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Bozo, et al.
is the main challenge of gene-activated matrix of bioactive materials, a high level of plasmid
approach . However, in our study, we have detected DNA delivery in cells in vivo and the efficacy of
[32]
a high prolonged level of plasmid DNA delivery large segmental bone defects substitution with
in vivo that might be caused by a positive effect and without pDNA-VEGFA loading have been
of 3D printed OCP-based scaffold. Indeed, some confirmed experimentally. The results of our study
authors suggested this effect for calcium phosphate demonstrated that combination of gene therapy
matrixes that could be a peculiar extrapolation and 3D printing with biomimetic post-treatment
[33]
of well-known calcium phosphate method used to is an effective approach to overcome current
increase plasmid DNA transfection in vitro. limitations in production of personalized implants
An osteoinductive effect of pDNA-VEGFA for critical size bone defect reconstruction.
along with the osteoconductive effect of the OCP
scaffold facilitated the restoration of bone integrity Authors’ contributions
in pigs. Moreover, morphological and structural Ilya Y. Bozo: Methodology, Investigation,
changes of 3D printed implants and their effects Writing - Original Draft. Roman V. Deev:
on adjacent tissues had similar features both in Study Design, Data Analysis. Igor V. Smirnov:
tibia and mandibular reconstruction. Materials Investigation, Visualization. Alexander Yu. Fedotov:
form test and control groups were characterized Investigation. Vladimir K. Popov: 3D Printing
by optimal osteointegration capability, since Methodology Development, Original Draft Writing.
there was no fibrous tissue encapsulation of the Anton V. Mironov: Investigation. Olga A. Mironova:
scaffold. A newly formed bone tissue followed 3D Printing Software Development. Alexander Yu.
the implant topography filling in all irregularities Gerasimenko: Investigation. Vladimir S. Komlev:
and pores. One of the peculiarities was that rapid Conceptualization, Methodology, Writing -
woven bone remodeled led into a lamellar tissue
occuping almost the entire volume of the newly Reviewing and Editing, Visualization, Supervision.
The manuscript was written through contributions
formed bone tissue in 6 months after surgery. At of all authors. All authors have given approval to
the latest time point, the 3D printed materials the final version of the manuscript.
became more porous. However, a half-resorption
period for OCP-based implants of that structure Acknowledgment
was not achieved in this study. In addition, sites of
cartilaginous callus formation, which are specific This work was supported by the Ministry of Science
for bones with enchondral ossification were not and Higher Education within the State Assignment
detected after tibia reconstruction that might be FSRC “Crystallography and Photonics” RAS in the
caused by osteoinductive effects mediated by part of 3D modeling of implants with predefined
angiogenesis stimulation. Increased angiogenesis architecture and the Russian Foundation for Basic
could made the reparative process to bypass a Research (grants no.18-29-11081 mk) in the part
cartilaginous callus stage at all or at least accelerate of the development of gene-activated materials.
it with cartilaginous tissue replacement by bone The authors acknowledge deep gratitude to
before 3-month time point. Moreover, there was M. Mavlikeev, A. Titova, A. Bilyalov, and M.
hematopoietic bone marrow formation within the Abyzova for their participation in the studies of
inter-trabecular spaces at the 1 time point. gene construct delivery and to P.A. Makarevich
st
for providing pDNA-Luc and to A.E. Baranchikov
5 Conclusions for high resolution SEM study.

In our work, 3D personalized gene-activated bone Conflicts of Interest
substitutes, based on the OCP and pDNA-VEGFA,
have been developed and produced with the use of The authors declare that they have no conflicts of
3D printing technology for the first time. The safety interest.

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