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sodium alginate scaffolds, consequently promoting of innervation by recruiting BMSCs and promoting their
osteogenic differentiation of the BMSCs encapsulated differentiation toward osteoblast lineage. With treatment
in the bioprinted scaffolds, and improving bone of the NSC-loading 3D-bioprinted constructs, for
metabolism, homeostasis and neurovascularization. 110,127,128 example, a rat cranial bone defect repair results revealed
Furthermore, the exosome-loaded 3D-bioprinted scaffolds that blood vessel and nerve ingrowth were enhanced by
can show a similar neuromodulatory effect, as evidenced neuronal regeneration and axonal outgrowth in the bone
by our recent research that following introduction into the injury lesion, consequently providing an appropriate
BMSC-laden 3D-bioprinted constructs, the SC-derived microenvironment for guiding bone regeneration.
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exosomes facilitated in vitro osteogenic differentiation of Different from the NSC-laden 3D-bioprinted constructs,
the BMSCs and in vivo bone regeneration with elevated the SCs and the BMSCs are often printed into the
vascularization and innervation levels (Figure 6). innervated bone organoids, in which the bioinks are a key
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Moreover, the exosomes derived from the neural stem factor for the regulation of osteogenesis and neurogenesis.
cells (NSCs) that were activated by traumatic brain injury A study from the Chinese Academy of Sciences has
presented robust capacities in accelerating osteogenic reported a 3D-printed tree-like TCP bioceramic scaffold
differentiation of BMSCs and bone fracture healing and for developing the co-culture systems of BMSCs and SCs,
were loaded into a 3D-printed TCP/hydrogel scaffold for and the SC co-culture significantly promoted the BMSC
activation of vascularized bone regeneration. 129 adhesion and proliferation on the scaffold surface, which
were influenced by the biophysical microstructures of
4.2. Multicellular 3D-bioprinted bone microtissues the tree-like bioceramics. They also found in another
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capable of neurovascularization research that 3D-bioprinted BMSC/SC co-culture systems
It is widely recognized that another unique advantage of 3D presented robust osteogenic efficacy, regardless of the
bioprinting is the fabrication of multicellular constructs, in vitro or in vivo assays used, and nanowire-like calcium
through which different cell types can be precisely silicate minerals were included in the multicellular
assembled, like how they are arranged in heterogeneous bioinks for supporting formation of the innervated bone
microtissues. With multicellular 3D bioprinting microtissues, providing convincing evidence that the
130
133
technology, live neural cells, such as NSCs and SCs, can multicellular bone organoids offer an innovative strategy
be loaded into BMSC-free or BMSC-laden 3D-bioprinted for tissue-engineered bone regeneration and represent a
constructs, forming BMSCs co-culture systems capable viable clinical therapy in future.

A B

C C D D

Figure 6. (A-D)BMSC-laden 3D-bioprinted constructs facilitate vascularized and innervated bone regeneration through neurogenesis cues. Reprinted
with permission. Copyright © 2023, KeAi Publishing.
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Abbreviations: BMSCs: Bone marrow-derived mesenchymal stem cells; Exos: Exosomes; SCs: Schwann cells.

Volume 1 Issue 1 (2025) 11 doi: 10.36922/OR8294