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Unravelling respiratory microflows in silico and in vitro: novel paths for targeted pulmonary delivery in infants and young children

Periodic Reporting for period 1 - RespMicroFlows (Unravelling respiratory microflows in silico and in vitro: novel paths for targeted pulmonary delivery in infants and young children)

Reporting period: 2016-06-01 to 2017-11-30

"Fundamental research on respiratory transport phenomena, and in particular approaches for pulmonary drug delivery, are overwhelmingly focused on efforts conducted in adults. Results are then typically translated (or scaled down) and adopted to children. Yet, children are not miniature adults: their distinct and developing lung structures and heterogeneous ventilation patterns set them aside from their parents. Whether concerned with inhalation aerosol therapies for topical delivery (e.g. asthma) or systemic delivery (e.g. vaccination), current methods and strategies for delivery face ongoing challenges with typically low yields in achieving optimal delivery of therapeutics (i.e. low deposition rates). Such delivery challenges are also true for liquid-based therapies such as surfactant replacement therapy (SRT) in treating pulmonary conditions of the newborn (e.g. infant respiratory distress syndrome).

To this day, the deposition of inhaled pharmaceutics in young children remains alarmingly low. While parents and the broader public may not be fully aware, the deposition efficiency of inhaled drugs in kids is typically less than 10% for a given dose. In particular, for diseases that require targeting deep alveolated airways (e.g. cystic fibrosis), lung deposition is further reduced to levels below 5%. In turn, low deposition efficiencies of inhaled aerosols often require treatments based on ""flooding"" the lungs with drugs to achieve sufficient drug deposition, and thus carrying the risk of local side effects including inflammation due to deposition “hot spots” and possible systemic side effects as a result of chronic drug therapy. In parallel to inhalation aerosols, liquid therapies are commonly instilled in premature babies suffering from infant respiratory distress syndrome (IRDS). Premature births (about 13 million births/year worldwide) contribute to >25% of global neonatal deaths and are often accompanied by a surfactant deficiency. Surfactant replacement therapy is the foremost strategy used to treat IRDS by instilling endotracheally a surfactant-laden bolus in the neonatal lungs. In many instances, however, the bolus has to be administered more than once to ensure reaching alveoli. Since data are frequently limited, the optimal method for surfactant delivery has yet to be proven.

RespMicroFlows sets out to radically revisit the challenges of pulmonary drug delivery in babies and young children. By developing advanced in silico numerical simulations together with in vitro platforms mimicking the respiratory airway environment, our efforts will not only deliver a gateway to reliably assess the outcomes of inhaling aerosols and predict deposition patterns in young populations, but furthermore we will unravel the fundamentals of liquid bolus transport to achieve optimal surfactant delivery strategies in premature neonates. By recreating cellular environments that capture underlying physiological functions, our advanced organ-on-chips will deliver both at true scale and in real time the first robust and reliable in vitro screening platforms of exogenous therapeutic materials in the context of inhaled aerosols and surfactant-laden installations. Combining advanced engineering-driven flow visualization solutions with strong foundations in transport phenomena, fluid dynamics and respiratory physiology, RespMicroFlows' ambitions are entrenched in delivering new paradigms in drug delivery"
We have achieved significant and exciting progress during this first reporting period, with efforts reaching across all Pillars (I through III) of the research project and tackling specific Aims of the project. These have principally covered in silico pulmonary flow and aerosol transport models (Pillar I, Aim 1), in vitro microfluidic airway models (Pillar I & II) and capillary blood models (Pillar II, Aim 4) as well as approaches for therapeutic assessments (Pillar III, Aim 5). In addition, our dissemination activities include the publication of an overview article on the project goals (EU Research, Spring 2017). Our main achievements so far are summarized through the following publications:

Journal Publications:
- Bauer K, Nof E and Sznitman J. Revisiting high-frequency oscillatory ventilation in vitro and in silico in neonatal conductive airways. Clinical Biomechanics, in press.
- Hofemeier P, Koshiyama K, Wada S and Sznitman J. One (sub-)acinus for all: Fate of inhaled aerosols in heterogeneous pulmonary acinar structures. European Journal of Pharmaceutical Sciences, in press.
- Fishler R, Verhoeven F, de Kruijf W and Sznitman J. Particle sizing of pharmaceutical aerosols via direct imaging of particle settling velocities. European Journal of Pharmaceutical Sciences, in press.
- Shachar-Berman L, Ostrovski Y, Kassinos SC and Sznitman J. Transport of ellipsoid fibers in oscillatory shear flows: implications for aerosol deposition in deep airways. European Journal of Pharmaceutical Sciences, in press.
- Stauber H, Waisman D, Korin N and Sznitman J. Red blood cell (RBC) suspensions in confined microflows: Pressure-flow relationship. Medical Engineering & Physics 48: 49-54, 2017.
- Fishler R, Sznitman J. Novel aerodynamic sizing method using image-based analysis of settling velocities. Inhalation 11: 21-25, 2017.
- Stauber H, Waisman D, Korin N and Sznitman J. Red blood cell dynamics in microfluidic networks of pulmonary alveolar capillaries, Biomicrofluidics 11: 014103, 2017.
- Fishler R, Ostrovski Y, Lu C-Y, and Sznitman J. Streamline crossing: an essential mechanism for aerosol dispersion in the pulmonary acinus, Journal of Biomechanics, 50: 222-227, 2017 .
- Hofemeier P and Sznitman J. The role of anisotropic expansion for pulmonary acinar deposition. Journal of Biomechanics 49: 3543-3548, 2016.
- Ostrovski Y, Hofemeier P and Sznitman J. Augmenting Regional and Targeted Delivery in the Pulmonary Acinus using Magnetic Particles, International Journal of Nanomedicine 11: 3385-3395, 2016.

Conference Proceedings:
- Fishler R, Sznitman J. Acini-on-Chip: Novel In Vitro Assessment of Particle Dynamics and Deposition in the Deep Lungs. RDD Europe 2017. Volume 1: 119-128, 2017.
- Fishler R, and Sznitman J. Computer Vision-based Aerodynamic Particle Sizing: A Rapid Method for Real-time Characterization of Inhaled Aerosols. RDD Europe 2017. Volume 2: 305-308, 2017.

The work was disseminated at various conferences and workshops, both by the PI as well as by members of the ERC team:

Invited Talks (PI):
- Sznitman J. Systemic drug delivery via the lungs: Can we do better? International Drug Discovery Science & Technology. Osaka, Japan, July 2017.
- Sznitman J. Acini-on-Chip: Novel in vitro assessments of particle dynamics and deposition in the deep lungs. Respiratory Drug Delivery Europe 2017. Nice, France, April 2017 (Podium Presentation).
- Sznitman J. Paradigms of targeted aerosol delivery in the deep lungs: lessons from in vitro and in silico studies. RMIT Enabling Capability Platforms Workshop on Inhaled Therapeutics for Treating Lung & Neurodegenerative Diseases. Melbourne, Australia, November 2016.
- Sznitman J. Unraveling the fate of inhaled aerosols in the pulmonary depths in silico and in vitro. Workshop on Pulmonary Drug Delivery (COST Action 1404 “SimInhale”). Prague, Czech Republic, October 2016.

Conference Presentations:
- Ostrovski Y and Sznitman J. Targeted delivery in upper airways using inhaled magnetic partic
Our progress over the first 18 months has already delivered new paradigms in both the tools developed and phenomena thereby uncovered pertaining to respiratory transport phenomena. This includes both in silico computational fluid dynamics (CFD) models for predicting inhaled aerosol deposition in the acinar depths (e.g. Hofemeier et a. Eur. J. Pharm Sci. in press) as well as biomimetic in vitro microfluidic pulmonary airway (Fishler et al. J. Biomech. 2017) and blood capillary models (Stauber et al. Biomicrofluidics 2017). Our efforts have in parallel delivered new state-of-the-art strategies for novel therapeutic aerosol delivery methods (Ostrovski et al. Int. J. Nanomed. 2016) as well as novel in vitro platforms for assessments of neonatal ventilation strategies (Bauer et al. Clin. Biomech. in press).

By the end of the project our efforts are anticipated to provide not only an arsenal of in vitro and in silico tools for pulmonary therapeutic delivery assessments but also devising proof-of-concept (targeted) delivery solutions.
3D printed neonatal upper airway model (Bauer et al., Clinical Biomechanics, in press)
Aerodynamic particle sizer of pharmaceutical aerosols (Fishler et al., Eur. J. Pharm. Sci. 2017)
Computational models of heterogeneous acinar structures (Hofemeier et al., Eur. J. Pharm. Sci. 2017)
Transport of ellipsoid particles in model airways (Shachar-Berman et al., Eur. J. Pharm. Sci. 2017)
Lung-on-chip model for aerosol deposition assays (Fishler et al., Journal of Biomechanics 2017)
Red blood cells flowing in microfluidic alveolar capillary models (Stauber et al. Biomicrofl 2017)