3D pulmonary fibrosis model for anti-fibrotic drug discovery by inkjet-bioprinting

Abstract

Pulmonary fibrosis is known as a chronic and irreversible disease characterized by excessive extracellular matrix accumulation and lung architecture changes. Large efforts have been made to develop prospective treatments and study the etiology of pulmonary fibrotic diseases utilizing animal models and spherical organoids. As part of these efforts, we created an all-inkjet-printed three-dimensional (3D) alveolar barrier model that can be used for anti-fibrotic drug discovery. Then, we developed a pulmonary fibrosis model by treating the 3D alveolar barrier with pro-fibrotic cytokine and confirmed that it is suitable for the fibrosis model by observing changes in structural deposition, pulmonary function, epithelial-mesenchymal transition, and fibrosis markers. The model was tested with two approved anti-fibrotic drugs, and we could observe that the symptoms in the disease model were alleviated. Consequently, structural abnormalities and changes in mRNA expression were found in the developed fibrosis model, which were shown to be recovered in all drug treatment groups. The all-inkjet-printed alveolar barrier model was reproducible for disease onset and therapeutic effects in the human body. This finding emphasized that the in vitro artificial tissue with faithfully implemented 3D microstructures using bioprinting technology may be employed as a novel testing platform and disease model to evaluate potential drug efficacy.

Advanced 3D In Vitro Lung Fibrosis Models: Contemporary Status, Clinical Uptake, and Prospective Outlooks

“…Afterward, this alveolar lung model was treated with TGF-β1 to examine pulmonary fibrosis. To observe fibrotic marker changes with disease development and the effect of antifibrotic medications, tissue shape, collagen deposition, pulmonary function, and EMT were evaluated . An organized network and a barrier regulating the movement of molecules from the adjoining vasculature to the neighboring tissue inside a bioengineered model are crucial for maintaining tissue viability and performance .…”

“…We think using an integrated strategy, such as 3D bioprinting combined with fluid flow, will aid in presenting the most comprehensive disease picture. Effects of Nintedanib and Pirfenidone have been successfully evaluated with clinical significance using these model systems. ,, Further screening of the non-approved drugs and different inhibitors can help answer why certain individuals are more susceptible to fibrosis than others. Phase I clinical trials could be shortened by optimizing dosing regimens for novel therapeutics through quantitative and predictive characteristics .…”

“…To observe fibrotic marker changes with disease development and the effect of antifibrotic medications, tissue shape, collagen deposition, pulmonary function, and EMT were evaluated. 146 An organized network and a barrier regulating the movement of molecules from the adjoining vasculature to the neighboring tissue inside a bioengineered model are crucial for maintaining tissue viability and performance. 147 Using stereolithography and photo-cross-linkable bioink, it is possible to print a distal lung model with a fine vasculature.…”

3D bioprinted vascularized lung cancer organoid models with underlying disease capable of more precise drug evaluation

“…In particular, treatment with agents that induce fibrosis from the external environment (e.g. bleomycin, TGF-β, etc) is excluded [58,59]. To recapitulate the actual patient's fibrotic environment, we tried to mimic the cell-derived fibrotic niche using human iLFs produced from IPF patients.…”

3D Inkjet-Bioprinted Lung-on-a-Chip

“…Bioprinting is a versatile technology that enables the automated fabrication of complex 3D-structured tissue models. , Computer-assisted deposition of cell-laden bioink enables the 3D fabrication of living tissues in a layer-by-layer manner, which allows high repeatability, reproducibility, and mass production by minimizing human intervention. , Among various bioprinting techniques, drop-on-demand inkjet bioprinting is capable of positioning living mammalian cells with micron resolution by ejecting a picolitre volume of the cell suspension, typically down to a single cell. , Inkjet offers the ability to construct thin and complex tissues layer-by-layer with different cell types by switching bioinks . The high-resolution patterning of living cells by inkjet has been demonstrated in 2D and 3D environments. , To date, bioprinting methods have been used for a wide range of tissues such as skin, , heart, bladder, , and lung. − Most of these studies have cultured bioprinted tissues under static conditions, so integrating with a microfluidic platform is a pivotal future step to mimic the in vivo environment by providing perfused culture conditions. Integrating inkjet bioprinting and the organ-on-a-chip platform has the synergistic potential to achieve a new generation of manufacturable in vitro models with structurally and physiologically more relevant 3D tissues in highly controlled cell–cell and cell-extracellular matrix communication interactions.…”