A microfluidic lung‐on‐a‐chip based on biomimetic hydrogel membrane

Lung‐on‐chips have showed great promise as a tool to recapitulate the respiratory system for investigation of lung diseases in the past decade. However, the commonly applied artificial elastic membrane (e.g., polydimethylsiloxane, PDMS) in the chip failed to mimic the alveolar basal membrane in the composition and mechanical properties. Here we replaced the PDMS film by a thin, biocompatible, soft, and stretchable membrane based on F127‐DA hydrogel that well approached to the composition and stiffness of extracellular matrix in human alveoli for construction of lung‐on‐a‐chip. This chip well reconstructed the mechanical microenvironments in alveoli so that the epithelial/endothelial functions were highly expressed with a well established alveolar‐capillary barrier. In opposite to the unexpectedly accelerated fibrotic process on the PDMS‐based lung‐on‐a‐chip, HPAEpiCs on hydrogel‐based chip only presented fibrosis under nonphysiologically high strain, well reflecting the features of pulmonary fibrosis in vivo. This physiologically relevant lung‐on‐a‐chip would be an ideal model in investigation of lung diseases and for development of antifibrosis drugs.

[1]  S. Saha,et al.  Recent advances in lung-on-a-chip models. , 2022, Drug discovery today.

[2]  J. Borenstein,et al.  The microfluidic artificial lung: Mimicking nature's blood path design to solve the biocompatibility paradox. , 2022, Artificial organs.

[3]  Yuanjin Zhao,et al.  A Biomimetic Human Lung‐on‐a‐Chip with Colorful Display of Microphysiological Breath , 2022, Advanced materials.

[4]  Carlos Ezio Garciamendez-Mijares,et al.  Reversed-engineered human alveolar lung-on-a-chip model , 2021, Proceedings of the National Academy of Sciences.

[5]  O. Guenat,et al.  Second-generation lung-on-a-chip with an array of stretchable alveoli made with a biological membrane , 2021, Communications biology.

[6]  O. Akbari,et al.  Distinct Roles of LFA-1 and ICAM-1 on ILC2s Control Lung Infiltration, Effector Functions, and Development of Airway Hyperreactivity , 2020, Frontiers in Immunology.

[7]  J. Qin,et al.  Biomimetic Human Disease Model of SARS‐CoV‐2‐Induced Lung Injury and Immune Responses on Organ Chip System , 2020, Advanced science.

[8]  Guoying Yu,et al.  Alveolar cells under mechanical stressed niche: critical contributors to pulmonary fibrosis , 2020, Molecular medicine.

[9]  R. Rottier,et al.  3D alveolar in vitro model based on epithelialized biomimetically curved culture membranes. , 2020, Biomaterials.

[10]  J. Bates,et al.  Multi-scale Models of Lung Fibrosis. , 2020, Matrix biology : journal of the International Society for Matrix Biology.

[11]  Joo-Hyeon Lee,et al.  Alveolar wars: The rise of in vitro models to understand human lung alveolar maintenance, regeneration, and disease , 2020, Stem cells translational medicine.

[12]  Chong Shen,et al.  Non-swelling hydrogel-based microfluidic chips. , 2019, Lab on a chip.

[13]  S. Yao,et al.  Resolvin D1 attenuates mechanical stretch-induced pulmonary fibrosis via epithelial-mesenchymal transition. , 2019, American journal of physiology. Lung cellular and molecular physiology.

[14]  Yuan Zhang,et al.  Biomimetic human lung-on-a-chip for modeling disease investigation. , 2019, Biomicrofluidics.

[15]  P. Bagchi,et al.  Three‐dimensional distribution of wall shear stress and its gradient in red cell‐resolved computational modeling of blood flow in in vivo‐like microvascular networks , 2019, Physiological reports.

[16]  L. Niklason,et al.  Extracellular matrix in lung development, homeostasis and disease. , 2018, Matrix biology : journal of the International Society for Matrix Biology.

[17]  N. Jeon,et al.  PDMS Sylgard 527-Based Freely Suspended Ultrathin Membranes Exhibiting Mechanistic Characteristics of Vascular Basement Membranes. , 2018, ACS applied materials & interfaces.

[18]  Chong Shen,et al.  Synthesis of F127/PAA hydrogels for removal of heavy metal ions from organic wastewater. , 2018, Colloids and surfaces. B, Biointerfaces.

[19]  Ruogang Zhao,et al.  Fibrotic microtissue array to predict anti-fibrosis drug efficacy , 2018, Nature Communications.

[20]  E. Young,et al.  Microfluidic lung airway-on-a-chip with arrayable suspended gels for studying epithelial and smooth muscle cell interactions. , 2018, Lab on a chip.

[21]  A. Mammoto,et al.  Primary Human Lung Alveolus‐on‐a‐chip Model of Intravascular Thrombosis for Assessment of Therapeutics , 2018, Clinical pharmacology and therapeutics.

[22]  Xinghua Gao,et al.  Nanofiber membrane supported lung-on-a-chip microdevice for anti-cancer drug testing. , 2018, Lab on a chip.

[23]  Donald E Ingber,et al.  Human Organ Chip Models Recapitulate Orthotopic Lung Cancer Growth, Therapeutic Responses, and Tumor Dormancy In Vitro. , 2017, Cell reports.

[24]  Y. Sakuma.  Epithelial‐to‐mesenchymal transition and its role in EGFR‐mutant lung adenocarcinoma and idiopathic pulmonary fibrosis , 2017, Pathology international.

[25]  C. Ruppert,et al.  Tissue remodelling in pulmonary fibrosis , 2017, Cell and Tissue Research.

[26]  J. Tarbell,et al.  Endothelial Glycocalyx-Mediated Nitric Oxide Production in Response to Selective AFM Pulling. , 2017, Biophysical journal.

[27]  J. Capadona,et al.  In vitro evaluation and in vivo demonstration of a biomimetic, hemocompatible, microfluidic artificial lung. , 2015, Lab on a chip.

[28]  A. E. El Haj,et al.  Hydrogels for lung tissue engineering: Biomechanical properties of thin collagen-elastin constructs. , 2014, Journal of the mechanical behavior of biomedical materials.

[29]  M. Selman,et al.  Revealing the pathogenic and aging-related mechanisms of the enigmatic idiopathic pulmonary fibrosis. an integral model. , 2014, American journal of respiratory and critical care medicine.

[30]  H. Chapman,et al.  Activated alveolar epithelial cells initiate fibrosis through secretion of mesenchymal proteins. , 2013, The American journal of pathology.

[31]  D. Navajas,et al.  Local micromechanical properties of decellularized lung scaffolds measured with atomic force microscopy. , 2013, Acta biomaterialia.

[32]  Wenxin Wang,et al.  Application of a microfluidic chip-based 3D co-culture to test drug sensitivity for individualized treatment of lung cancer. , 2013, Biomaterials.

[33]  Linhong Deng,et al.  Substrate stiffness influences TGF-β1-induced differentiation of bronchial fibroblasts into myofibroblasts in airway remodeling. , 2013, Molecular medicine reports.

[34]  Ashley C. Brown,et al.  Physical and chemical microenvironmental cues orthogonally control the degree and duration of fibrosis‐associated epithelial‐to‐mesenchymal transitions , 2013, Journal of Pathology.

[35]  T. Barker,et al.  Matrix stiffness-induced myofibroblast differentiation is mediated by intrinsic mechanotransduction. , 2012, American journal of respiratory cell and molecular biology.

[36]  Daniel C Leslie,et al.  A Human Disease Model of Drug Toxicity–Induced Pulmonary Edema in a Lung-on-a-Chip Microdevice , 2012, Science Translational Medicine.

[37]  Arthur S Slutsky,et al.  Mechanical stress induces lung fibrosis by epithelial–mesenchymal transition* , 2012, Critical care medicine.

[38]  Thomas A. Wynn,et al.  Integrating mechanisms of pulmonary fibrosis , 2011, The Journal of experimental medicine.

[39]  Patrick Tabeling,et al.  Benzophenone absorption and diffusion in poly(dimethylsiloxane) and its role in graft photo-polymerization for surface modification. , 2011, Langmuir : the ACS journal of surfaces and colloids.

[40]  D. Ingber,et al.  Reconstituting Organ-Level Lung Functions on a Chip , 2010, Science.

[41]  C. Hogaboam,et al.  Murine models of pulmonary fibrosis. , 2008, American journal of physiology. Lung cellular and molecular physiology.

[42]  M. Beers,et al.  Surfactant protein C: its unique properties and emerging immunomodulatory role in the lung. , 2006, Microbes and infection.

[43]  G. Laurent,et al.  Pulmonary fibrosis: searching for model answers. , 2005, American journal of respiratory cell and molecular biology.

[44]  A. Nicholson,et al.  Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis. , 2005, The American journal of pathology.

[45]  Yu Wang,et al.  Mechanical stretch promotes alveolar epithelial type II cell differentiation. , 2001, Journal of applied physiology.

[46]  B. Guery,et al.  Keratinocyte growth factor increases transalveolar sodium reabsorption in normal and injured rat lungs. , 1997, American journal of respiratory and critical care medicine.

[47]  G. Ahlborg,et al.  Metabolism of Big endothelin-1 (1–38) and (22–38) in the human circulation in relation to production of endothelin-1 (1–21) , 1995, Regulatory Peptides.

[48]  S. Alahari,et al.  Regulation of epithelial-mesenchymal transition through epigenetic and post-translational modifications , 2016, Molecular Cancer.

[49]  Jennie B. Leach,et al.  Extracellular Matrix , 2015, Neuromethods.

[50]  A. Koutsiaris,et al.  Volume flow and wall shear stress quantification in the human conjunctival capillaries and post-capillary venules in vivo. , 2007, Biorheology.

[51]  N. Secher,et al.  Decrease in pulmonary diffusion capacity after maximal exercise. , 1986, Journal of sports sciences.