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International Journal of Bioprinting 3D-bioprinted multicellular lung organoids

including various inflammatory lung diseases such as lung tissue repair and wound healing. 52,53 Therefore, the
pulmonary hypertension and pulmonary edema. 36,37 main challenge in developing lung organoids is to simulate
The interactions among these various cell types help the developmental process and complex structure and
maintain proper lung functions and enable recovery from function of the real human lung. In addition, bronchial
environmental damage. A deep understanding of the organoids can be differentiated into various epithelial cells,
lungs‘ anatomical structure and the functions of these cells including club cells, basal cells, and other cell types that
provides foundational knowledge that is crucial for the exist in the real bronchi, to reproduce the secretion and
function of mucus in the real bronchi.
Recently, they
54,55
treatment and management of respiratory diseases. This have also been used to simulate lung development to study
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comprehensive understanding is essential for optimizing the mechanisms of genetic and infantile lung diseases such
clinical interventions and developing more effective as bronchopulmonary dysplasia. 56–58
treatments for specific respiratory conditions.
Currently, researchers are trying to overcome this
2.2. Definition and description of organoids challenge by optimizing the type of cells, 3D culture
An organoid is an assembly of cells cultured in 3D conditions, and composition of the ECM. However, the
environments to mimic the structure and function of a existing studies present several limitations. First, there
human organ or tissue. This advanced technology is are limitations in perfectly recreating the structure of
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useful in various fields such as regenerative medicine, alveoli and bronchioles. For example, the significantly
disease modeling, and drug development. Traditional higher proportion of AT2/AT1 cells in alveolar organoids
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animal disease modeling and 2D cell cultures are limited compared to human lung tissue indicates that organoids
in their ability to accurately mimic human organs or are not yet perfect mimics. This is probably because
disease pathogenesis. For example, lung diseases in most organoids are made by inducing a certain amount
humans are often mostly irreversible, whereas mouse of differentiation of AT2 into AT1 cells. 59–61 Second, lung
animal models have a rapid recovery, which limits their organoids are mainly composed of cells derived from
ability to simulate diseases caused by cellular senescence specific stem cells. Therefore, it is difficult to differentiate
and viral infections. 41–43 In addition, due to differences in all cell types present in the lungs from stem cells. For
gene and protein structures from humans, it is difficult to example, ECs are key regulators of interleukins, which
apply therapeutic strategies from animal disease models are important for homeostasis and inflammation. 62–64 In
to humans due to clear differences in mechanisms. addition, immune cells such as macrophages regulate
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Traditional 2D cell cultures are grown as monolayers of the lung microenvironment through the release of pro-
cells on flat surfaces, which limits cell–cell interactions inflammatory cytokines and chemokines. 65–67 The absence
and spatial arrangements compared to real human organs of these cells can lead to inaccurate results in drug efficacy
and tissue. In contrast, organoids are made using real testing and disease mechanism studies using organoids.
human cells, so they have the same genes as humans, and Therefore, increasing the similarity of lung organoids to
the tissue environment they create can more accurately actual lung tissue is essential to enhance their potential.
mimic disease, enabling precise prediction of how they will In addition, developing lung organoid models for
respond in the organ. 45,46 They also use complex culture reproducible organoid production and mass production
media, including ECM, to simulate the cells‘ natural for high-throughput drug efficacy validation systems will
environment. This not only provides physical support improve their utility. 68
for the cells but also a variety of biochemical signals that
regulate their differentiation and function. 47 Recently, several studies have been reported to
overcome these challenges. To overcome the limitation of
2.3. Advantages and limitation of 3D lung alveolar organoids consisting of only AT1 and AT2 cells,
organoid models da Rosa et al. cultured Wharton‘s jelly mesenchymal stem
Lung organoids are primarily generated using human cells using sodium alginate and gelatin matrix bioprinting,
pluripotent stem cells (hPSCs), which form the various and confirmed their differentiation into ciliated and goblet
cell types that compose lung tissue. 48,49 During this process, cells. There is also active research to validate alveolar
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they use the ECM to form 3D structures, which can recreate organoids to mimic the tumor microenvironment. Mu
various functions of the lungs. For example, the development et al. co-cultured PBMCs from peripheral blood with
of lung alveolar organoids can simulate the structure of air patient-derived NSCLC organoids and demonstrated
sacs in the lungs by inducing differentiation into AT1 cells tumor suppression by T-cell responses. The potential of
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for gas exchange and AT2 cells for repairing AT1 cells. 50,51 lung organoids depends on their similarity to real lung
In other studies, organoid models have also been reported tissue, and the composition of the microenvironment must
to identify fibroblast activation, which is important for continue to be studied.

Volume 10 Issue 6 (2024) 4 doi: 10.36922/ijb.4092