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Pallab Datta, et. al.

miR-26a, -148b, -27a, and -489, have shown to regulate like all technologies, will likely become more cost-
osteogenesis in MSCs [78–80] . Of these compounds, miR- effective over time, with more efficiency in production
148b has been shown to induce de novo osteogenesis and equipment manufacturing. Last, but often most
in bone marrow-derived MSC and ASC and has been challenging, will be the often daunting regulatory
demonstrated to enhance progenitor osteogenesis and hur dles for clinical translation from cartilage basic
bone repair both in vitro and in vivo [79,81–83] . Several science [92,93] . This can prove costly and time-consuming,
miRNAs such as miR-146a, miR-9, miR-29a and miR- and many technologies and developers have floundered
140 play a role in the regulation of chondrogenesis [84–89] . when attempting to jump through the many hoops of the
In addition, different drug delivery systems can regulatory process.
be incorporated into “bioinks” and be deposited in
regions that require controlled release of cell-signaling 4. Future Perspectives
molecules [90] . For example, at the osteochondral inter- Although research in 3D bioprinting is expanding at a
face, chemokine-guided migration of endogenous cells is rapid rate, it is essential that tissue-specific development
desired to provide subchondral bone integration followed roadmaps are adopted by independent groups to delivery
by cell differentiation [33] . By modulating bioprinting clinically-relevant constructs. With particular regards
parameters, the release of chemokines and cytokine to osteochondral tissue, it is critical that bioprinting
signals promoting cell migration and differentiation is capable of manipulating both soft- as well as hard-
can be controlled in a sequential man ner providing for matrix materials. In this context, it may be a viable
precise spatiotemporal control of osteochondral tissue concept to explore scaffold-free bioprinting for cartilage
development. tissue and a mechanically strong support matrix for

3. Challenges in Clinical Translation of bone tissue. Already, scaffold-free bioprinting has
Bioprinted Osteochondral Tissues recently shown promise towards cartilage differentiation
for osteochondral healing as shown in Figure 2B1
Challenges to clinical translation include both clinical and B2 [94] . If these can be combined effectively with
and administrative/translational [91] . Clinically, the PCL biofabrication, a viable solution can be designed.
bio printed tissue will need to incorporate with the Secondly, with respect to the tissue heterogeneity,
surrounding host chondral surfaces and host subchondral advances in designing of constructs with gradient
bone. If allogeneic, this will be expected to have similar porosity are essential. The gradient scaffolds should
potential incorporation challenges as viable allograft also be capable of delivering growth factors/genes with
osteoarticular allografts. Autograft osteochondral precise spatiotemporal control to achieve functional
com posites will need tissue harvest, cell expansion, constructs in required time frames.
printing and the maturation of the fabricated construct,
making one-stage printing in-situ challenging. The Conflict of Interest and Funding
composite printed grafts themselves will need sufficient No conflict of interest was reported by all authors.
biomechanical strength at implantation to sustain joint This work has been supported in part by National
motion and immediate rehabilitation to avoid iatrogenic Science Foundation (#1600118), a grant from Sichuan
stiffness and pain. This will be more of a challenge with REVOTEK Co. Ltd., and the National Institute Dental
larger animal models as well as clinical translation. To and Craniofacial Research of the National Institutes of
help reconcile, customized bioreactors will need to be Health (RDE024790A). The authors also acknowledge
designed for cultivating bioprinted grafts to enhance Fast Track Young Scientist Award from SERB-
their biological and mechanical time-zero properties. Department of Science and Technology, Government of
Post-operative rehabilitation will have to account for India, to Pallab Datta. Yin Yu is a co-founder and board
initial time-zero strength with limited weight bearing member of, and holds equity interest in, CartilaGen Inc.
for a small period of time. In addition, the inflammatory
milieu in the synovium with osteoarthritis will have to References
be addressed so as to not create an unfavorable envi-
ronment for the bioprinted graft. This may require 1. Lories R J and Luyten F P, 2011, The bone–cartilage unit in
biological treatment directly to the synovium or possibly osteoarthritis. Nature Reviews Rheumatology, vol.7: 43–49.
incorporated into the graft. Administratively, like https://dx.doi.org/10.1038/nrrheum.2010.197
many chondral and osteochondral restorative options, 2. Stephens R L, Yang H, Rivier J, et al., 1988, Intracisternal
bioprinting of composite osteochondral tissues will need injection of CRF antagonist blocks surgical stress-induced
to demonstrate cost-efficacy. As many of the components
(and equipment needed) to graft fabrication may be inhibition of gastric secretion in the rat. Peptides, vol.9(5):
very expensive, cost prohibition may be an issue. This, 1067–1070.

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