Project

Back to overview

How does the 3-dimensional structure of the pulmonary acinus develop, regenerate, and change during breathing? What are the functional consequences for ventilation and particle deposition?

English title How does the 3-dimensional structure of the pulmonary acinus develop, regenerate, and change during breathing? What are the functional consequences for ventilation and particle deposition?
Applicant Schittny Johannes C.
Number 175953
Funding scheme Project funding (Div. I-III)
Research institution Institut für Anatomie Medizinische Fakultät Universität Bern
Institution of higher education University of Berne - BE
Main discipline Structural Research
Start/End 01.10.2017 - 30.09.2023
Approved amount 748'886.00
Show all

All Disciplines (3)

Discipline
Structural Research
Physiology : other topics
Embryology, Developmental Biology

Keywords (13)

X-ray tomography; alveolarization; pulmonary acinus; computer simulation; pneumonectomy; ventilation; three-dimensional imaging; pulmonary particle deposition; breathing; lung development; alpha8 intergrin; computational fluid dynamics; lung regeneration

Lay Summary (German)

Lead
Die menschliche Lunge enthält ca. 16‘000 funktionale Einheiten, in denen der Gasaustausch stattfindet. Diese sogenannten Acini werden durch die Bronchien und Bronchiolen mit Atemluft versorgt. Sie werden vor der Geburt gebildet. Ihr Volumen vergrössert sich auf mehr als das 10-fache von der Geburt bis zur erwachsenen Lunge. Wenig ist bis jetzt bekannt, wie sich die 3-dimensionale Struktur der Acini vergrössert, regeneriert und während der Atmung verändert. Mit diesem Forschungsgesuch möchten wir erstens diese Veränderungen der 3D-Strukturen der Acini untersuchen und zweitens ihre funktionellen Konsequenzen in Bezug auf die Atmung und die Partikeldeposition verstehen.
Lay summary

Inhalt und Ziel des Forschungsprojekts:

In der letzten Antragsperiode haben wir sowohl die Methode der hochauflösenden MikroCT-Aufnahmen von Lungen lebender oder gerade verstorbener Mäuse und Ratten, als auch die Werkzeuge zur Analyse der Acini der Lunge entwickelt. In der laufenden Antragsperiode möchten wir diese Methoden anwenden um die 3-dimensionale Struktur der Acini während der Lungenentwicklung und –reifung, der Regeneration und der Atmung zu untersuchen. Folgende Hypothesen wurden aufgestellt:

  • Während der Atmung zeigen die Acini eine unregelmässige Verformung, aber kein Schliessen und Öffnen der Lungenbläschen

  • Die Acini wachsen durch eine Verlängerung und Erweiterung der Luftwege ohne dass neue Luftwege gebildet werden und ohne dass sich die Zahl der Acini erhöht

  • Während der Regeneration nimmt die Grösse der Acini zu, aber ihre Anzahl bleibt unverändert

  • Die Vergrösserung der Acini verringert die Geschwindigkeit des Austausches der Atemluft

  • Die Partikeldeposition ist im Eingangsbereich der Acini am grössten. Dieser Bereich wirkt als Partikelfilter für die nachfolgenden Luftwege

 

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts:

Die pulmonale Partikeldeposition hat zwei Seiten: Umweltpartikel sind in der Regel toxisch und unerwünscht. In der Lunge applizierte Arzneimittel können dagegen eine neue Form der Therapie darstellen, da hiermit Arzneimittel, die sonst per Injektion appliziert werden müssen, sehr einfach als Spray zum Inhalieren gegeben werden können. Im vorliegenden Gesuch möchten wir den Mechanismus und die lokalen Konzentrationsunterschiede der Partikeldeposition näher untersuchen. Das letztere ist sehr wichtig, da nicht die mittlere, sondern die lokale Konzentration für die Toxizität und den Therapieerfolg entscheidend ist.

Direct link to Lay Summary Last update: 22.02.2018

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
Tenascin-C inactivation impacts lung structure and function beyond lung development
Gremlich Sandrine, Roth-Kleiner Matthias, Equey Lucile, Fytianos Kleanthis, Schittny Johannes C., Cremona Tiziana P. (2020), Tenascin-C inactivation impacts lung structure and function beyond lung development, in Scientific Reports, 10(1), 5118-5118.
Tenascin-C deficiency impairs alveolarization and microvascular maturation during postnatal lung development
Mund Sonja I., Schittny Johannes C. (2020), Tenascin-C deficiency impairs alveolarization and microvascular maturation during postnatal lung development, in Journal of Applied Physiology, 128(5), 1287-1298.
Pulmonary acini exhibit complex changes during postnatal rat lung development
Haberthür David, Yao Eveline, Barré Sébastien F, Cremona Tiziana P., Tschanz Stefan A., Schittny Johannes C. (2020), Pulmonary acini exhibit complex changes during postnatal rat lung development, in bioRxiv, ePub(ePub), 1-17.
Micrometer-resolution X-ray tomographic full-volume reconstruction of an intact post-mortem juvenile rat lung
Borisova Elena, Lovric Goran, Miettinen Arttu, Fardin Luca, Bayat Sam, Larsson Anders, Stampanoni Marco, Schittny Johannes C., Schlepütz Christian M. (2020), Micrometer-resolution X-ray tomographic full-volume reconstruction of an intact post-mortem juvenile rat lung, in Histochemistry and Cell Biology, ePub(ePub), 1-12.
Gestation and lactation exposure to nicotine induces transient postnatal changes in lung alveolar development
BlaskovicS., DonatiY., ZanettiF., Ruchonnet-MétraillerI., LemeilleS., CremonaT.P., SchittnyJ.C., Barazzone-ArgiroffoC. (2020), Gestation and lactation exposure to nicotine induces transient postnatal changes in lung alveolar development, in Am J Physiol Lung Cell Mol Physiol.
Tenascin-C expression controls the maturation of articular cartilage in mice
GruberB.L., MienaltowskiM.J., MacLeodJ.N., SchittnyJ.C., KasperS., FlückM. (2020), Tenascin-C expression controls the maturation of articular cartilage in mice, in BMC Res. Notes, 13(78).
Normative data for multiple breath washout outcomes in school-aged Caucasian children
Anagnostopoulou Pinelopi, Latzin Philipp, Jensen Renee, Stahl Mirjam, Harper Alana, Yammine Sophie, Usemann Jakob, Foong Rachel E., Spycher Ben, Hall Graham L., Singer Florian, Stanojevic Sanja, Mall Marcus, Ratjen Felix, Ramsey Kathryn A. (2019), Normative data for multiple breath washout outcomes in school-aged Caucasian children, in European Respiratory Journal, 1901302-1901302.
NRStitcher: non-rigid stitching of terapixel-scale volumetric images
Miettinen Arttu, Oikonomidis Ioannis Vogiatzis, Bonnin Anne, Stampanoni Marco (2019), NRStitcher: non-rigid stitching of terapixel-scale volumetric images, in Bioinformatics, 35(24), 5290-5297.
NRStitcher: non-rigid stitching of terapixel-scale volumetric images
Miettinen Arttu, Oikonomidis Ioannis Vogiatzis, Bonnin Anne, Stampanoni Marco (2019), NRStitcher: non-rigid stitching of terapixel-scale volumetric images, in Bioinformatics, 35(24), 5290-5297.
Efficacy and safety of the combination fluticasone propionate plus salmeterol in asthmatic preschoolers: An observational study
Hatziagorou Elpis, Kouroukli Eleana, Galogavrou Maria, Papanikolaou Dafni, Terzi Dr. Despoina, Anagnostopoulou Pinelopi, Kirvassilis Fotios, Panagiotakos Demosthenes B, Tsanakas John (2019), Efficacy and safety of the combination fluticasone propionate plus salmeterol in asthmatic preschoolers: An observational study, in Journal of Asthma, 56(6), 573-580.
An innovative lung model for multiple breath washout testing in health and disease
Kohler Lena, Singer Florian, Latzin Philipp, Obrist Dominik, Anagnostopoulou Pinelopi, Vomsattel Sarah, Kentgens Anne-Christiane, Guidi Marisa, Binggeli Severin (2019), An innovative lung model for multiple breath washout testing in health and disease, in Clinical Biomechanics, 66, 74-80.
Variability of Tidal Breathing Parameters in Preterm Infants and Associations with Respiratory Morbidity during Infancy: A Cohort Study
Usemann Jakob, Suter Andrea, Zannin Emanuela, Proietti Elena, Fouzas Sotirios, Schulzke Sven, Latzin Philipp, Frey Urs, Fuchs Oliver, Korten Insa, Anagnostopoulou Pinelopi, Gorlanova Olga, Frey Urs, Latzin Philipp, Proietti Elena, Usemann Jakob (2019), Variability of Tidal Breathing Parameters in Preterm Infants and Associations with Respiratory Morbidity during Infancy: A Cohort Study, in The Journal of Pediatrics, 205, 61-69.e1.
A multi-scale model of gas transport in the lung to study heterogeneous lung ventilation during the multiple-breath washout test
Hasler David, Anagnostopoulou Pinelopi, Nyilas Sylvia, Latzin Philipp, Schittny Johannes, Obrist Dominik (2019), A multi-scale model of gas transport in the lung to study heterogeneous lung ventilation during the multiple-breath washout test, in {PLOS} Computational Biology, 15(6), 1007079-1007079.
Respiratory rate in infants with cystic fibrosis throughout the first year of life and association with lung clearance index measured shortly after birth
Korten Insa, Kieninger Elisabeth, Yammine Sophie, Cangiano Giulia, Nyilas Sylvia, Anagnostopoulou Pinelopi, Singer Florian, Kuehni Claudia E., Regamey Nicolas, Frey Urs, Casaulta Carmen, Spycher Ben D., Latzin Philipp (2019), Respiratory rate in infants with cystic fibrosis throughout the first year of life and association with lung clearance index measured shortly after birth, in Journal of Cystic Fibrosis, 18(1), 118-126.
Dynamics of respiratory symptoms during infancy and associations with wheezing at school age
Usemann Jakob, Xu Binbin, Delgado-Eckert Edgar, Korten Insa, Anagnostopoulou Pinelopi, Gorlanova Olga, Kuehni Claudia, Röösli Martin, Latzin Philipp, Frey Urs (2018), Dynamics of respiratory symptoms during infancy and associations with wheezing at school age, in ERJ Open Research, 4(4), 00037-2018-00037-2018.
Comparison of different analysis algorithms to calculate multiple-breath washout outcomes
Anagnostopoulou Pinelopi, Kranz Nadja, Wolfensberger Jeremias, Guidi Marisa, Nyilas Sylvia, Koerner-Rettberg Cordula, Yammine Sophie, Singer Florian, Latzin Philipp (2018), Comparison of different analysis algorithms to calculate multiple-breath washout outcomes, in ERJ Open Research, 4(3), 00021-2017-00021-2017.
A modified CO2/O2 Guedel airway improves capnographic accuracy compared with a CO2/O2 nasal cannulaAn infant manikin study
Moll Jens, Anagnostopoulou Pinelopi, Frei Franz J., Erb Thomas O. (2018), A modified CO2/O2 Guedel airway improves capnographic accuracy compared with a CO2/O2 nasal cannulaAn infant manikin study, in European Journal of Anaesthesiology, 1-1.
Automated computer-assisted quantitative analysis of intact murine lungs at the alveolar scale.
LovricG., MoksoR., ArcaduF., Vogiatzis OikonomidiI., SchittnyJ.C., Roth-KleinerM., StampanoniM. (2017), Automated computer-assisted quantitative analysis of intact murine lungs at the alveolar scale., in PloS one, 12(9), e0183979.
Development of the lung.
SchittnyJ.C. (2017), Development of the lung., in Cell and tissue research, 367, 427-444.
Anatomy and development of the respiratory system
Anagnostopoulou Pinelopi, SchittnyJohannes C., Anatomy and development of the respiratory system, in Midulla F., Ebner E. (ed.), European Respiratory Society, Lausanne, 1.

Datasets

Micrometer-resolution X-ray tomographic imaging of a complete intact post mortem juvenile rat lung

Author Borisova, Elena; Lovric, Goran; Fardin, Luca; Bayat, Sam; Larsson, Anders; Stampanoni, Marco; Schittny, Johannes C.; Schlepütz, Christian
Publication date 18.03.2020
Persistent Identifier (PID) https://doi.org/10.16907/7eb141d3-11f1-47a6-9d0e-76f8832ed1b2
Repository PSI Public Data Repository
Abstract
In the associate article to these data sets, we present an X-ray tomographic imaging method that is well suited for pulmonary disease studies in animal models, to resolve the full pathway from gas intake to gas exchange. Current state-of-the-art synchrotron-based tomographic phase-contrast imaging methods allow for three-dimensional microscopic imaging data to be acquired non-destructively in scan times of the order of seconds with good soft tissue contrast. However, when studying multi-scale hierarchically structured objects, such as the mammalian lung, the overall sample size typically exceeds the field of view illuminated by the X-rays in a single scan, and the necessity for achieving a high spatial resolution conflicts with the need to image the whole sample. Several image-stitching and calibration techniques to achieve extended high-resolution fields of view have been reported, but those approaches tend to fail when imaging non-stable samples, thus precluding tomographic measurements of large biological samples, which are prone to degradation and motion during extended scan times. In this work, we demonstrate a full-volume three-dimensional reconstruction of an intact rat lung under immediate post mortem conditions and at an isotropic voxel size of (2.75 µm)^3. We present the methodology for collecting multiple local tomographies with 360 degree extended field of view scans followed by locally non-rigid volumetric stitching. Applied to the lung, it allows to resolve the entire pulmonary structure from the trachea down to the parenchyma in a single dataset. For related publication see https://link.springer.com/article/10.1007/s00418-020-01868-8

Collaboration

Group / person Country
Types of collaboration
Dr. Pinelopi Anagnostopoulou, Medical School, University of Cyprus, Nicosia, Cyprus Cyprus (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Dr. Otmar Schmidt/Helmholtz Zentrum München, German Res. Center for Environmental Health, ILBD+CPC Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Dr. med. Marcus A. Mall, Einstein-Professor, Charité - Universitätsmedizin Berlin Germany (Europe)
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
ATS International Conference 2020 Poster X-ray Tomographic In Situ Imaging Of An Entire Post Mortem Juvenile Rat Lung At Microscopical Resolution 15.05.2020 Philadelphia, United States of America Schittny Johannes C.; Borisova Elena; Lovric Goran;
Invited talk: Dr. Otmar Schmid, Helmholtz Zentrum München - German Research Center for Environmental Health, ILBD+CPC (canceled due to COVID-19 Individual talk How 3D-imaging changed the view of lung development and particle deposition 27.04.2020 Neuherberg bei München, Germany Schittny Johannes C.;
Invited talk: Dr. Pinelopi Anagnostopoulou, Medical School, University of Cyprus, Nicosia, Cyprus (canceled due to COVID-19) Individual talk How 3D-imaging changed the view of lung development and particle deposition 16.04.2020 Nicosia, Cyprus Schittny Johannes C.;
Third Aerosol Dosimetry Conference, UC Irvine, California Talk given at a conference Age-dependent Deposition Patterns and Quantitative Biokinetics of Inhaled20 nm Gold Nanoparticles in Rat Lungs 10.10.2019 Irvine, United States of America Schittny Johannes C.;
29th International Congress of the European-Respiratory-Society (ERS) Poster A multi-scale model of gas transport in the lung to study heterogeneous lung ventilation during the multiple-breath washout test 28.09.2019 Madrid, Spain Schittny Johannes C.; Anagnostopoulou Pinelopi;
The International Society for Aerosols in Medicine 22nd Congress Poster A Mathematical Model to Understand the Clearance of the Lung in Cystic Fibrosis 25.05.2019 Montreux, United States of America Schittny Johannes C.; Anagnostopoulou Pinelopi;
Invited talk: Prof. Dr. Connie Hsia, UT Southwestern Medical Center Individual talk How 3-dimensional Imaging Changes Our Understanding of Lung Development 19.05.2019 Dallas, TX, United States of America Lovric Goran; Anagnostopoulou Pinelopi; Vogiatzis-Oikonomidis Ioannis; Schittny Johannes C.;
ATS International Conference 2019 Poster A Postnatal Increase of the Fractal Dimension of the Pulmonary Rat Acini Indicates a Nonuniform Acinar Development and an Increase of Acinar Complexity 17.05.2019 Dallas, TX, United States of America Schittny Johannes C.; Vogiatzis-Oikonomidis Ioannis;
ATS International Conference 2019 Poster A Multi-scale Lung Model To Study Heterogeneous Ventilation During The Multiple-Breath Washout Test 17.05.2019 Dallas, TX, United States of America Anagnostopoulou Pinelopi; Schittny Johannes C.;
Joint annual meeting Swiss Society of Paediatrics, Swiss Society of Paediatric Surgery and Swiss Society of Child and Adolescent Psychiatry and Psychotherapy Poster Respiratory rate in infants with cystic fibrosis throughout the first year of life and association with lung clearance index measured shortly after birth 24.05.2018 Lausanne, Switzerland Anagnostopoulou Pinelopi;
The International Society for Aerosols in Medicine - 2018 SYMPOSIUM Poster Age‐dependent Deposition Patterns and Quantitative Biokinetics of Inhaled 20nm Gold Nanoparticles in Rat Lungs 19.05.2018 San Diego, United States of America Schittny Johannes C.;
ATS International Conference 2018 Talk given at a conference Age-dependent Deposition Patterns and Quantitative Biokinetics of Inhaled 20nm Gold Nanoparticles in Rat Lungs 18.05.2018 San Diego, CA, United States of America Schittny Johannes C.;
ATS International Conference 2018 Poster Spatial distribution of ventilator induced lung injury. An in-vivo synchrotron phase-contrast microscopy study in BALB/c mice 18.05.2018 San Diego, CA, United States of America Schittny Johannes C.; Lovric Goran; Vogiatzis-Oikonomidis Ioannis;
ATS International Conference 2018 Poster Surface Charge Effects on Inhaled Engineered Nanomaterial Delivery and Retention in the Respiratory Tract of Mice 18.05.2018 San Diego, CA, United States of America Schittny Johannes C.;
ISAM symposium Updates and Controversies Related to Inhaled Aerosols Poster Age-Dependent Deposition Patterns and Quantitative Biokinetics of Inhaled 20nm Gold Nanoparticles in Rat Lungs 18.05.2018 San Diego, CA, United States of America Schittny Johannes C.;
ATs International Conference 2018 Poster An increase in the fractal dimension of the pulmonary acini is an indication for their non-uniform development 18.05.2018 San Diego, United States of America Vogiatzis-Oikonomidis Ioannis; Schittny Johannes C.; Lovric Goran;
28th International Congress of the European-Respiratory-Society (ERS) Poster Normative data for the new setup of the SF6 multiple-breath washout in unsedated infants 15.05.2018 Paris, France Anagnostopoulou Pinelopi;
International Joint Meeting of the German and Swiss Societies for Matrix Biology, Stuttgart Talk given at a conference Tenascin C Knockout Mice Have an Altered Lung Function at Newborn and Adult Age 22.03.2018 Stuttgart, Germany Schittny Johannes C.;
PULMOSENS Meeting, Schloss Reisensburg, Universität Ulm Talk given at a conference How 3-dimensional Imaging Changes Our Understanding of Lung Development 04.10.2017 Reisensburg, Germany Schittny Johannes C.;


Self-organised

Title Date Place

Knowledge transfer events



Self-organised

Title Date Place
2. Supervision of the matura thesis of Taha El Moudden (Gymnase français de Bienne) 08.06.2019 Bern, Switzerland

Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Excursion of high school students (Gymnasium NMS-Bern) to the Paul-Scherrer-Institut German-speaking Switzerland 2020
Other activities Expert of the Swiss Universities at the matura examinations of the major biology and chemistry German-speaking Switzerland 2020
Talks/events/exhibitions Supervision of the matura thesis of Taha El Moudden (Gymnase français de Bienne) Western Switzerland 2019

Associated projects

Number Title Start Funding scheme
150823 Serial block face SEM 01.12.2013 R'EQUIP
113155 High resolution micro-computer tomograph skyscan 1172 micro-CT system 01.01.2007 R'EQUIP
153468 How does the 3-dimensional structure of the pulmonary acinus develop and regenerate and which functional consequences does it have? 01.09.2014 Project funding (Div. I-III)
125397 How is the 3D-structure of the gas-exchange area altered during lung development and how is this influenced by the extracellular matrix? 01.10.2009 Project funding (Div. I-III)
135550 In-vivo study of lung physiology with sub-second X-ray tomographic microscopy 01.05.2011 Interdisciplinary projects
183297 A modular sample manipulator for dynamic tomography under real conditions 01.01.2019 R'EQUIP

Abstract

Background. The bronchioalveolar duct junction (BADJ) demarks the entrance to the acini/ventilatory units. It stays constant after it is once formed. During alveolarization the mean acinar volume increases ~10 fold. These changes have a strong influence on acinar ventilation and particle deposition. Because high-resolution imaging and analysis tools are still limited, [1] the 3-dimensional (3D) structure of the acini and it development, [2] the alterations taking place during breathing at alveolar and acinar level, and [3] the sites of acinar particle deposition are by far not well understood. Aim. We developed unique protocols [1] for pulmonary synchrotron radiation X-ray tomographic microscopy (SRXTM) of live and post mortem animals and [2] for an automated analysis of the acinar airways. We would like to use these tools [1] to elucidate how the 3D structure of the pulmonary acinus develops, regenerates, and changes during breathing, [2] to estimate the functional consequences of the observed alterations, and [3] to generate the first high-resolution in vivo 3D maps of acinar particle depositions for the still missing verification of the in silico simulations of acinar particle deposition. Hypothesis. [1] During breathing the alveoli and alveolar ducts show an irregular extension and hysteresis, but no significant alveolar opening and closure. [2] The acini grow by elongation and widening of their airways without increasing the number of generations. The remaining space between the airways is “filled” with clusters of alveoli sharing one common entrance. [3] Compensatory acinar growth e.g. after pneumonectomy results in abnormally large acini without an increase of their number. [4] The increasing acinar complexity during development and regeneration reduces gas washout. [5] The deposition of inhaled particles is highest in the proximal parts of the acini. These parts serve as a filter for the distal regions. Inside the alveoli, local “hotspots” of particle deposition exist. Experimental design (numbered as the hypotheses). [1-3] Live and post mortem mice and rats during ventilation, mouse lungs after pneumonectomy, and lungs of a8 integrin -/- mice (model for enlarged acini), as well as the required controls will be imaged by SRXTM at the beamline TOMCAT at the Swiss Light Source (voxel ~1 µm, pressures of 2-25 cm H2O during breath hold or continues ventilation). Compliance (deltaV/deltaP), thickness maps (distribution of airspaces), vector displacement field, surface curvature, and the skeleton of individual acini will be calculated to characterize the alteration of the acinar 3D geometry during development, regeneration, and breathing. [4] Our in silico simulation of the LCI (lung clearance index after multiple breath gas washout) will be further developed to simulate the effects of structural alteration of the acini as obtained under 1-3. [5] Mice and rats will be exposed to gold, barium sulfate, tungsten oxide, and europium-doped gadolinium oxide particles (0.03-1 µm) and their excised lungs will be imaged by SRXTM. Our analytical tools (see above) will be used to draw a map of particle deposition in acini and alveoli. In addition, Prof. Dr. Josué Sznitman (Technion, Haifa, Israel) will apply his in silico tools for the simulation of acinar ventilation and particle deposition to our scanned lung structures in order to validate his tools based on our structural 3D datasets of exposed animals and our quantitative data of particle deposition. Expected value of the proposed project. In mammalian lungs gas-washout is a measure for acinar ventilation and itself very much dependent on the 3D geometry of the acini. An in-depth understanding of this relationship has a very high potential to improve clinical diagnosis (e.g. the LCI) and therapies. Furthermore, a detailed knowledge of the anisotropic deformations of the acinar airway and alveoli represents a basis for understanding ventilation induced lung injury. Pulmonary, in particular acinar, particle deposition has a huge impact on the heath - be it as toxic environmental or as beneficial therapeutical particles. In both cases the local concentration represents the predominant factor for the effect. Besides the better understanding of toxicological effects, the relation between the acinar geometry and pulmonary particle deposition will foster [1] the development of new formulations of drugs for a pulmonary application. These formulations are revolutionizing therapies by opening up a very promising route of a parenteral systemic application. [2] A large body of in silico simulations and even in vitro true-scale models of acinar ventilation and particle deposition exists. However, the verification by in vivo experiments is still lacking and we aim to deliver the necessary data for this verification.
-