosol deposition between models. Notably, the idealized model better predicted deposition characteristics of Subject A, the more "adult"-like model, including the relationship between the impaction parameter, dp2Q and the fraction of deposition across a range of flow rates and particle diameters, as well as deposition of an approximate pharmaceutical particle size distribution model. Our results with even this limited dataset suggest that there are key personalized metrics that are influenced by anatomical development, which should be considered when developing pediatric inhalable therapeutics. Quantifying anatomical development and correlating to aerosol deposition has the potential for high-throughput developmental characterization and informing desired aerosol characteristics for pediatric applications.

Scalable, process-oriented beam lattices: generation, characterization, and compensation for open cellular structures.

Additively manufactured lattices are emerging as promising candidates for structural, thermal, chemical, and biological applications. However, achieving a satisfactory prototype or final part with this level of complexity requires synthesis of disparate knowledge from the distinctly digital and physical processing stages. This work proposes an integrated framework for processing self-supporting, open lattice structures that do not require supports and facilitate material removal in post-processing steps. We describe a minimal yet comprehensive design strategy for generating uniform lattice structures with conformal open lattice skins for an arbitrary unit cell configuration. Using continuous liquid interface production (CLIP™) on a Carbon M1, printability is evaluated for five unique bending-dominated lattice structures at unit cell length scales from 0.5 - 3.5 mm and strut diameters ranging from 0.11 - 1.05 mm. Using a cubic lattice as a basis, we further examine dimensional fidelity with respect to 2D lattice void dimensions and part position, finding differences between length scales and within parts, due to physical processing artifacts. Finally, we demonstrate a functional grading strategy based on process control methods to compensate for dimensional deviations. Using an iterative approach based on a naïve process model, deviation of the planar strut radius in a cubic lattice was decreased by approximately 85% after two iterations. These insights and strategies can be readily applied to other structures, characterization techniques, and additive manufacturing processes, thereby improving the exchange of information between digital and physical processing and lowering the energy barriers to producing high-quality lattice parts.

Scalable 3D-printed lattices for pressure control in fluid applications.

Additive manufacturing affords precise control over geometries with high degrees of complexity and pre-defined structure. Lattices are one class of additive-only structures which have great potential in directing transport phenomena because they are highly ordered, scalable, and modular. However, a comprehensive description of how these structures scale and interact in heterogeneous systems is still undetermined. To advance this aim, we designed cubic and Kelvin lattices at two sub-5 mm length scales and compared published correlations to the experimental pressure gradient in pipes ranging from 12-52 mm diameter. We further investigated all combinations of the four lattices to evaluate segmented combinatorial behavior. The results suggest that a single correlation can describe pressure behavior for different lattice geometries and scales. Furthermore, combining lattice systems in series has a complex effect that is sensitive to part geometry. Together, these developments support the promise for tailored, modular lattice systems at laboratory scales and beyond.

Check the gap: Facemask performance and exhaled aerosol distributions around the wearer.

Current facemask research focuses on material characterization and efficiency; however, facemasks are often not tested such that aerosol distributions are evaluated from the gaps in the sides, bottom, and nose areas. Poor evaluation methods could lead to misinformation on optimal facemasks use; a high-throughput, reproducible method which illuminates the issue of fit influencing aerosol transmission is needed. To this end, we have created an in vitro model to quantify particle transmission by mimicking exhalation aerosols in a 3D printed face-nose-mouth replica via a nebulizer and quantifying particle counts using a hand-held particle counter. A sewn, sewn with pipe cleaner nose piece, and sewn with a coffee filter facemask were used to evaluate current common homemade sewn facemask designs, benchmarked against industry standard surgical, N95 respirator tightly fit, and N95 respirator loosely fit facemasks. All facemasks have significantly reduced particle counts in front of the facemask, but the side and top of the facemask showed increases in particle counts over the no facemask condition at that same position, suggesting that some proportion of aerosols are being redirected to these gaps. An altered size distribution of aerosols that escape at the vulnerable positions was observed; escaped particles have larger count median diameters, with a decreased ratio of smaller to larger particles, possibly due to hygroscopic growth or aggregation. Of the homemade sewn facemasks, the facemask with a coffee filter insert performed the best at reducing escaped aerosols, with increased efficiency also observed for sewn masks with a pipe cleaner nose piece. Importantly, there were minimal differences between facemasks at increasing distances, which supports that social distance is a critical element in reducing aerosol transmission. This work brings to light the importance of quantifying particle count in positions other than directly in front of the facemask and identifies areas of research to be explored.

Ultra-Fast Degradation of Chemical Warfare Agents Using MOF-Nanofiber Kebabs.

The threat associated with chemical warfare agents (CWAs) motivates the development of new materials to provide enhanced protection with a reduced burden. Metal-organic frame-works (MOFs) have recently been shown as highly effective catalysts for detoxifying CWAs, but challenges still remain for integrating MOFs into functional filter media and/or protective garments. Herein, we report a series of MOF-nanofiber kebab structures for fast degradation of CWAs. We found TiO2 coatings deposited via atomic layer deposition (ALD) onto polyamide-6 nanofibers enable the formation of conformal Zr-based MOF thin films including UiO-66, UiO-66-NH2 , and UiO-67. Cross-sectional TEM images show that these MOF crystals nucleate and grow directly on and around the nanofibers, with strong attachment to the substrates. These MOF-functionalized nanofibers exhibit excellent reactivity for detoxifying CWAs. The half-lives of a CWA simulant compound and nerve agent soman (GD) are as short as 7.3 min and 2.3 min, respectively. These results therefore provide the earliest report of MOF-nanofiber textile composites capable of ultra-fast degradation of CWAs.