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International Journal of Bioprinting 3D-bioprinted multicellular lung organoids

In the realm of drug development and respiratory 1.2. The emergence of bioprinting technology for
research, creating and utilizing accurate disease models lung models
is crucial for understanding disease mechanisms and Previous studies have used either two-dimensional
testing potential treatments. To replicate actual respiratory (2D) cell culture methods or 3D constructs to create in
diseases, various agents including bleomycin (BLM), vitro alveolar models. 2D cell culture methods involve
particulate matter (PM2.5), tobacco smoke, and porcine growing cells in a flat, 2D layer, which allows for easy
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pancreatic elastase (PPE) have long been fundamental observation and manipulation of cells. These methods
tools in the study of pulmonary diseases. While the are cost-effective and relatively simple, making them a
3–6
BLM model is widely used to study pulmonary fibrosis, popular choice for initial studies. However, 2D cultures
it primarily induces acute lung injury, which typically fail to replicate the 3D environment of tissues, leading to
resolves over time in mice. Models utilizing tobacco differences in cell morphology, polarization, and function
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smoke, PM2.5, and PPE exposure are essential for studying compared to in vivo conditions. This limitation hampers
diseases like COPD. In addition, lung cancer mouse models the study of cell–cell and cell–matrix interactions, which
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induced by gene mutations such as EGFR and P53 are also are crucial for understanding cellular behavior in a more
significant in research. However, these models present physiologically relevant context. 17
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substantial limitations that can hinder the translation On the other hand, 3D constructs provide a 3D scaffold
of research findings to human applications. The rapid that supports more complex cell growth, allowing cells to
clearance mechanisms in mice contrast with the slower, interact with their surroundings in a manner more akin
more cumulative effects observed in human lungs, leading to natural tissues. These constructs can be created using a
to differences in disease manifestation and severity. The variety of materials, including hydrogels, which mimic the
differences in metabolism and immune responses between extracellular matrix (ECM) and provide biochemical cues
mice and humans can also result in variations in drug to the cells. 3D culture systems can better simulate the
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processing and side effects. 10,11 Compounds metabolized physical and biochemical environment of tissues, resulting
differently can demonstrate efficacy or toxicity in mice in more accurate representations of cellular functions,
that do not translate to humans. This discrepancy poses differentiation patterns, and responses to stimuli. However,
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a significant challenge to the predictive value of mouse these approaches still face limitations, such as the difficulty
models for human pharmacology. in precisely controlling the spatial distribution of cells
and materials, as well as the challenge of replicating the
The use of animals in research, especially for conditions intricate architecture of native tissues at a high resolution.
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that could be studied through alternative methods, also To address these limitations, 3D bioprinting technology
raises ethical concerns. Furthermore, maintaining animal has emerged. This technology allows for precise control
facilities is costly and resource-intensive, which could over the spatial distribution of materials and cells,
otherwise be allocated towards developing and refining enabling the recreation of complex tissue structures using
alternative models. Given these limitations, there is an a variety of materials, including hydrogels and polymers.
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increasing emphasis on developing alternative models Consequently, 3D bioprinting offers significant advantages
that can better mimic human lung diseases. Advances for the development of in vitro alveolar models by better
in organ-on-a-chip technology, three-dimensional (3D) replicating the structural complexity of alveoli and
bioprinting, and ex vivo human lung tissue cultures offer enhancing the cellular environment. This is crucial for
promising avenues. These technologies not only replicate accurately representing cell growth, differentiation, and
human tissue architecture and physiological responses native physiological conditions, which are essential for
more accurately but also allow for the study of human- applications such as drug screening and disease research. 21
specific disease processes and treatment responses. 13–15 The
shift towards these innovative models could significantly This review focuses on the application of bioprinting
improve the predictive accuracy of preclinical trials and technologies in modeling lung disease. Firstly, we examine
enhance the development of more effective therapies. organoids for disease modeling in the lung, discussing
their advantages and limitations. Following this, we
Hence, while traditional in vivo mouse models have explore research involving 3D bioprinting technology,
provided foundational insights into pulmonary diseases, proposing strategies to overcome the aforementioned
their limitations in translating findings to human conditions challenges. Despite the promise of these technologies,
necessitate the development of advanced, human-relevant there are inherent limitations that need to be addressed.
models. The integration of these new technologies into Finally, we delve into bioprinting-based lung organoid
respiratory research and drug development is crucial for disease modeling techniques and strategies, discussing
making significant strides in treating lung diseases. their potential and the future directions for this field.

Volume 10 Issue 6 (2024) 2 doi: 10.36922/ijb.4092