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Madeleine Petersson-Sjögren,1,2 Jonas Jakobsson,3 H Laura Aaltonen,4,5 Hanna Nicklasson,6,7 Jenny Rissler,1,2,8 Gunnar Engström,9 Per Wollmer,6 Jakob Löndahl1,2 1Division of Ergonomics and Aerosol Technology, Department of Design Sciences, Lund University, Lund, Sweden; 2NanoLund, Lund University, Lund, Sweden; 3Division of Nuclear Physics, Department of Physics, Lund University, Lund, Sweden; 4Department of Translational Medicine, Medical Imaging and Physiology, Lund University, Malmö, Sweden; 5Department of Radiology, University of Washington, Seattle, WA, USA; 6Department of Translational Medicine, Clinical Physiology and Nuclear Medicine, Skåne University Hospital, Malmö, Sweden; 7MVIC Medicon Valley Inhalation Consortium AB, Lund, Sweden; 8Division of Bioeconomy and Health, RISE Research Institutes of Sweden, Borås, Sweden; 9Department of Clinical Sciences, Lund University, Malmö, SwedenCorrespondence: Jakob Löndahl, Division of Ergonomics and Aerosol Technology, Lund University, Box 118, Lund, SE-221 00, Sweden, Email jakob.londahl@design.lth.seBackground: Airspace Dimensions Assessment with nanoparticles (AiDA) is a new method for non-invasive measurement of pulmonary distal airspaces. The aim of this study was to compare AiDA measurements with other pulmonary function variables to better understand the potential of AiDA in a clinical context.Methods: AiDA measurements and pulmonary function tests were performed in 695 subjects as part of the Swedish CArdioPulmonary bioImage Study. The measurement protocol included spirometry, measurement of diffusing capacity of carbon monoxide, oscillometry and pulmonary computed tomography. AiDA indices were compared to all other pulmonary examination measurements using multivariate statistical analysis.Results: Our results show that AiDA measurements were significantly correlated with other pulmonary function examination indices, although covariance was low. We found that AiDA variables explained variance in the

Madeleine Petersson-Sjögren,1,2 Jonas Jakobsson,3 H Laura Aaltonen,4,5 Hanna Nicklasson,6,7 Jenny Rissler,1,2,8 Gunnar Engström,9 Per Wollmer,6 Jakob Löndahl1,2 1Division of Ergonomics and Aerosol Technology, Department of Design Sciences, Lund University, Lund, Sweden; 2NanoLund, Lund University, Lund, Sweden; 3Division of Nuclear Physics, Department of Physics, Lund University, Lund, Sweden; 4Department of Translational Medicine, Medical Imaging and Physiology, Lund University, Malmö, Sweden; 5Department of Radiology, University of Washington, Seattle, WA, USA; 6Department of Translational Medicine, Clinical Physiology and Nuclear Medicine, Skåne University Hospital, Malmö, Sweden; 7MVIC Medicon Valley Inhalation Consortium AB, Lund, Sweden; 8Division of Bioeconomy and Health, RISE Research Institutes of Sweden, Borås, Sweden; 9Department of Clinical Sciences, Lund University, Malmö, SwedenCorrespondence: Jakob Löndahl, Division of Ergonomics and Aerosol Technology, Lund University, Box 118, Lund, SE-221 00, Sweden, Email jakob.londahl@design.lth.seBackground: Airspace Dimensions Assessment with nanoparticles (AiDA) is a new method for non-invasive measurement of pulmonary distal airspaces. The aim of this study was to compare AiDA measurements with other pulmonary function variables to better understand the potential of AiDA in a clinical context.Methods: AiDA measurements and pulmonary function tests were performed in 695 subjects as part of the Swedish CArdioPulmonary bioImage Study. The measurement protocol included spirometry, measurement of diffusing capacity of carbon monoxide, oscillometry and pulmonary computed tomography. AiDA indices were compared to all other pulmonary examination measurements using multivariate statistical analysis.Results: Our results show that AiDA measurements were significantly correlated with other pulmonary function examination indices, although covariance was low. We found that AiDA variables explained variance in the

To assess pulmonary function and chronic obstructive pulmonary disease (COPD) development over time in patients with primary Sjögren syndrome (pSS), as well as the association between pulmonary function, radiographic findings, respiratory symptoms, and clinical features of pSS, taking cigarette consumption into account., Funding agencies: ALF-Skåne, the Internal Research Funds of Skåne University Hospital, the Swedish Rheumatism Association, and the Swedish Heart and Lung Foundation.

Chronic obstructive pulmonary disease (COPD) consists of emphysema and bronchial disease. The pulmonary function tests currently used to diagnose COPD have poor sensitivity for early disease. This may delay diagnosis and lead to a poorer prognosis compared to establishing the diagnosis at an earlier stage.The aim of this thesis was to investigate a new nanoparticle-based method, termed Airspace Dimension Assessment (AiDA), to chart distal airspace morphology, and to examine the technique as a possible diagnostic biomarker foremphysema. In AiDA, inhaled nanoparticles’ deposition behavior is utilized to characterize distal airspace properties.Nanoparticles, as opposed to larger particles, are able to penetrate into the distal lung, where they deposit almost exclusively by diffusion. The particles’ likelihood to deposit is dependent on the diffusion distance. The thesis isbased on the hypothesis that in persons with enlarged, emphysematous airspaces, fewer particles will deposit, as opposed to healthy persons with narrower airspaces.In paper I, significant nanoparticle deposition differences between 19 COPD-patients with mainly moderate-to advanced emphysema and 19 healthy controls were found. The deposition correlated to disease severity as measured by computed tomography (CT) densitometry and diffusion capacity for carbon monoxide (DL,CO). In paper II, nanoparticle deposition was used to calculate distal airspace radius in 19 healthy volunteers. The radius correlated to lung density as measured by magnetic resonance imaging (MRI). In paper III, the average radius in 403 individuals without previous pulmonary disease or respiratory symptoms was found to be 293 ± 36 μm. The radius and its variation in population was found to be approximately comparative to other methods. It was noted that the radius was on average 13 μm larger in male ever-smokers compared to never-smokers, which may reflect early smoking-related changes. In paper IV, we concluded that in a population

H Laura Aaltonen,1,2,* Simon S Kindvall,3,* Jonas K Jakobsson,4 Jakob Löndahl,4 Lars E Olsson,3,5 Sandra Diaz,1,2 Sophia Zackrisson,1,2 Per Wollmer1,2 1Department of Medical Imaging and Physiology, Skåne University Hospital, Malmö, Sweden; 2Department of Translational Medicine, Lund University, Malmö, Sweden; 3Department of Medical Radiation Physics, Lund University, Malmö, Sweden; 4Department of Design Sciences, Lund University, Lund, Sweden; 5Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Malmö, Sweden *These authors contributed equally to this work Background: Airspace Dimension Assessment with inhaled nanoparticles is a novel method to determine distal airway morphology. This is the first empirical study using Airspace Dimension Assessment with nanoparticles (AiDA) to estimate distal airspace radius. The technology is relatively simple and potentially accessible in clinical outpatient settings. Method: Nineteen never-smoking volunteers performed nanoparticle inhalation tests at multiple breath-hold times, and the difference in nanoparticle concentration of inhaled and exhaled gas was measured. An exponential decay curve was fitted to the concentration of recovered nanoparticles, and airspace dimensions were assessed from the half-life of the decay. Pulmonary tissue density was measured using magnetic resonance imaging (MRI). Results: The distal airspace radius measured by AiDA correlated with lung tissue density as measured by MRI (ρ = -0.584; p = 0.0086). The linear intercept of the logarithm of the exponential decay curve correlated with forced expiratory volume in one second (FEV1) (ρ = 0.549; p = 0.0149). Conclusion: The AiDA method shows potential to be developed into a tool to assess conditions involving changes in distal airways, eg, emphysema. The intercept may reflect airway properties; this finding should be further investigated. Keywo

H Laura Aaltonen,1,2,* Simon S Kindvall,3,* Jonas K Jakobsson,4 Jakob Löndahl,4 Lars E Olsson,3,5 Sandra Diaz,1,2 Sophia Zackrisson,1,2 Per Wollmer1,2 1Department of Medical Imaging and Physiology, Skåne University Hospital, Malmö, Sweden; 2Department of Translational Medicine, Lund University, Malmö, Sweden; 3Department of Medical Radiation Physics, Lund University, Malmö, Sweden; 4Department of Design Sciences, Lund University, Lund, Sweden; 5Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Malmö, Sweden *These authors contributed equally to this work Background: Airspace Dimension Assessment with inhaled nanoparticles is a novel method to determine distal airway morphology. This is the first empirical study using Airspace Dimension Assessment with nanoparticles (AiDA) to estimate distal airspace radius. The technology is relatively simple and potentially accessible in clinical outpatient settings. Method: Nineteen never-smoking volunteers performed nanoparticle inhalation tests at multiple breath-hold times, and the difference in nanoparticle concentration of inhaled and exhaled gas was measured. An exponential decay curve was fitted to the concentration of recovered nanoparticles, and airspace dimensions were assessed from the half-life of the decay. Pulmonary tissue density was measured using magnetic resonance imaging (MRI). Results: The distal airspace radius measured by AiDA correlated with lung tissue density as measured by MRI (ρ = -0.584; p = 0.0086). The linear intercept of the logarithm of the exponential decay curve correlated with forced expiratory volume in one second (FEV1) (ρ = 0.549; p = 0.0149). Conclusion: The AiDA method shows potential to be developed into a tool to assess conditions involving changes in distal airways, eg, emphysema. The intercept may reflect airway properties; this finding should be further investigated. Keywo

Jakob Löndahl,1,2 Jonas KF Jakobsson,1,2 David M Broday,3 H Laura Aaltonen,4 Per Wollmer4 1Division of Ergonomics and Aerosol Technology (EAT), Department of Design Sciences, 2NanoLund, Lund University, Lund, Sweden; 3Faculty of Civil and Environmental Engineering, Technion, Haifa, Israel; 4Department of Translational Medicine, Lund University, Malmö, Sweden Abstract: There is a need for efficient techniques to assess abnormalities in the peripheral regions of the lungs, for example, for diagnosis of pulmonary emphysema. Considerable scientific efforts have been directed toward measuring lung morphology by studying recovery of inhaled micron-sized aerosol particles (0.4–1.5 µm). In contrast, it is suggested that the recovery of inhaled airborne nanoparticles may be more useful for diagnosis. The objective of this work is to provide a theoretical background for the use of nanoparticles in measuring lung morphology and to assess their applicability based on a review of the literature. Using nanoparticles for studying distal airspace dimensions is shown to have several advantages over other aerosol-based methods. 1) Nanoparticles deposit almost exclusively by diffusion, which allows a simpler breathing maneuver with minor artifacts from particle losses in the oropharyngeal and upper airways. 2) A higher breathing flow rate can be utilized, making it possible to rapidly inhale from residual volume to total lung capacity (TLC), thereby eliminating the need to determine the TLC before measurement. 3) Recent studies indicate better penetration of nanoparticles than micron-sized particles into poorly ventilated and diseased regions of the lungs; thus, a stronger signal from the abnormal parts is expected. 4) Changes in airspace dimensions have a larger impact on the recovery of nanoparticles. Compared to current diagnostic techniques with high specificity for morphometric changes of the lungs, computed tomography and magnetic r

Jakob Löndahl,1,2 Jonas KF Jakobsson,1,2 David M Broday,3 H Laura Aaltonen,4 Per Wollmer4 1Division of Ergonomics and Aerosol Technology (EAT), Department of Design Sciences, 2NanoLund, Lund University, Lund, Sweden; 3Faculty of Civil and Environmental Engineering, Technion, Haifa, Israel; 4Department of Translational Medicine, Lund University, Malmö, Sweden Abstract: There is a need for efficient techniques to assess abnormalities in the peripheral regions of the lungs, for example, for diagnosis of pulmonary emphysema. Considerable scientific efforts have been directed toward measuring lung morphology by studying recovery of inhaled micron-sized aerosol particles (0.4–1.5 µm). In contrast, it is suggested that the recovery of inhaled airborne nanoparticles may be more useful for diagnosis. The objective of this work is to provide a theoretical background for the use of nanoparticles in measuring lung morphology and to assess their applicability based on a review of the literature. Using nanoparticles for studying distal airspace dimensions is shown to have several advantages over other aerosol-based methods. 1) Nanoparticles deposit almost exclusively by diffusion, which allows a simpler breathing maneuver with minor artifacts from particle losses in the oropharyngeal and upper airways. 2) A higher breathing flow rate can be utilized, making it possible to rapidly inhale from residual volume to total lung capacity (TLC), thereby eliminating the need to determine the TLC before measurement. 3) Recent studies indicate better penetration of nanoparticles than micron-sized particles into poorly ventilated and diseased regions of the lungs; thus, a stronger signal from the abnormal parts is expected. 4) Changes in airspace dimensions have a larger impact on the recovery of nanoparticles. Compared to current diagnostic techniques with high specificity for morphometric changes of the lungs, computed tomography and magnetic r