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microvessels is necessary for the proliferation and migration of cells into injected masses. As shown in
Figure 5A-D, the spaces between PDLLA microspheres filled with cells over time, thus suggesting the
formation of blood vessel-like pathways that may supply nutrients for cell proliferation inside the PDLLA
filler mass.

To investigate the formation of neotissues, we performed IHC analyses on the actin and type I collagen
in sections of the PDLLA filler masses. Myofibroblasts were found between the microspheres as early as
two weeks after injection and continued to develop and eventually penetrated the PDLLA microspheres.
Similarly, extracellular type I collagen was detected in spaces between and on the outer surfaces of the
microspheres at the 4th week and was found inside the individual microspheres by the 20th week.

This animal study suggests that injected PDLLA filler mass maintains its volume by facilitating the
formation of new tissues, which ultimately replace the volume of the PDLLA filler mass and presumably
hydrolyze the PDLLA.

We can divide the volume maintenance into two stages. The first stage of the volume increase is from the
volume of the injected PDLLA microspheres. The second stage is volume maintenance, and it is due to
the formation of new tissues and collagen with cell inflow between and inside PDLLA microspheres. The
volume of new tissues and collagen replaces the volume of PDLLA microspheres, which are eventually
hydrolyzed.

In 2012, a clinical study was performed to determine the efficacy and safety of PDLLA filler injections for
[21]
penile augmentation . The significant penile augmentation effect lasted for 18 months after injection
and was well tolerated without serious adverse effects. Subsequently, 58 people were recruited into a
randomized, evaluator-blinded, comparative study that was conducted on August 1, 2012 to March 6, 2013.
In this study, the efficacy and safety of PDLLA microspheres injections for the correction of nasolabial
[22]
folds were compared with those of HA. PDLLA microspheres were not inferior to HA , and 30 subjects
completed the 24-month long-term safety evaluation follow up, which showed that PDLLA microspheres
[23]
are safe and effective for use as fillers for nasolabial fold correction . Complications such as granuloma
formation [24-27] and accidental vascular occlusion [26-28] could occur, similar to other subdermal fillers, and
need to be investigated further.

In this study, rat body weights did not change during the experimental period, and no evidence of test
substance migration to other organs was found. The injected volumes were maintained for 20 weeks in
part because of the inflow and growth of cells, actin, and type I collagen inside the microspheres. The
formation of neotissues that replace the original volume of the PDLLA filler mass was further suggested
by observations of microvessels inside PDLLA filler masses. Therefore, injectable PDLLA polymer is
biodegradable and has efficacy and safety as a subdermal tissue filler.

DECLARATIONS
Acknowledgments
The authors want to give special thanks to Dr. Lee Suat-Yee, a pathologist of Chung Shan Medical
University Hospital, Taichung, Taiwan, for her kindly help of reviewing for all the histology results. The
authors also thank Enago - https://www.enago.tw/ for their assistance in manuscript editing.

Authors’ contributions
Concept and design: Kim JY
Data acquisition, technical and material support: Kang M
Data analysis, manuscript preparation: Yang DY, Lee SH
Critical revision and completion of manuscript: Lin CY, Lin JY