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International Journal of Bioprinting Applications of 3D printing in aging

have shown that oxidative stress, defective mitochondrial to simulate physical and biochemical signaling, various
function, protein misfolding and aggregation, and glial 3D culture systems, such as cell biology-based models
cell proliferation play a significant part in the degenerative (spheres and organs) and engineered models (scaffolds and
death of dopaminergic neurons [66,67] . microfluidic platforms), are now becoming more and more
popular [76,77] . For example, human pluripotent stem cells
3.1.3. Amyotrophic lateral sclerosis were differentiated by Jo et al. into massive multicellular
[77]
A defining feature of ALS is the progressive degeneration organoid structures with unique neuronal cell layers that
of motor neurons in the brain and spinal cord, a rare expressed markers specific to the human midbrain. More
neurological illness that affects both upper and lower motor importantly, dopamine synthesis, electrically active, and
neurons. The clinical manifestations are progressive muscle functionally developed midbrain dopaminergic (mDA)
weakness and atrophy throughout the body, and patients neurons were found in the 3D midbrain-like organoid.
eventually die due to swallowing and breathing difficulties. The 3D midbrain-like organoids (MLO) were found to be
The imbalance of neural protein homeostasis, abnormal structurally similar to neuromelanin-like particles from
proteins proliferation and spreading in a prion-like human substantia nigra tissue. Unlike human mDA neurons
manner, mitochondria malfunction, glutamate-mediated produced using a 2D technique, MLOs are produced from
excitatory neurotoxicity, impaired intraneuronal substance mouse embryonic stem cells. The emergence of pluripotent
transport, and RNA metabolism disorders, are all currently stem cell-based neural-like organs more realistically
recognized mechanisms of ALS pathogenesis [68-70] . simulates the developmental progress of the nervous
system. It offers a non-ethically constrained platform for
3.1.4. The role of 3D printing in the treatment and studying human neurodevelopment, a new platform for
research of neurological diseases drug screening, and a highly informative complement to
Although great efforts have been made over the years to existing 2D culture methods and animal model systems .
[78]
study NDD, only limited progress is made because the In addition, organoids have made it possible to obtain
human nervous system is one of the most hierarchically cells closer to natural human development for cell therapy.
and functionally complicated biological systems. The However, the organoid-based 3D models are limited by the
inherent difficulty in obtaining human tissue samples relatively simple structure as well as the absence of vascular
presents the biggest hurdle to the understanding of human nerve distribution and extracellular microenvironment.
central nervous system development; therefore, research in
this area traditionally rely on studies conducted in animal The emergence of 3D bioprinting has provided a new
models . Animal models are the gold standard because tool for 3D culture, and the combination of 3D printing
[71]
they have the highest level of physiological relevance. and organoid can effectively address the aforementioned
Nevertheless, owing to significant genetic, biochemical, problems. 3D printing can automatically reproduce
and metabolic differences between species, animal models predesigned models using cells and biological materials
frequently do not accurately reflect the reality of human to simulate the complex tissue structure and natural
patients . Furthermore, animal tests are time-consuming physiological environment. Lozano et al. proposed a
[72]
[13]
and expensive. Meanwhile, ex vivo models cultured with new approach for bioprinting 3D brain-like structures
neural sectioning and cell-based 2D in vitro culture models consisting of discrete layers of primary neuronal cells
have been widely used. The former has the advantage of encapsulated in hydrogels (Figure 2A). The brain-like
easy experimental manipulation and easy correction for structure was 3D-printed by using a bioink composed of
image analysis. However, once the section is separated peptide-modified gellan gum RGD (RGD-GG; RGD stands
from the body, significant functionality is rapidly lost . for arginine-glycine-aspartic acid) and primary cortical
[73]
The latter is also widely used today due to its ease of neurons. The bioinks had the ability to accommodate
manipulation and low cost, but 2D cultures are usually and support the cell growth and network formation in
insufficient to reproduce specific physiological features specific hierarchical structures, and can be 3D-printed
due to many limitations such as insufficient intercellular into multilayer brain-like structures by direct ink writing
interactions with the extracellular matrix . A more (DIW). More precise 3D in vitro microstructures could be
[74]
complex environment and longer lifespan are provided by duplicated using these 3D-printed brain-like structures,
3D cell cultures which also tend to be more instructive and which would help us comprehend the mechanisms of
prescriptive . A superior in vitro complement to animal brain damage and neurodegenerative disorders. NDD
[75]
models is thought to be 3D neuronal models because of usually lead to irreversible neuronal damage and death.
their closer physiological relevance. As a result of their Promoting neuronal targeting and regeneration is one
capability of producing more accurate neural tissue-like solution to treating NDD, and directly 3D printing neural
structures that combine various cell types and materials stem cells (NSCs) to create novel scaffolds that promote

Volume 9 Issue 4 (2023) 237 https://doi.org/10.18063/ijb.732