Lung Physiological Variations in COVID-19 Patients and Inhalation Therapy Development for Remodeled Lungs

Jinxiang Xi, Brendan Walfield, Xiuhua April Si, Alexander A. Bankier


In response to the unmet need for effective treatments for symptomatic patients, research efforts of inhaled therapy for COVID-19 patients have been pursued since the pandemic began. However, inhalation drug delivery to the lungs is sensitive to the lung anatomy and physiology, which can be significantly altered due to the viral infection. The ensued ventilation heterogeneity will change distribution and thus dosimetry of inhaled medications, rendering previous correlations concepts? of pulmonary drug delivery in healthy lungs less reliable. In this study, we first reviewed the recent developments of inhaled therapeutics and vaccines, as well as the latest knowledge of the lung structural variations documented by CT of COVID-19 patients' lungs. We then quantified the volume ratios of the poorly aerated lungs and non-aerated lungs in eight COVID-19 patients, which ranged 2-8% and 0.5-3%, respectively. The need to consider the diseased lung physiologies in estimating pulmonary delivery was emphasized. Diseased lung geometries with varying lesion sites and complexities were reconstructed using Statistical Shape Modeling (SSM). A new segmentation method was applied that could generate patient-specific lung geometries with an increased number of branching generations. The synergy of the CT-based lung segmentation and SSM-based airway variation showed promise for developing representative COVID-infected lung morphological models and investigating inhalation therapeutics in COVID-19 patients.


Doi: 10.28991/SciMedJ-2021-0303-1

Full Text: PDF


COVID-19; Airway Remodeling; Inhalation Therapy; Inhaled Vaccine; Bronchial Constriction; Statistical Shape Modeling (SSM).


WHO (2021). World health orgnization coronavirus (COVID-19) dashboard: Available on: (accessed on February 2021).

Mitchell, J. P., Berlinski, A., Canisius, S., Cipolla, D., Dolovich, M. B., Gonda, I., … Boushey, H. (2020). Urgent Appeal from International Society for Aerosols in Medicine (ISAM) During COVID-19: Clinical Decision Makers and Governmental Agencies Should Consider the Inhaled Route of Administration: A Statement from the ISAM Regulatory and Standardization Issues Networking Group. Journal of Aerosol Medicine and Pulmonary Drug Delivery, 33(4), 235–238. doi:10.1089/jamp.2020.1622.

Xi, J., Talaat, M., Si, X. A., & Chandra, S. (2021). The application of statistical shape modeling for lung morphology in aerosol inhalation dosimetry. Journal of Aerosol Science, 151, 105623. doi:10.1016/j.jaerosci.2020.105623.

Hussain, M., Renate, W.-H., Werner, H. (2011). Effect of intersubject variability of extrathoracic morphometry, lung airways dimensions and respiratory parameters on particle deposition. Journal of Thoracic Disease, 3(3), 156-170. doi:10.3978/j.issn.2072-1439.2011.04.03.

Nayak, A. P., Deshpande, D. A., & Penn, R. B. (2018). New targets for resolution of airway remodeling in obstructive lung diseases. F1000Research, 7, 680. doi:10.12688/f1000research.14581.1.

Sköld, C. M. (2010). Remodeling in asthma and COPD - differences and similarities. The Clinical Respiratory Journal, 4, 20–27. doi:10.1111/j.1752-699x.2010.00193.x.

Staquicini, D. I., Barbu, E. M., Zemans, R. L., Dray, B. K., Staquicini, F. I., Dogra, P., Cardó-Vila, M., Miranti, C. K., Baze, W. B., Villa, L. L., Kalil, J., Sharma, G., Prossnitz, E. R., Wang, Z., Cristini, V., Sidman, R. L., Berman, A. R., Panettieri, R. A., Jr., Tuder, R. M., Pasqualini, R., Arap, W. (2021). Targeted phage display-based pulmonary vaccination in mice and non-human primates. Med, 2(3), 321-342.e328. doi:10.1016/j.medj.2020.10.005.

Abdellatif, A. A. H., Tawfeek, H. M., Abdelfattah, A., El-Saber Batiha, G., Hetta, H. F. (2021). Recent updates in COVID-19 with emphasis on inhalation therapeutics: Nanostructured and targeting systems. J Drug Deliv Sci Technol, 63(102435. doi:10.1016/j.jddst.2021.102435.

Piepenbrink, M. S., Park, J. G., Oladunni, F. S., Deshpande, A., Basu, M., Sarkar, S., Loos, A., Woo, J., Lovalenti, P., Sloan, D., Ye, C., Chiem, K., Bates, C. W., Burch, R. E., Erdmann, N. B., Goepfert, P. A., Truong, V. L., Walter, M. R., Martinez-Sobrido, L., Kobie, J. J. (2021). Therapeutic activity of an inhaled potent SARS-CoV-2 neutralizing human monoclonal antibody in hamsters. Cell Rep Med, 2(3), 100218. doi:10.1016/j.xcrm.2021.100218.

Ramakrishnan, S., Nicolau, D. V., Langford, B., Mahdi, M., Jeffers, H., Mwasuku, C., … Bafadhel, M. (2021). Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial. The Lancet Respiratory Medicine. doi:10.1016/s2213-2600(21)00160-0.

Rheault, T., Bengtsson, T., Rickard, K. (2020). Ensifentrine, a dual PDE3/PDE4 inhibitor, improves FEV1 regardless of smoking status or history of chronic bronchitis. Eur Respir J, 56(suppl 64), 4786. doi:10.1183/13993003.congress-2020.4786.

Kobayashi, J., Murata, I. (2020). Nitric oxide inhalation as an interventional rescue therapy for COVID-19-induced acute respiratory distress syndrome. Ann Intensive Care, 10(1), 61. doi:10.1186/s13613-020-00681-9.

Safaee Fakhr, B., Wiegand, S. B., Pinciroli, R., Gianni, S., Morais, C. C. A., Ikeda, T., … Berra, L. (2020). High Concentrations of Nitric Oxide Inhalation Therapy in Pregnant Patients with Severe Coronavirus Disease 2019 (COVID-19). Obstetrics & Gynecology, 136(6), 1109–1113. doi:10.1097/aog.0000000000004128.

Halpin, D. M. G., Singh, D., Hadfield, R. M. (2020). Inhaled corticosteroids and COVID-19: a systematic review and clinical perspective. Eur Respir J, 55(2001009. doi:10.1183/13993003.01009-2020.

Singh, D., Halpin, D. M. G. (2020). Inhaled corticosteroids and COVID-19-related mortality: confounding or clarifying? Lancet Respir Med, 8(11), 1065-1066. doi:10.1016/S2213-2600(20)30447-1.

Haren, F. M. P., Richardson, A., Yoon, H., Artigas, A., Laffey, J. G., Dixon, B., … Page, C. (2021). INHALEd nebulised unfractionated HEParin for the treatment of hospitalised patients with COVID-19 (INHALE-HEP): Protocol and statistical analysis plan for an investigator‐initiated international metatrial of randomised studies. British Journal of Clinical Pharmacology. doi:10.1111/bcp.14714

Mary, A., Hénaut, L., Macq, P. Y., Badoux, L., Cappe, A., Porée, T., Eckes, M., Dupont, H., Brazier, M. (2020). Rationale for COVID-19 treatment by nebulized interferon-β-1b–Literature review and personal preliminary experience. Front Pharmacol, 11(1885). doi:10.3389/fphar.2020.592543.

Albariqi, A. H., Chang, R. Y. K., Tai, W., Ke, W.-R., Y.T, M., Chow, P. T., Kwok, P. C. L., Chan, H.-K. (2021). Inhalable hydroxychloroquine powders for potential treatment of COVID-19. J Aerosol Med Pulm Drug Deliv, 34(1), 20-31. doi:10.1089/jamp.2020.1648.

Ferrer, G., Betancourt, A., Go, C. C., Vazquez, H., Westover, J. B., Cagno, V., Tapparel, C., Sanchez-Gonzalez, M. A. (2020). A nasal spray solution of grapefruit seed extract plus Xylitol displays virucidal activity against SARS-Cov-2 in vitro. BioRxiv, Preprint, 394114. doi:10.1101/2020.11.23.394114.

Abdellatif, A. A. H. (2020). A plausible way for excretion of metal nanoparticles via active targeting. Drug Dev Ind Pharm, 46(5), 744-750. doi:10.1080/03639045.2020.1752710.

Abdellatif, A. A. H., Ibrahim, M. A., Amin, M. A., Maswadeh, H., Alwehaibi, M. N., Al-Harbi, S. N., Alharbi, Z. A., Mohammed, H. A., Mehany, A. B. M., Saleem, I. (2020). Cetuximab conjugated with octreotide and entrapped calcium Alginate-beads for targeting Somatostatin Receptors. Sci Rep, 10(1), 4736. doi:10.1038/s41598-020-61605-y.

Gai, J., Ma, L., Li, G., Zhu, M., Qiao, P., Li, X., Zhang, H., Zhang, Y., Chen, Y., Ji, W., Zhang, H., Cao, H., Li, X., Gong, R., Wan, Y. (2021). A potent neutralizing nanobody against SARS-CoV-2 with inhaled delivery potential. MedComm, 2(1), 101-113. doi:10.1002/mco2.60.

Iwabuchi, K., Yoshie, K., Kurakami, Y., Takahashi, K., Kato, Y., Morishima, T. (2020). Therapeutic potential of ciclesonide inahalation for COVID-19 pneumonia: Report of three cases. J Infect Chemother, 26(6), 625-632. doi:10.1016/j.jiac.2020.04.007.

Matsuyama, S., Kawase, M., Nao, N., Shirato, K., Ujike, M., Kamitani, W., … Fukushi, S. (2020). The Inhaled Steroid Ciclesonide Blocks SARS-CoV-2 RNA Replication by Targeting the Viral Replication-Transcription Complex in Cultured Cells. Journal of Virology, 95(1). doi:10.1128/jvi.01648-20.

Wu, Y., Wang, T., Guo, C., Zhang, D., Ge, X., Huang, Z., Zhou, X., Li, Y., Peng, Q., Li, J. (2020). Plasminogen improves lung lesions and hypoxemia in patients with COVID-19. QJM: Int J Med, 113(8), 539-545. doi:10.1093/qjmed/hcaa121.

Wang, Z., Wang, Y., Vilekar, P., Yang, S. P., Gupta, M., Oh, M. I., Meek, A., Doyle, L., Villar, L., Brennecke, A., Liyanage, I., Reed, M., Barden, C., Weaver, D. F. (2020). Small molecule therapeutics for COVID-19: repurposing of inhaled furosemide. PeerJ, 8(e9533. doi:10.7717/peerj.9533.

Brennecke, A., Villar, L., Wang, Z., Doyle, L. M., Meek, A., Reed, M., … Weaver, D. F. (2020). Is Inhaled Furosemide a Potential Therapeutic for COVID-19? The American Journal of the Medical Sciences, 360(3), 216–221. doi:10.1016/j.amjms.2020.05.044.

van Haren, F. M. P., Page, C., Laffey, J. G., Artigas, A., Camprubi-Rimblas, M., Nunes, Q., Smith, R., Shute, J., Carroll, M., Tree, J., Carroll, M., Singh, D., Wilkinson, T., Dixon, B. (2020). Nebulised heparin as a treatment for COVID-19: scientific rationale and a call for randomised evidence. Crit Care, 24(1), 454. doi:10.1186/s13054-020-03148-2.

Pindiprolu, S., Kumar, C. S. P., Kumar Golla, V. S., P, L., K, S. C., S, K. E., R, K. R. (2020). Pulmonary delivery of nanostructured lipid carriers for effective repurposing of salinomycin as an antiviral agent. Med Hypotheses, 143(109858. doi:10.1016/j.mehy.2020.109858.

Sahakijpijarn, S., Moon, C., Koleng, J. J., Christensen, D. J., Williams Iii, R. O. (2020). Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing. Pharmaceutics, 12(11). doi:10.3390/pharmaceutics12111002.

Dimbath, E., Maddipati, V., Stahl, J., Sewell, K., Domire, Z., George, S., Vahdati, A. (2021). Implications of microscale lung damage for COVID-19 pulmonary ventilation dynamics: A narrative review. Life Sci, 274(119341. doi:10.1016/j.lfs.2021.119341.

Mohanty, S. K., Satapathy, A., Naidu, M. M., Mukhopadhyay, S., Sharma, S., Barton, L. M., Stroberg, E., Duval, E. J., Pradhan, D., Tzankov, A., Parwani, A. V. (2020). Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and coronavirus disease 19 (COVID-19) - anatomic pathology perspective on current knowledge. Diagn Pathol, 15(1), 103. doi:10.1186/s13000-020-01017-8.

Fernández-Pérez, G. C., Oñate Miranda, M., Fernández-Rodríguez, P., Velasco Casares, M., Corral de la Calle, M., Franco López, Á., … Oñate Cuchat, J. M. (2021). SARS-CoV-2: what it is, how it acts, and how it manifests in imaging studies. Radiología (English Edition), 63(2), 115–126. doi:10.1016/j.rxeng.2020.10.006.

Kim, E. A., Lee, K. S., Primack, S. L., Yoon, H. K., Byun, H. S., Kim, T. S., Suh, G. Y., Kwon, O. J., Han, J. (2002). Viral pneumonias in adults: radiologic and pathologic findings. Radiographics, 22 Spec No(S137-149. doi:10.1148/radiographics.22.suppl_1.g02oc15s137.

Hanley, B., Lucas, S. B., Youd, E., Swift, B., Osborn, M. (2020). Autopsy in suspected COVID-19 cases. J Clin Pathol, 73(5), 239-242. doi:10.1136/jclinpath-2020-206522.

Zhou, B., Zhao, W., Feng, R., Zhang, X., Li, X., Zhou, Y., Peng, L., Li, Y., Zhang, J., Luo, J., Li, L., Wu, J., Yang, C., Wang, M., Zhao, Y., Wang, K., Yu, H., Peng, Q., Jiang, N. (2020). The pathological autopsy of coronavirus disease 2019 (COVID-2019) in China: a review. Pathog Dis., 78(3). doi:10.1093/femspd/ftaa026.

Calabrese, F., Pezzuto, F., Fortarezza, F., Hofman, P., Kern, I., Panizo, A., von der Thüsen, J., Timofeev, S., Gorkiewicz, G., Lunardi, F. (2020). Pulmonary pathology and COVID-19: lessons from autopsy. The experience of European Pulmonary Pathologists. Virchows Archiv: Eur J Pathol, 477(3), 359-372. doi:10.1007/s00428-020-02886-6.

Santurro, A., Scopetti, M., D'Errico, S., Fineschi, V. (2020). A technical report from the Italian SARS-CoV-2 outbreak. Postmortem sampling and autopsy investigation in cases of suspected or probable COVID-19. Forensic Sci Med Pathol, 16(3), 471-476. doi:10.1007/s12024-020-00258-9.

Tian, S., Hu, W., Niu, L., Liu, H., Xu, H., & Xiao, S.-Y. (2020). Pulmonary Pathology of Early-Phase 2019 Novel Coronavirus (COVID-19) Pneumonia in Two Patients with Lung Cancer. Journal of Thoracic Oncology, 15(5), 700–704. doi:10.1016/j.jtho.2020.02.010

Yao, X. H., He, Z. C., Li, T. Y., Zhang, H. R., Wang, Y., Mou, H., Guo, Q., Yu, S. C., Ding, Y., Liu, X., Ping, Y. F., Bian, X. W. (2020). Pathological evidence for residual SARS-CoV-2 in pulmonary tissues of a ready-for-discharge patient. Cell Res, 30(6), 541-543. doi:10.1038/s41422-020-0318-5.

Copin, M. C., Parmentier, E., Duburcq, T., Poissy, J., Mathieu, D. (2020). Time to consider histologic pattern of lung injury to treat critically ill patients with COVID-19 infection. Intensive Care Med, 46(6), 1124-1126. doi:10.1007/s00134-020-06057-8.

Batah, S. S., Fabro, A. T. (2021). Pulmonary pathology of ARDS in COVID-19: A pathological review for clinicians. Respir Med, 176(106239. doi:10.1016/j.rmed.2020.106239.

Menter, T., Haslbauer, J. D., Nienhold, R., Savic, S., Hopfer, H., Deigendesch, N., Frank, S., Turek, D., Willi, N., Pargger, H., Bassetti, S., Leuppi, J. D., Cathomas, G., Tolnay, M., Mertz, K. D., Tzankov, A. (2020). Postmortem examination of COVID-19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction. Histopathology, 77(2), 198-209. doi:10.1111/his.14134.

Barisione, E., Grillo, F., Ball, L., Bianchi, R., Grosso, M., Morbini, P., Pelosi, P., Patroniti, N. A., De Lucia, A., Orengo, G., Gratarola, A., Verda, M., Cittadini, G., Mastracci, L., Fiocca, R. (2021). Fibrotic progression and radiologic correlation in matched lung samples from COVID-19 post-mortems. Virchows Archiv : an international journal of pathology, 478(3), 471-485. doi:10.1007/s00428-020-02934-1.

Bourgonje, A. R., Abdulle, A. E., Timens, W., Hillebrands, J. L., Navis, G. J., Gordijn, S. J., Bolling, M. C., Dijkstra, G., Voors, A. A., Osterhaus, A. D., van der Voort, P. H., Mulder, D. J., van Goor, H. (2020). Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19). J Pathol, 251(3), 228-248. doi:10.1002/path.5471.

Bauer, C., Krueger, M., Lamm, W. J. E., Glenny, R. W., Beichel, R. R. (2020). lapdMouse: associating lung anatomy with local particle deposition in mice. J Appl Physiol, 128(2), 309-323. doi:10.1152/japplphysiol.00615.2019.

Soy, M., Keser, G., Atagündüz, P., Tabak, F., Atagündüz, I., Kayhan, S. (2020). Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment. Clin Rheumatol, 39(7), 2085-2094. doi:10.1007/s10067-020-05190-5.

Yuan, J., Chiofolo, C. M., Czerwin, B. J., Karamolegkos, N., Chbat, N. W. (2021). Alveolar tissue fiber and surfactant effects on lung mechanics—model development and validation on ARDS and IPF patients. IEEE Open J Eng Med, 2(44-54. doi:10.1109/OJEMB.2021.3053841.

De Backer, J. W., Vos, W. G., Burnell, P., Verhulst, S. L., Salmon, P., De Clerck, N., De Backer, W. (2009). Study of the variability in upper and lower airway morphology in Sprague-Dawley rats using modern micro-CT scan-based segmentation techniques. Anat Rec, 292(5), 720-727. doi:10.1002/ar.20877.

Hofmann, W., Asgharian, B., Winkler-Heil, R. (2002). Modeling intersubject variability of particle deposition in human lungs. J Aerosol Sci, 33(219-235. doi:10.1016/S0021-8502(01)00167-7.

Schroeter, J. D., Garcia, G. J. M., Kimbell, J. S. (2010). A computational fluid dynamics approach to assess interhuman variability in hydrogen sulfide nasal dosimetry. Inhal Toxicol, 22(4), 277-286. doi:10.3109/08958370903278077.

Thekedar, B., Oeh, U., Szymczak, W., Hoeschen, C., Paretzke, H. G. (2011). Influences of mixed expiratory sampling parameters on exhaled volatile organic compound concentrations. J Breath Res, 5(1). doi:10.1088/1752-7155/5/1/016001.

Vijverberg, S. J. H., Koenderman, L., Koster, E. S., van der Ent, C. K., Raaijmakers, J. A. M., Maitland-van der Zee, A. H. (2011). Biomarkers of therapy responsiveness in asthma: pitfalls and promises. Clin Exp Allergy, 41(5), 615-629. doi:10.1111/j.1365-2222.2011.03694.x.

Xi, J., Kim, J., Si, X. A., & Zhou, Y. (2013). Diagnosing obstructive respiratory diseases using exhaled aerosol fingerprints: A feasibility study. Journal of Aerosol Science, 64, 24–36. doi:10.1016/j.jaerosci.2013.06.003

Xi, J., Yang, T. (2019). Variability in oropharyngeal airflow and aerosol deposition due to changing tongue positions. J Drug Deliv Sci Technol, 49(674-682. doi:10.1016/j.jddst.2019.01.006.

Xi, J., Si, X. A., Kim, J. W., (2015). Characterizing respiratory airflow and aerosol condensational growth in children and adults using an imaging-CFD approach, in: Heat Transfer and Fluid Flow in Biological Processes, Academic Press, pp. 125-155. doi:10.1016/B978-0-12-408077-5.00005-5.

Xi, J., Kim, J., Si, X. A. (2016). Effects of nostril orientation on airflow dynamics, heat exchange, and particle depositions in human noses. Eur J Mech B Fluids, 55(215-228. doi:10.1016/j.euromechflu.2015.08.014.

Si, X., Xi, J., Kim, J. (2013). Effect of laryngopharyngeal anatomy on expiratory airflow and submicrometer particle deposition in human extrathoracic airways. Open J Fluid Dyn, 3(4), 286-301. doi:10.4236/ojfd.2013.34036.

Xi, J., Longest, P. W. (2008). Evaluation of a drift flux model for simulating submicrometer aerosol dynamics in human upper tracheobronchial airways. Ann Biomed Eng, 36(10), 1714-1734. doi:10.1007/s10439-008-9552-6.

Xi, J., Zhang, Z., Si, X. (2015). Improving intranasal delivery of neurological nanomedicine to the olfactory region using magnetophoretic guidance of microsphere carriers. Int J Nanomedicine, 10(1211-1222. doi:10.2147/IJN.S77520.

Xi, J., Si, X. A., Peters, S., Nevorski, D., Wen, T., Lehman, M. (2017). Understanding the mechanisms underlying pulsating aerosol delivery to the maxillary sinus: In vitro tests and computational simulations. Int J Pharm, 520(1-2), 254-266. doi:10.1016/j.ijpharm.2017.02.017.

Garcia, G. J. M., Schroeter, J. D., Segal, R. A., Stanek, J., Foureman, G. L., Kimbell, J. S. (2009). Dosimetry of nasal uptake of water-soluble and reactive gases: A first study of interhuman variability. Inhal Toxicol, 21(5-7), 607-618. doi:10.1080/08958370802320186.

Xi, J., Berlinski, A., Zhou, Y., Greenberg, B., Ou, X. (2012). Breathing resistance and ultrafine particle deposition in nasal–laryngeal airways of a newborn, an infant, a child, and an adult. Ann Biomed Eng, 40(12), 2579-2595. doi:10.1007/s10439-012-0603-7.

Segal, R. A., Kepler, G. M., Kimbell, J. S. (2008). Effects of differences in nasal anatomy on airflow distribution: A comparison of four individuals at rest. Ann Biomed Eng, 36(11), 1870-1882. doi:10.1007/s10439-008-9556-2.

Lanza, E., Muglia, R., Bolengo, I., Santonocito, O. G., Lisi, C., Angelotti, G., Morandini, P., Savevski, V., Politi, L. S., Balzarini, L. (2020). Quantitative chest CT analysis in COVID-19 to predict the need for oxygenation support and intubation. Eur Radiol, 30(12), 6770-6778. doi:10.1007/s00330-020-07013-2.

Xi, J., Longest, P. W. (2007). Transport and deposition of micro-aerosols in realistic and simplified models of the oral airway. Ann Biomed Eng, 35(4), 560-581. doi:10.1007/s10439-006-9245-y.

Corley, R. A., Kabilan, S., Kuprat, A. P., Carson, J. P., Minard, K. R., Jacob, R. E., Timchalk, C., Glenny, R., Pipavath, S., Cox, T., Wallis, C. D., Larson, R. F., Fanucchi, M. V., Postlethwait, E. M., Einstein, D. R. (2012). Comparative computational modeling of airflows and vapor dosimetry in the respiratory tracts of rat, monkey, and human. Toxicol Sci, 128(2), 500-516. doi:10.1093/toxsci/kfs168.

Longest, P. W., Vinchurkar, S. (2007). Validating CFD predictions of respiratory aerosol deposition: effects of upstream transition and turbulence. J Biomech, 40(305-316. doi:10.1016/j.jbiomech.2006.01.006.

Xi, J., Longest, P. W., Martonen, T. B. (2008). Effects of the laryngeal jet on nano- and microparticle transport and deposition in an approximate model of the upper tracheobronchial airways. J Appl Physiol, 104(6), 1761-1777. doi:10.1152/japplphysiol.01233.2007.

Watz, H., Breithecker, A., Rau, W. S., Kriete, A. (2005). Micro-CT of the human lung: imaging of alveoli and virtual endoscopy of an alveolar duct in a normal lung and in a lung with centrilobular emphysema--initial observations. Radiology, 236(3), 1053-1058. doi:10.1148/radiol.2363041142.

Parameswaran, H., Bartolák-Suki, E., Hamakawa, H., Majumdar, A., Allen, P. G., Suki, B. (2009). Three-dimensional measurement of alveolar airspace volumes in normal and emphysematous lungs using micro-CT. J Appl Physiol, 107(2), 583-592. doi:10.1152/japplphysiol.91227.2008.

Hochhegger, B., Langer, F. W., Irion, K., Souza, A., Moreira, J., Baldisserotto, M., Pallaoro, Y., Muller, E., Medeiros, T. M., Altmayer, S., Marchiori, E. (2019). Pulmonary acinus: understanding the computed tomography findings from an acinar perspective. Lung, 197(3), 259-265. doi:10.1007/s00408-019-00214-7.

Tippe, A., Tsuda, A. (2000). Recirculating flow in an expanding alveolar model: Experimental evidence of flow-induced mixing of aerosols in the pulmonary acinus. J Aerosol Sci, 31(8), 979-986. doi:10.1016/S0021-8502(99)00572-8.

Kitaoka, H., Tamura, S., Takaki, R. (2000). A three-dimensional model of the human pulmonary acinus. J Appl Physiol, 88(6), 2260-2268. doi:10.1152/jappl.2000.88.6.2260.

Darquenne, C., Paiva, N. (1996). Two- and three-dimensional simulations of aerosol transport and deposition in alveolar zone of human lung. J Appl Physiol, 80(4), 1401-1414. doi:10.1152/jappl.1996.80.4.1401.

Hofemeier, P., Koshiyama, K., Wada, S., Sznitman, J. (2018). One (sub-)acinus for all: Fate of inhaled aerosols in heterogeneous pulmonary acinar structures. Eur J Pharm Sci, 113(53-63. doi:10.1016/j.ejps.2017.09.033.

Talaat, M., Si, X. A., Kitaoka, H., Xi, J. (2021). Septal destruction enhances chaotic mixing and increases cellular doses of nanoparticles in emphysematous acinus. Nano Express, 2(1), 010015. doi:10.1088/2632-959x/abe0f8.

Talaat, M., Si, X. A., Tanbour, H., Xi, J. (2019). Numerical studies of nanoparticle transport and deposition in terminal alveolar models with varying complexities. Med One, 4(5), e190018. doi:10.20900/mo.20190018.

Xi, J., Talaat, M. (2019). Nanoparticle deposition in rhythmically moving acinar models with iteralveolar septal apertures. Nanomaterials, 9(8). doi:10.3390/nano9081126.

Chandra, S. S., Xia, Y., Engstrom, C., Crozier, S., Schwarz, R., Fripp, J. (2014). Focused shape models for hip joint segmentation in 3D magnetic resonance images. Med Image Anal, 18(3), 567-578. doi:10.1016/

Castro-Mateos, I., Pozo, J. M., Cootes, T. F., Wilkinson, J. M., Eastell, R., Frangi, A. F. (2014). Statistical shape and appearance models in osteoporosis. Curr Osteoporos Rep, 12(2), 163-173. doi:10.1007/s11914-014-0206-3.

Fitzpatrick, C., FitzPatrick, D., Lee, J., Auger, D. (2007). Statistical design of unicompartmental tibial implants and comparison with current devices. Knee, 14(2), 138-144. doi:

Quan, W., Matuszewski, B. J., Shark, L.-K. (2016). Statistical shape modelling for expression-invariant face analysis and recognition. Pattern Anal Appl, 19(3), 765-781. doi:10.1007/s10044-014-0439-x.

Macdonald-Wallis, C. (2014). Statistical Analysis of Human Growth and Development. International Journal of Epidemiology, 43(2), 635–636. doi:10.1093/ije/dyu068.

Krishan, K., Chatterjee, P. M., Kanchan, T., Kaur, S., Baryah, N., Singh, R. K. (2016). A review of sex estimation techniques during examination of skeletal remains in forensic anthropology casework. Forensic Sci Int, 261(165.e161-168. doi:10.1016/j.forsciint.2016.02.007.

Hauser, R., Smolinski, J., Gos, T. (2005). The estimation of stature on the basis of measurements of the femur. Forensic Sci Int, 147(2-3), 185-190. doi:10.1016/j.forsciint.2004.09.070.

Jakab, A., Blanc, R., Berenyi, E. L., Szekely, G. (2012). Generation of individualized thalamus target maps by using statistical shape models and thalamocortical tractography. Am J Neuroradiol, 33(11), 2110-2116. doi:10.3174/ajnr.A3140.

Xi, J., Zhao, W. (2019). Correlating exhaled aerosol images to small airway obstructive diseases: A study with dynamic mode decomposition and machine learning. PloS ONE, 14(1). doi:10.1371/journal.pone.0211413.

Talaat, M., Si, X. A., Dong, H., Xi, J. (2021). Leveraging statistical shape modeling in computational respiratory dynamics: nanomedicine delivery in remodeled airways. Comput Meth Prog Biomed, 204(106079. doi:10.1016/j.cmpb.2021.106079.

Si, X. A., Talaat, M., Su, W. C., Xi, J. (2021). Inhalation dosimetry of nasally inhaled respiratory aerosols in the human respiratory tract with locally remodeled conducting lungs. Inhal Toxicol, in press(1-17. doi:10.1080/08958378.2021.1912860.

Kitaoka, H., Nieman, G. F., Fujino, Y., Carney, D., DiRocco, J., Kawase, I. (2007). A 4-dimensional model of the alveolar structure. J Physiol Sci, 57(3), 175-185. doi:10.2170/physiolsci.RP000807.

Kitaoka, H. (2011). The origin of frequency dependence of respiratory resistance: An airflow simulation study using a 4D pulmonary lobule model. Respirology, 16(3), 517-522. doi:10.1111/j.1440-1843.2011.01925.x.

Full Text: PDF

DOI: 10.28991/SciMedJ-2021-0303-1


  • There are currently no refbacks.

Copyright (c) 2021 Jinxiang Xi, Brendan Walfield, Xiuhua April Si, Alexander A Bankier