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Bozo, et al.
constructs; however, periosteal osteogenesis was
less evident.
In 6 months after implantation, the peripheral
part of gene-activated materials was actively
substituted with bone tissue. A border with the
implant along its entire length was composed of
newly formed bone tissue trabeculae (Figure 6)
without fibrous tissue. A woven bone tissue
remodeled into lamellar tissue. The implant
surface was rarefied and had a great number of
optically empty cavities sized to 300 μm. Still,
no cellular and tissue elements extended into
the material. There were no cellular signs of
osteoclastic resorption. Inter-trabecular spaces
were in part colonized with hematopoietic bone
marrow. There was an optimal osteointegration in
3D printed OCP implants with similar dynamics
of bone tissue rearrangement into lamellar tissue;
however, the colonization of inter-trabecular
spaces with blood-forming (hematopoietic) bone
marrow was less active.
4 Discussion
Bone reconstructive surgery in traumatology and
orthopedics, neurosurgery, oral and maxillofacial
surgery still remains challenging. Small defects
can be managed with the use of osteoconductive
bone substitutes, including a combination with
“improvised” techniques for biologic activity
enhancement such as mixing with autologous
bone fragments, platelet-, or growth factor-
enriched plasma, etc. However, large/critical
size bone defects and alveolar ridge atrophy of
significant size are characterized by “osteogenic
insufficiency,” a loss of cambial cellular elements
and/or factors, invloved in bone regeneration,
therefore intensive osteoinduction is required .
[9]
Additive manufacturing or 3D printing
techniques provide substantial opportunities
for effective personalized treatment of patients
with large bone defects. However, to overcome
osteogenic insufficiency, custom-made implants
should be combined with osteogenesis-stimulating
factors such as living cells, growth factors, or gene
constructs that encode them. 3D bioprinting of
tissue-engineered constructs are most intensively
International Journal of Bioprinting (2020)–Volume 6, Issue 3
developed, probably due to the attractive idea to
create a fully functional tissue or organ ex vivo
for subsequent clinical transplantation [6,10,16,17]
or for usage as an in vitro model to study the
[18]
disease pathogenesis and drugs development .
However, in addition to well-known technological
problems, tissue engineering is associated with
high costs and considerable difficulties in clinical
[9]
translation from a regulatory point of view .
Furthermore, additive manufacturing is actively
used to produce personalized bone implants with
growth factors [19,20] . However, protein molecules,
being short-lived, and short-distant, cannot exhibit
their full biological effect.
Although 3D bioprinting has become more
complex in an attempt to combine different
[21]
approaches , there is a search for simpler
alternatives that involves, for instance, the use
of gene constructs for creating personalized
bone substitutes. Despite significant advances
in the research of standardized gene-activated
matrices [22-24] and additive manufacturing
technologies for bone grafting, to date there are
only a few studies related with personalized gene-
activated tissue substitutes [25,26] , and none of them
described calcium phosphate-based ceramic being
used as a scaffold without any hydrogels or other
materials that are easy to be printed.
Based on our previous results in OCP
studies , 3D printing of OCP-based implants
[11]
[27]
and standardized gene-activated materials [23,28] , we
have started the development of a personalized
gene-activated bone substitute based on the OCP
and plasmid DNA that delivers VEGFA gene,
applicable for large bone defects substitution
and guided bone regeneration. We expected the
increased level of VEGFA to promote angiogenesis
and reparative osteogenesis. Moreover, a direct
stimulating effects of VEGF on proliferation and
differentiation of bone cells and non-canonic
[29]
intracrine effects specific for a VEGF gene
transfer were described. Additional prerequisites
[30]
to use this gene construct in the study were our
previously obtained clinical data on a successful
treatment of a patient with mandibular non-
unions with the use of a gene-activated material,
delivering VEGFA .
[28]
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