Abstract
Surfactant instillation into the lungs is used to treat several respiratory disorders such as neonatal respiratory distress syndrome (NRDS). The success of the treatments significantly depends on the uniformity of distribution of the instilled surfactant in airways. This is challenging to directly evaluate due to the inaccessibility of lung airways and great difficulty with imaging them. To tackle this problem, we developed a 3D physical model of human lung airway tree. Using a defined set of principles, we first generated computational models of eight generations of neonates’ tracheobronchial tree comprising the conducting zone airways. Similar to native lungs, these models contained continuously-branching airways that rotated in the 3D space and reduced in size with increase in the generation number. Then, we used additive manufacturing to generate physical airway tree models that precisely replicated the computational designs. We demonstrated the utility of the physical models to study surfactant delivery in the lungs and showed the effect of orientation of the airway tree in the gravitational field on the distribution of instilled surfactant between the left and right lungs and within each lung. Our 3D lung airway tree model offers a novel tool for quantitative studies of therapeutics delivery.
This is a preview of subscription content, access via your institution.








References
Anderson, J. C., R. C. Molthen, C. A. Dawson, S. T. Haworth, J. L. Bull, M. R. Glucksberg, and J. B. Grotberg. Effect of ventilation rate on instilled surfactant distribution in the pulmonary airways of rats. J. Appl. Physiol. 97:45–56, 2004.
Andreeva, A. V., M. A. Kutuzov, and T. A. Voyno-Yasenetskaya. Regulation of surfactant secretion in alveolar type II cells. Am. J. Physiol. Lung Cell Mol. Physiol. 293:259–271, 2007.
Atefi, E., J. A. Mann, Jr, and H. Tavana. Ultralow interfacial tensions of aqueous two-phase systems measured using drop shape. Langmuir. 30:9691–9699, 2014.
Baroud, C. N., S. Tsikata, and M. Heil. The propagation of low-viscosity fingers into fluid-filled branching networks. J. Fluid Mech. 546:285–294, 2006.
Borgas, M. S., and J. B. Groberg. Monolayer flow on a thin film. J. Fluid Mech. 193:151–170, 1988.
Cassidy, K. J., J. L. Bull, M. R. Glucksberg, C. A. Dawson, S. T. Haworth, R. Hirschl, N. Gavriely, and J. B. Grotberg. A rat lung model of instilled liquid transport in the pulmonary airways. J. Appl. Physiol. 90:1955–1967, 2001.
Cassidy, K. J., N. Gavriely, and J. B. Grotberg. Liquid plug flow in straight and bifurcating tubes. J. Biomech. Eng. 123:580–589, 2001.
Choi, J. W., H.-C. Kim, and R. Wicker. Multi-material stereolithography. J. Mater. Proc. Technol. 211:318–328, 2011.
Copploe, A., M. Vatani, R. Amini, J. W. Choi, and H. Tavana. Engineered airway models to study liquid plug splitting at bifurcations: effects of orientation and airway size. J. Biomech. Eng. 2018. https://doi.org/10.1115/1.4040456.
Filoche, M., C. F. Tai, and J. B. Grotberg. Three-dimensional model of surfactant replacement therapy. Proc. Natl. Acad. Sci. USA. 112:9287–9292, 2015.
Fujioka, H., and J. B. Grotberg. Steady propagation of a liquid plug in a two-dimensional channel. J. Biomech. Eng. 126:567–577, 2004.
Fujioka, H., and J. B. Grotberg. The steady propagation of a surfactant-laden liquid plug in a two-dimensional channel. Phys. Fluids. 17:082102, 2005.
Gaver, D. P., and J. B. Groberg. Droplet spreading on a thin viscous film. J. Fluid Mech. 235:399–414, 1992.
Gaver, III, D. P., R. W. Samsel, and J. Solway. Effects of surface tension and viscosity on airway reopening. J. Appl. Physiol. 69:74–85, 1990.
Ghadiali, S. N., and D. P. Gaver, 3rd. An investigation of pulmonary surfactant physicochemical behavior under airway reopening conditions. J. Appl. Physiol. 88:493–506, 2000.
Grotberg, J. B. Respiratory fluid mechanics and transport processes. Annu. Rev. Biomed. Eng. 3:421–457, 2001.
Grotberg, J. B. Respiratory fluid mechanics. Phys. Fluids. 23:21301, 2011.
Halpern, D., O. E. Jensen, and J. B. Grotberg. A theoretical study of surfactant and liquid delivery into the lung. J. Appl. Physiol. 85:333–352, 1998.
Hope, R. L., R. N. Roth, and P. A. Jacobs. Adaptive slicing with sloping layer surfaces. Rapid Prototyp. J. 3:89–98, 1997.
Kitaoka, H., R. Takaki, and B. Suki. A three-dimensional model of the human airway tree. J. Appl. Physiol. 87:2207–2217, 1999.
Lasalvia, M., S. Castellani, P. D’Antonio, G. Perna, A. Carbone, A. L. Colia, A. B. Maffione, V. Capozzi, and M. Conese. Human airway epithelial cells investigated by atomic force microscopy: a hint to cystic fibrosis epithelial pathology. Exp. Cell Res. 348:46–55, 2016.
Lewis, J. F., and R. A. Veldhuizen. The future of surfactant therapy during ALI/ARDS. Semin. Respir. Crit. Care Med. 27:377–388, 2006.
Lista, G., F. Castoldi, S. Bianchi, and F. Cavigioli. Surfactant and mechanical ventilation. Acta Biomed. 83(Suppl 1):21–23, 2012.
Perun, M. L., and D. P. Gaver, 3rd. An experimental model investigation of the opening of a collapsed untethered pulmonary airway. J. Biomech. Eng. 117:245–253, 1995.
Petrak, D., E. Atefi, L. Yin, W. Chilian, and H. Tavana. Automated, spatio-temporally controlled cell microprinting with polymeric aqueous biphasic system. Biotechnol. Bioeng. 111:404–412, 2014.
Phalen, R. F., H. C. Yeh, G. M. Schum, and O. G. Raabe. Application of an idealized model to morphometry of the mammalian tracheobronchial tree. Anat. Rec. 190:167–176, 1978.
Polin, R. A., and W. A. Carlo. Surfactant replacement therapy for preterm and term neonates with respiratory distress. Pediatrics. 133:156–163, 2014.
Saad, S. M., Z. Policova, E. J. Acosta, and A. W. Neumann. Effect of surfactant concentration, compression ratio and compression rate on the surface activity and dynamic properties of a lung surfactant. Biochim. Biophys. Acta. 103–16:2012, 1818.
Sabourin, E., S. A. Houser, and J. H. Bøhn. Adaptive slicing using stepwise uniform refinement. Rapid Prototyp. J. 2:20–26, 1996.
Sauret, V., P. M. Halson, I. W. Brown, J. S. Fleming, and A. G. Bailey. Study of the three-dimensional geometry of the central conducting airways in man using computed tomographic (CT) images. J. Anat. 200:123–134, 2002.
Stevens, T. P., and R. A. Sinkin. Surfactant replacement therapy. Chest. 131:1577–1582, 2007.
Szpinda, M., M. Daroszewski, A. Wozniak, A. Szpinda, and C. Mila-Kierzenkowska. Tracheal dimensions in human fetuses: an anatomical, digital and statistical study. Surg. Radiol. Anat. 34:317–323, 2012.
Tavana, H., D. Huh, J. B. Groberg, and S. Takayama. Microfluidics, lung surfactant, and respiratory disorders. Lab. Med. 40:203–209, 2009.
Tavana, H., C. H. Kuo, Q. Y. Lee, B. Mosadegh, D. Huh, P. J. Christensen, J. B. Grotberg, and S. Takayama. Dynamics of liquid plugs of buffer and surfactant solutions in a micro-engineered pulmonary airway model. Langmuir. 26:3744–3752, 2010.
Veldhuizen, E. J., and H. P. Haagsman. Role of pulmonary surfactant components in surface film formation and dynamics. Biochim. Biophys. Acta. 1467:255–270, 2000.
Weibel, E. R., and D. M. Gomez. Architecture of the human lung. Use of quantitative methods establishes fundamental relations between size and number of lung structures. Science. 137:577–585, 1962.
West, J. B. Respiratory Physiology: The Essentials. Oxford: Blackwell Scientific, 2015.
Zheng, Y., H. Fujioka, J. C. Grotberg, and J. B. Grotberg. Effects of inertia and gravity on liquid plug splitting at a bifurcation. J. Biomech. Eng. 128:707–716, 2006.
Acknowledgments
Financial support was provided by a University of Akron Firestone Fellowship to H.T and a grant CA216413 from National Institutes of Health.
Conflict of interest
The authors do not have any conflict of interest to declare.
Author information
Authors and Affiliations
Corresponding author
Additional information
Associate Editor Joel Stitzel oversaw the review of this article.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Supplementary material 1 (MOV 7872 kb)
Supplementary material 2 (MOV 10029 kb)
Rights and permissions
About this article
Cite this article
Copploe, A., Vatani, M., Choi, JW. et al. A Three-Dimensional Model of Human Lung Airway Tree to Study Therapeutics Delivery in the Lungs. Ann Biomed Eng 47, 1435–1445 (2019). https://doi.org/10.1007/s10439-019-02242-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10439-019-02242-z
Keywords
- 3D lung airway tree
- Computational design
- Additive manufacturing
- Physical models
- Surfactant delivery