Architecture of the Human Lung

Weibel, Ewald R.; Gómez, Domingo

doi:10.1126/science.137.3530.577

Cited by 405 publications

(200 citation statements)

References 5 publications

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“…The complex hierarchical structures and flow patterns in the rat airways affect the distribution of liquid film (23,26) in a way not fully accounted for by our model. The effects of airway bifurcations on plug transport have not been considered, and it was assumed that liquid plugs split evenly at the airway branches.…”

Section: Discussionmentioning

confidence: 99%

“…Pulmonary airway model for liquid delivery. The pulmonary airways can be classified into the proximal (G 0 -G 15 ) and the distal (G 16 -G 23+ ), depending on their distance from the trachea, where G N is the Nth airway generation (23)(24)(25). The proximal airways can be further divided into large (G 0 -G 5 ) and small (G 6 -G 15 ) airways, based on diameter.…”

Section: Resultsmentioning

confidence: 99%

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Targeted delivery of liquid microvolumes into the lung

Kim

O’Neill

Dorrello

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The ability to deliver drugs to specific sites in the lung could radically improve therapeutic outcomes of a variety of lung diseases, including cystic fibrosis, severe bronchopneumonia, chronic obstructive pulmonary disease, and lung cancer. Using conventional methods for pulmonary drug administration, precise, localized delivery of exact doses of drugs to target regions remains challenging. Here we describe a more controlled delivery of soluble reagents (e.g., drugs, enzymes, and radionuclides) in microvolume liquid plugs to targeted branches of the pulmonary airway tree: upper airways, small airways (bronchioles), or the most distal alveoli. In this approach, a soluble liquid plug of very small volume (<1 mL) is instilled into the upper airways, and with programmed air ventilation of the lungs, the plug is pushed into a specific desired (more distal) airway to achieve deposition of liquid film onto the lung epithelium. The plug volume and ventilation conditions were determined by mathematical modeling of plug transport in a tubular geometry, and targeted liquid film deposition was demonstrated in rat lungs by three different in vivo imaging modalities. The experimental and modeling data suggest that instillation of microvolumes of liquid into a ventilated pulmonary airway could be an effective strategy to deliver exact doses of drugs to targeted pathologic regions of the lung, especially those inaccessible by bronchoscopy, to increase in situ efficacy of the drug and minimize systemic side effects.pulmonary drug delivery | lung disease | liquid instillation | lung airway | alveoli E ffective treatment strategies for lung diseases such as cystic fibrosis, tuberculosis, bronchopneumonia, and lung cancer would involve a small, highly concentrated dose of drug delivered directly to the pathologic site (1, 2). Unfortunately, delivery of a precise drug dose to specific sites in the lung is challenging using conventional systemic drug administration methods, resulting in inefficient treatments for many lung diseases (3, 4). For example, orally administered drugs often require high doses to achieve therapeutic effects due to first-pass metabolism, which in turn leads to systemic side effects (5). Although drugs administered i.v. can avoid first-pass metabolism, they can still incur a range of side effects (6).On the other hand, inhalation of aerosolized drugs has the advantage of noninvasively bringing a drug locally into the lung, and so it has been a first-line treatment option for many lung diseases in the outpatient setting (7,8). In particular, dry powder inhalers can allow for local delivery of drugs in specific lung regions (9). Because properties of powders such as particle size, density, and cohesiveness strongly affect particle transport behavior, dry powders should be prepared with appropriate properties conducive to delivery into specific locations in the structurally complex pulmonary airway tree (10).Alternatively, microvolumes of a liquid plug containing the drug could be instilled into the lung using ...

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Section: Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Targeted delivery of liquid microvolumes into the lung

Kim

O’Neill

Dorrello

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…It follows that the color interface is enormously stretched by the end of the inspiration, entering multiple airway pathways where about 2 23 distal acinar ducts (for human lungs; ref. 34) are connected to a single trachea sampling millions of alveolar spaces. At this point, however, little folding of the interface has taken place yet.…”

Section: Discussionmentioning

confidence: 99%

Chaotic mixing deep in the lung

Tsuda

Rogers

Hydon

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

114

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Our current understanding of the transport and deposition of aerosols (viruses, bacteria, air pollutants, aerosolized drugs) deep in the lung has been grounded in dispersive theories based on untested assumptions about the nature of acinar airflow fields. Traditionally, these have been taken to be simple and kinematically reversible. In this article, we apply the recently discovered fluid mechanical phenomenon of irreversible low-Reynolds number flow to the lung. We demonstrate, through flow visualization studies in rhythmically ventilated rat lungs, that such a foundation is false, and that chaotic mixing may be key to aerosol transport. We found substantial alveolar flow irreversibility with stretched and folded fractal patterns, which lead to a sudden increase in mixing. These findings support our theory that chaotic alveolar flow-characterized by stagnation saddle points associated with alveolar vortices-governs gas kinematics in the lung periphery, and hence the transport, mixing, and ultimately the deposition of fine aerosols. This mechanism calls for a rethinking of the relationship of exposure and deposition of fine inhaled particles.P athogenic aerosols play a major role in causing or exacerbating many pulmonary diseases such as lung cancer, bronchitis, emphysema, and asthma (1-4) and in spreading infectious diseases such as influenza, anthrax, and tuberculosis (5-8). The long-term effects of particulate air pollution on public health are striking; they have been shown to be equivalent to a shortening of life expectancy of approximately 2 years in the United States (9, 10). The magnitude of this effect is comparable to the deaths caused by all cancers (11). Fine particles-less than a few micrometers in diameter-are of great concern because they can penetrate deep into the pulmonary acinus (i.e., the gas exchange region of the lung). The critical factor that determines the fate of inhaled fine particles-whether deposited deep in the lung or exhaled in the next breath-is the kinematic interaction of inhaled and residual alveolar gas, but the underlying mechanism of this interaction is still not well understood.Because gas flow in the alveolar region occurs at very low Reynolds number (12) and the wall motion of the lung during breathing is essentially reversible (13-16), it has long been assumed that flow patterns deep in the lung are well described as a kinematically reversible Stokes flow (17-21). This means that, apart from the effects of molecular diffusion, a fluid ''particle'' that is transported by Stokes flow returns [by reversing the flow (22)] to its original position at the completion of one breathing cycle. This assumption implies that there is negligible flow-induced mixing between inhaled particles and the alveolar residual gas (17-21) and consequently little deposition of fine particles (18, 21). Experimental studies, however, consistently demonstrate appreciable aerosol mixing (23, 24) and deposition (25) deep in the lung, which cannot be accounted for by any known mechanism such as inerti...

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“…respiratory tract is based on impaction and sedimentation probability equations for single particles. They are derived for simplified situations [130] and make use of standardized lung models, for instance, as defined by Findeisen or Weibel [131]. Although such computations teach about the effects of particle size and velocity on drug deposition in the lungs, they bear a significant degree of uncertainty for drug deposition in patients, as diseased lungs may deviate considerably from the standardized models (and conditions) used for the computations.…”

Section: Dpi Design and Pulmonary Drug Deposition And Distributionmentioning

confidence: 99%

Dry powder inhalation: past, present and future

Boer

Hagedoorn

Hoppentocht

et al. 2016

Expert Opinion on Drug Delivery

226

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Introduction: Early dry powder inhalers (DPIs) were designed for low drug doses in asthma and COPD therapy. Nearly all concepts contained carrier-based formulations and lacked efficient dispersion principles. Therefore, particle engineering and powder processing are increasingly applied to achieve acceptable lung deposition with these poorly designed inhalers. Areas covered: The consequences of the choices made for early DPI development with respect of efficacy, production costs and safety and the tremendous amount of energy put into understanding and controlling the dispersion performance of adhesive mixtures are discussed. Also newly developed particle manufacturing and powder formulation processes are presented as well as the challenges, objectives, and new tools available for future DPI design. Expert opinion: Improved inhaler design is desired to make DPIs for future applications cost-effective and safe. With an increasing interest in high dose drug delivery, vaccination and systemic delivery via the lungs, innovative formulation technologies alone may not be sufficient. Safety is served by increasing patient adherence to the therapy, minimizing the use of unnecessary excipients and designing simple and self-intuitive inhalers, which give good feedback to the patient about the inhalation maneuver. For some applications, like vaccination and delivery of hygroscopic formulations, disposable inhalers may be preferred. ARTICLE HISTORY

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Architecture of the Human Lung

Cited by 405 publications

References 5 publications

Targeted delivery of liquid microvolumes into the lung

Targeted delivery of liquid microvolumes into the lung

Chaotic mixing deep in the lung

Dry powder inhalation: past, present and future

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