Methods for dynamic synchrotron X-ray respiratory imaging in live animals

Morgan, Kaye S.; Parsons, David; Cmielewski, Patricia; McCarron, Alexandra; Gradl, Regine; Farrow, Nigel; Siu, Karen Kit Wan; Takeuchi, Akihisa; Suzuki, Yoshio; Uesugi, Kentaro; Uesugi, Masayuki; Yagi, Naoto; Hall, Chris; Klein, Mitzi; Maksimenko, Anton; Stevenson, Andrew W.; Häusermann, Daniel M.; Dierolf, Martin; Pfeiffer, Franz; Donnelley, Martin

doi:10.1107/s1600577519014863

Cited by 30 publications

(30 citation statements)

References 67 publications

(59 reference statements)

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“…It has been reported that addition of lung surfactant could facilitate pulmonary delivery both in terms of speed of dispersion and uniformity of distribution as surfactant is known to reduce surface tension of the applied bulk liquid . In this case, the mouse was intubated for syringe‐assisted slow‐instillation, but breathing spontaneously and in vivo X‐ray image acquisition (100 ms per breath) near the end of inhalation was triggered by monitoring the motion of the chest with an optical displacement sensor . In vivo PB‐PCXI revealed that delivery of 4 µL of iodine‐polystyrene NP liquid resulted in highly localized, small puddles of liquid into either the right or left lung, but not to both sides ( Figure a and Video S5, Supporting Information).…”

Section: Resultsmentioning

confidence: 99%

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Multimodal Precision Imaging of Pulmonary Nanoparticle Delivery in Mice: Dynamics of Application, Spatial Distribution, and Dosimetry

Yang

Gradl

Dierolf

et al. 2019

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Targeted delivery of nanomedicine/nanoparticles (NM/NPs) to the site of disease (e.g., the tumor or lung injury) is of vital importance for improved therapeutic efficacy. Multimodal imaging platforms provide powerful tools for monitoring delivery and tissue distribution of drugs and NM/NPs. This study introduces a preclinical imaging platform combining X-ray (two modes) and fluorescence imaging (three modes) techniques for timeresolved in vivo and spatially resolved ex vivo visualization of mouse lungs during pulmonary NP delivery. Liquid mixtures of iodine (contrast agent for X-ray) and/or (nano)particles (X-ray absorbing and/or fluorescent) are delivered to different regions of the lung via intratracheal instillation, nasal aspiration, and ventilator-assisted aerosol inhalation. It is demonstrated that in vivo propagation-based phase-contrast X-ray imaging elucidates the dynamic process of pulmonary NP delivery, while ex vivo fluorescence imaging (e.g., tissue-cleared light sheet fluorescence microscopy) reveals the quantitative 3D drug/particle distribution throughout the entire lung with cellular resolution. The novel and complementary information from this imaging platform unveils the dynamics and mechanisms of pulmonary NM/NP delivery and deposition for each of the delivery routes, which provides guidance on optimizing pulmonary delivery techniques and noveldesigned NM for targeting and efficacy.The ORCID identification number(s) for the author(s) of this article can be found under https://doi.

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Section: Resultsmentioning

confidence: 99%

“…As the X‐ray beam had a fixed horizontal orientation, mice needed to be positioned in a head‐high position. Therefore, mice were placed in a specially designed mouse holder on an x–y–z rotation stage to facilitate positioning in the X‐ray beam …”

Section: Methodsmentioning

confidence: 99%

Multimodal Precision Imaging of Pulmonary Nanoparticle Delivery in Mice: Dynamics of Application, Spatial Distribution, and Dosimetry

Yang

Gradl

Dierolf

et al. 2019

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“…As such, we are unable to offer any insights into the intra-breath alveolar and acinar dynamics, which could provide important insights into, for example, how the elastance of an individual alveolus is altered by VILI. Phase contrast synchrotron computed tomography offers a pathway to analyze alveolar dynamics in future studies ( Chang et al, 2015 ; Morgan et al, 2020 ). Another limitation is that the high inspiratory pressures and zero PEEP used to generate VILI in the current study are far outside clinical guidelines for safe ventilation.…”

Section: Discussionmentioning

confidence: 99%

Three Alveolar Phenotypes Govern Lung Function in Murine Ventilator-Induced Lung Injury

et al. 2020

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Mechanical ventilation is an essential lifesaving therapy in acute respiratory distress syndrome (ARDS) that may cause ventilator-induced lung injury (VILI) through a positive feedback between altered alveolar mechanics, edema, surfactant inactivation, and injury. Although the biophysical forces that cause VILI are well documented, a knowledge gap remains in the quantitative link between altered parenchymal structure (namely alveolar derecruitment and flooding), pulmonary function, and VILI. This information is essential to developing diagnostic criteria and ventilation strategies to reduce VILI and improve ARDS survival. To address this unmet need, we mechanically ventilated mice to cause VILI. Lung structure was measured at three air inflation pressures using design-based stereology, and the mechanical function of the pulmonary system was measured with the forced oscillation technique. Assessment of the pulmonary surfactant included total surfactant, distribution of phospholipid aggregates, and surface tension lowering activity. VILI-induced changes in the surfactant included reduced surface tension lowering activity in the typically functional fraction of large phospholipid aggregates and a significant increase in the pool of surface-inactive small phospholipid aggregates. The dominant alterations in lung structure at low airway pressures were alveolar collapse and flooding. At higher airway pressures, alveolar collapse was mitigated and the flooded alveoli remained filled with proteinaceous edema. The loss of ventilated alveoli resulted in decreased alveolar gas volume and gas-exchange surface area. These data characterize three alveolar phenotypes in murine VILI: flooded and non-recruitable alveoli, unstable alveoli that derecruit at airway pressures below 5 cmH 2 O, and alveoli with relatively normal structure and function. The fraction of alveoli with each phenotype is reflected in the proportional changes in pulmonary system elastance at positive end expiratory pressures of 0, 3, and 6 cmH 2 O.

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“…meter for the diagnosis of emphysema in a pre-clinical study with ex vivo mice (Schleede et al, 2012b). A detailed overview over the different methods for dynamic respiratory X-ray imaging with living animals has been given by Morgan et al (2020). As mentioned earlier, (differential) phase-contrast imaging provides improved soft-tissue contrast.…”

Section: Grating-based Phase-contrast Imagingmentioning

confidence: 99%

The versatile X-ray beamline of the Munich Compact Light Source: design, instrumentation and applications

et al. 2020

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Inverse Compton scattering provides means to generate low-divergence partially coherent quasi-monochromatic, i.e. synchrotron-like, X-ray radiation on a laboratory scale. This enables the transfer of synchrotron techniques into university or industrial environments. Here, the Munich Compact Light Source is presented, which is such a compact synchrotron radiation facility based on an inverse Compton X-ray source (ICS). The recent improvements of the ICS are reported first and then the various experimental techniques which are most suited to the ICS installed at the Technical University of Munich are reviewed. For the latter, a multipurpose X-ray application beamline with two end-stations was designed. The beamline's design and geometry are presented in detail including the different set-ups as well as the available detector options. Application examples of the classes of experiments that can be performed are summarized afterwards. Among them are dynamic in vivo respiratory imaging, propagation-based phase-contrast imaging, grating-based phase-contrast imaging, X-ray microtomography, K-edge subtraction imaging and X-ray spectroscopy. Finally, plans to upgrade the beamline in order to enhance its capabilities are discussed.

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Methods for dynamic synchrotron X-ray respiratory imaging in live animals

Cited by 30 publications

References 67 publications

Multimodal Precision Imaging of Pulmonary Nanoparticle Delivery in Mice: Dynamics of Application, Spatial Distribution, and Dosimetry

Multimodal Precision Imaging of Pulmonary Nanoparticle Delivery in Mice: Dynamics of Application, Spatial Distribution, and Dosimetry

Three Alveolar Phenotypes Govern Lung Function in Murine Ventilator-Induced Lung Injury

The versatile X-ray beamline of the Munich Compact Light Source: design, instrumentation and applications

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