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International Journal of Bioprinting Bioprinting of DNA hydrogels for bone organoids

Figure 3. In vitro construction of bone organoids. (A) Woven bone organoid. Reprinted with permission from Akiva A, Melke J, Ansari S, et al., Adv Funct
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Mater. Copyright © 1999-2023 John Wiley & Sons, Inc . (B) Bone marrow organoid. (from ref . licensed under Creative Commons Attribution 4.0
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license). (C) Callus organoid (from ref . licensed under Creative Commons Attribution 4.0 license). (D) Cartilage organoid. Reprinted from Biomaterials,
273:120820, Hall GN, Tam WL, Andrikopoulos KS, et al., Patterned, organoid-based cartilaginous implants exhibit zone specific functionality forming
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osteochondral-like tissues in vivo, Copyright (2021), with permission from Elsevier . (E) Trabecular bone organoid (from ref . licensed under Creative
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Commons Attribution NonCommercial License 4.0 (CC BY-NC)
utilizing DNA-functionalized bioinks, which allow for the tissue morphology, and to overcome the growth
combination of concepts in dynamic DNA nanotechnology volume limitation. It has been widely documented that
with additive patterning techniques . Accordingly, we Matrigel is a building material of organoid cultures.
[22]
TM
believe 3D bioprinting of light-based DNA hydrogel is However, limitations of Matrigel such as xenogenous
TM
achievable and highly promising in tissue engineering. origins, variable composition, non-programmability, and
poor mechanical properties still hinder its application
3. Implication for bone organoids clinically . Accordingly, newly developed hydrogels are
[25]
TM
Bone organoids can simulate the inherent construction growing as promising candidates to replace Matrigel
of a 3D tissue microenvironment in vitro to reflect the for bone organoids build-up.
main structure and characteristics of bone (Figure 3), and As aforementioned, DNA-based hydrogels with
thus, play a great role in biomedical field and regenerative their self-assembled nanostructure could be used in
medicine field . The key to bone organoids is to culture multidisciplinary fields due to their programmability,
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functional 3D tissues in vitro while the matrix gel is tunable mechanical properties, ease of functionalization,
the foundation for the system build-up. Bone organoid conditional response, and practical structural constructs.
construction can be divided into self-organization without The broad application of DNA hydrogels in drug delivery
scaffolding and co-culture with bioactive materials . and tissue engineering has been recently unraveled .
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The self-organization without scaffolding method mainly Of note, DNA hydrogels could potentially be adopted in
induces the cells to form high-density spheroids by an bone repair and osteoarthritis (OA) therapy . The DNA
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external force, thereby allowing cell–cell interactions hydrogel in combination with bone marrow stem cells
and metabolic gradients of biomimetic natural tissues. (BMSCs) retarded the progression of OA by conferring
For instance, cells derived from human periosteum are exceptional protection for BMSCs against the shear force.
used for the production of micro-spheroids which can The study further unraveled that the DNA hydrogel is
further differentiate into callus organoids. The organoids capable of rapid formation of high-quality cartilage,
obtained the capacity to form ectopic bone microorgans reducing the osteophyte and normalizing the sub-chondral
in vivo . However, this method is limited by the size, bone under the condition of high friction in OA.
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which cannot exceed 500 μm due to insufficient oxygen The construction of bone organoids in vitro requires
supply. Therefore, the current construction of bone not only appropriate bone-like matrix but also multiple
organoids requires bioactive matrix gel as the support types of cells (e.g., osteoblasts, osteoclasts, macrophages)
to achieve spatial distribution of cells and controllable
involved in de novo bone formation. As aforementioned,

Volume 9 Issue 2 (2023) 435 https://doi.org/10.18063/ijb.688