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International Journal of Bioprinting 3D-bioprinted respiratory disease model

1. Introduction Tissue engineering focuses on integrating engineering
design principles with molecular biology to create
It is well-known and documented that respiratory diseases functional tissues, including skin, liver, kidney, and
have a significant impact on healthcare systems globally. bone, among others. While various branches of tissue
Aside from pandemics, chronic respiratory diseases, engineering focus on regenerative medicine applications,
including chronic obstructive pulmonary disease (COPD), such as organ/tissue transplants or grafts, a significant
pulmonary cystic fibrosis, and asthma, are the third leading segment of respiratory tissue engineering (RTE) is focused
cause of death worldwide. Further, there are approximately on expanding the respiratory modeling capacity to allow
1,2
one billion influenza A cases per year, with 3–5 million researchers and medical professionals to gain a better
resulting in severe illness, along with many other viral understanding of both pre-existing and emerging diseases,
3,4
respiratory infections. The influenza A virus (IAV), which as well as expanding pre-clinical options for screening
can be further classified into subtypes based on their viral therapeutics. 22-24 Currently, 2D in vitro and animal
surface proteins (H1N1, H3N2, etc.), is the most common models are used in pre-clinical research for respiratory
type of virus that infects humans. It preferentially infects diseases; however, there is still a lack of understanding of
the respiratory epithelium through α2,6-linked sialic acid various pathogens and conditions, with many promising
receptors found on the nasal epithelium to the respiratory therapeutics from these trials failing at the clinical
bronchioles. Tight junctions between epithelial cells, stage. 25-27 As 2D in vitro models often lack relevance due
5-8
apical polarity, and antimicrobial and mucosal excretions, to their simplicity, and animal models may not accurately
all act as a first line of defense against infection; however, reflect human physiology, there is a knowledge gap that
if the virus crosses these barriers and bonds to a sialic could be addressed by developing complex humanized 3D
acid receptor, it is internalized via receptor-mediated tissue constructs.
endocytosis where conformational changes induce the Bioprinting is a promising approach to developing such
release of viral RNA and proteins into the cytoplasm. 3D humanized constructs. By depositing human cell-
9,10
28
These viral proteins then enter the nucleus and utilize the laden biomaterials in a layer-by-layer manner, bioprinting
host’s machinery to initiate viral replication. 5,6,9 During allows for the recapitulation of hierarchical structures,
this process, pattern recognition receptors recognize the such as the respiratory epithelium. 22,29,30 Biocompatible
relevant pathogen-associated molecular patterns (PAMPs), materials, including alginate, gelatin, and collagen, are
triggering various signaling pathways to initiate a stronger commonly utilized in tissue engineering as they exhibit
immune response. 5,6,9 a combination of printability/compatibility with ionic
As part of the immune response to infection, various or thermal crosslinking, cell binding motifs, and post-
cytokines/chemokines are released, including interleukins printing mechanical stability. 31-33 While 3D hierarchical
(IL)-8, 29, and 1β along with interferon gamma-induced constructs improve upon the relevance and complexity of
protein 10 (IP-10). 11-13 IL-8, also known as chemokine 2D models, methods of further increasing the relevance
C-X-C motif ligand 8, is produced by epithelial cells of these constructs include the use of bioreactors during
and macrophages, and it induces chemotaxis in target culture to mimic the biomechanical stimulus that native
cells to facilitate the migration of neutrophils or other tissues experience, as well as incorporating biochemical
granulocytes to the site of infection, further stimulating stimuli such as growth factors to guide cellular growth
phagocytosis. 14,15 IL-29 is a type III interferon, primarily and differentiation. 33-36 Respiratory tissue is subjected to
produced by epithelial cells. Upon viral infection, IL- constant expansion and relaxation, shear forces imposed
16
29 is released and exhibits antiviral responses aiming by airflow, and pressure changes. It was previously found
to stimulate the production of antiviral proteins and that including these stimuli on bioprinted respiratory
upregulate the expression of major histocompatibility tissue stimulates cellular proliferation. 34,37,38 Controlled
complex I molecules. 16,17 IL-1β is a cytokine that is cleaved release of growth factors through the use of growth
by cytosolic caspase 1 to form mature IL-1β. Produced by factor-incorporating nanoparticles was also reported to
18
33
activated macrophages and monocytes, IL-1β plays a role promote epithelialization.
in mediating the inflammatory response and apoptosis. 18,19 The current state of the field is promising, with various
IP-10 is a small cytokine secreted by monocytes and models developed, including 3D-printed models focused
fibroblasts, and it acts as a chemoattractant for immune on creating an in vitro air-blood barrier, 39,40 as well as
cells among other functions. 20,21 Collectively, along with others that have demonstrated the feasibility of infecting
various other signaling molecules and pathways, these 3D-bioprinted respiratory constructs with IAV 39,41 and
chemokines can be used to demonstrate the extent of a their use in bacterial and inhibitor studies. These studies
42
cellular immune response to infection. have identified 3D bioprinting as a promising avenue

Volume 10 Issue 6 (2024) 408 doi: 10.36922/ijb.3895