3.3 Photothermal effect and E2 release from bilayer scaffolds
The application of PDA particles in smart drug delivery systems for
controlled and sustained release of biomolecules has been considered as
an efficient way to promote tissue regeneration[39]. Previous studies have already indicated that
oral administration of E2 would have a very poor therapeutic effect in
treating uterine injuries as compared to in situ controlled
release [40]. PDA is an excellent photothermal
agent with good biocompatibility and biodegradability. Moreover, due to
the inherent molecule structure, PDA particles exhibit a pH-sensitive
behavior. Therefore, the release of biomolecules from PDA particles can
be easily regulated by NIR laser irradiation and environment pH. In the
current study, since E2 as a biomolecule for uterine regeneration was
encapsulated in PDA particles and the synthesized PDA@E2 particles were
incorporated in electrospun fibers, the release of E2 from S+F-PDA@E2
bilayer scaffolds could be precisely tuned by NIR laser irradiation
and/or environment pH. Firstly, the photothermal effect of S+F and
S+F-PDA@E2 bilayer scaffolds were investigated. Fig.6(A)(B) displays
temperature changes of S+F and S+F-PDA@E2 bilayer scaffolds under the
irradiation of the NIR laser at the energy density of 0.5 and 1.0
W/cm2, respectively. S+F-PDA@E2 bilayer scaffolds
could be heated up to 35 ℃ and 49 ℃ after being irradiated by 0.5
W/cm2 and 1.0 W/cm2 NIR laser,
respectively, for 3 min. Such high temperatures caused by NIR laser
could accelerate Brownian movements of E2 molecules. The accelerated
movement of E2 molecules would further result in more E2 released from
bilayer scaffolds. Indeed, with the irradiation of NIR laser, more E2
was released in comparison to unirradiated samples [Fig.6(C)].
On the other hand, because human uterus presents a dynamic pH
environment, it is essential to study E2 release kinetics in buffer
solutions of different pH values. In the current study, the E2 release
behavior were studied in solutions of pH 4.5, 7.4, and 9.0,
respectively. As shown in Fig.6(D), E2 could be sustainably released in
long-term (over 28 days), and the E2 release kinetics could match the
Higuchi model (Fig.S12). The sustained release of E2 would have
significant therapeutic effect on uterine regeneration. It is well-known
that a long-term biomolecule delivery can prolong the beneficial effect
and thus promote tissue regeneration [41].
Moreover, in contrast to an acidic environment, E2 could be quickly
released in a basic solution, which may be attributed to the
disintegration of PDA particles and degradation of PLGA/GelMA
electrospun fibers in an alkaline environment.
Estrogen plays a critical role in regulating menstruation and
endometrium regeneration. The safety and efficacy of E2 for endometrium
regeneration has been clinically proved [42].
Endometrium stromal cells and glandular epithelial cells in the
endometrium have many estrogen receptors. When E2 binds to their
receptors, it enables increases in expressions of angiogenic growth
factors such as VEGF, bFGF and TGF-β1 [43]. These
angiogenic growth factors would facilitate endothelial cell migration,
proliferation, differentiation, tube formation, and thus increase
angiogenesis and blood vessel density, thereby improving the
reconstruction of uterine tissues. Previous studies have investigated
the possibility in using hydrogels or scaffolds to deliver E2 in
situ for uterus injury treatment [40, 44].
However, the problem was that E2 released from these hydrogels or
scaffolds could not reach a controlled and sustained long-term delivery
state. In the current study, the in-site release of E2 from bilayer
scaffolds could not only be regulated by the NIR laser irradiation but
also be modulated by environment pH, which is highly beneficial for
uterine regeneration.