Periorbital rejuvenation presents significant challenges: hyaluronic acid (HA) fillers carry risks of edema and the Tyndall effect, whereas traditional poly-L-lactic acid (PLLA) may lead to nodule formation and delayed inflammatory reactions. To address these limitations, the PLLA-b-poly (ethylene glycol) (PLLA-b-PEG)/HA composite filler is designed to optimize tissue compatibility and minimize these specific adverse reactions.
To comprehensively evaluate the physicochemical properties, biocompatibility, and clinical efficacy of this filler for periorbital volume deficiency.
Physicochemical validation included SEM morphology, extrusion force, osmolality, and mechanical support testing. In vivo safety and collagenogenesis were assessed via histology in a rabbit model. Additionally, a retrospective clinical study of 15 subjects with infraorbital hollowing evaluated efficacy at 1, 3, and 6 months using the Allergan Infraorbital Hollows Scale (AIHS) and Global Aesthetic Improvement Scale (GAIS). All subjects also underwent clinical safety follow-up through 12–14 months; in a subset of subjects, additional 12–14-month photographs were available for descriptive review, but these images were not included in the formal efficacy analysis.
The filler exhibited uniform microspheres, physiological osmolality (302 mOsmol/kg), and superior mechanical support. In vivo, it showed mild inflammation with neocollagenesis. In the retrospective clinical analysis (N = 15), the median AIHS score improved significantly from 2.0 at baseline to 1.0 at 6 months (p < 0.0001). At 6 months, 93.3% of subjects achieved ≥ 1-grade improvement. GAIS improvement rates were stable (p > 0.05), with no significant difference between subject and investigator ratings. Adverse events were mild, and no delayed or late-onset adverse events, such as nodules or granulomas, were identified during the extended safety follow-up.
The PLLA-b-PEG/HA filler demonstrates unique physicochemical properties and a dual-action mechanism of immediate filling and long-term regeneration, establishing it as a promising, safe treatment for periorbital rejuvenation.
The periorbital region is a key contributor to facial aesthetics and often displays the first visible signs of aging [1, 2]. Many factors drive this process, including bone changes and soft-tissue loss. Specifically, the bone of the orbital rim resorbs over time, which reduces support. At the same time, deep fat pads like the retro-orbicularis oculi fat (ROOF) and the sub-orbicularis oculi fat (SOOF) shrink. This causes the face to lose its forward projection [3, 4]. Clinically, these structural deficiencies manifest as noticeable hollowing, the formation of tear troughs, and tissue sagging. Consequently, the primary strategy for rejuvenation focuses on replacing this lost volume and correcting tissue descent. In this process, the pretarsal fullness is a vital feature for East Asian beauty standards. People commonly call this feature “aegyo-sal” or the “charming roll.” Anatomically, it is a bulge of the orbicularis oculi muscle. This shape makes the eyes look larger and more expressive [5, 6].
Volume restoration in the periorbital area is technically challenging due to the extremely thin skin [7]. This anatomical characteristic renders the physicochemical properties of the filler selected for this area critical for a natural aesthetic result. Although hyaluronic acid (HA) fillers remain a common treatment, their strong water-binding properties can lead to prolonged swelling or the Tyndall effect [8-10]. Collagen fillers offer an alternative. However, their effects are relatively short-lived. Clinical data indicate that these implants typically degrade within 3 to 6 months [11]. This rapid absorption means patients require frequent retreatment to maintain the correction. Additionally, animal-derived collagen carries a potential risk of hypersensitivity reactions. This risk requires patients to undergo skin allergy testing before the doctor can perform the procedure [12]. Poly - L-lactic acid (PLLA) is a collagen-stimulating polymer with durable effects [13], yet conventional, unmodified PLLA has been used cautiously in the tear trough. Its hydrophobic nature makes the microparticles more likely to clump, and in delicate periorbital tissues, this may provoke excessive inflammation and lead to visible nodules or granulomas [14, 15].
The Poly(L-lactic acid)-b-Poly (ethylene glycol) (PLLA-b-PEG) composite gel addresses these challenges by combining the immediate volume of HA with PEG-modified PLLA microspheres. Formulated at physiologic osmolality to minimize swelling, this material attracts attention for its prolonged efficacy and favorable biocompatibility [16]. The formulation employs a specialized manufacturing process to create microspheres with a controlled particle size between 20 and 45 μm. The primary goal of this structural modification is to improve the dispersion of particles within the gel carrier and the host tissue. By addressing the hydrophobic limitations of traditional PLLA, this design aims to reduce the risk of nodule formation and inflammatory reactions, making the material potentially suitable for correcting volume deficits in delicate facial areas [17, 18].
Previous clinical studies have verified the safety and efficacy of this material in other areas of the face [19-21]. However, the present study aimed to verify the physiological characteristics of the PLLA-b-PEG/HA gel specifically for periorbital rejuvenation. We comprehensively assessed its safety and efficacy through laboratory materials research, in vivo animal experimentation, and a retrospective case series evaluation. Additionally, this study intends to provide meaningful theoretical references for innovative clinical interventions dedicated to treating periorbital volume loss.
PLLA-b-PEG microspheres and the HA gel were supplied by the Beijing Engineering Laboratory of Neobiodegradable Materials (Beijing, China). These were formulated using cross-linking agents and protocols consistent with commercial HA fillers, as detailed in our previously published work (PMID: 39 037 908). The injectable suspensions used for laboratory research, animal models, and human subjects were specifically a cross-linked sodium hyaluronate gel incorporating PLLA-b-PEG microspheres, developed by Imeik Technology Development Co. Ltd. (Beijing, China). The composition was as follows: 180 mg/mL PLLA-b-PEG microspheres, 17 mg/mL hyaluronate, and 3 mg/mL lidocaine hydrochloride. This product has received approval from the National Medical Products Administration (NMPA) of China. Additionally, a poly (lactic acid) (PLA) facial filler was obtained from SinoBiom Technology Development Co. Ltd. (Changchun, China).
Samples of PLLA-b-PEG microspheres, PLA facial filler, and freeze-dried PLLA-b-PEG/HA filler were individually mounted on conductive adhesive tape and sputter-coated at 10 mA for 90 s. The morphology of the microspheres and their distribution within the gel matrix were subsequently characterized using scanning electron microscopy (SEM, ZEISS GeminiSEM 300, Germany).
The material extrusion force test for PLLA-b-PEG/HA filler—preloaded into 1 mL peelable prefilled syringes and paired with 27G sharp needles, a packaging method filed with the NMPA—was conducted using an electronic universal testing machine at a test speed of 30 mm/min.
To characterize water absorption, 0.2 mL aliquots of both the PLLA-b-PEG/HA filler and HA hydrogel were placed in separate petri dishes. A predetermined volume of physiological saline was added to each dish. After 5 min, excess saline was aspirated using a syringe to assess the absorption properties of the materials.
For osmotic pressure measurement, a 0.1 g aliquot of the gel was transferred to a centrifuge tube and centrifuged to eliminate entrapped air bubbles. The osmotic pressure was then measured using a freezing point osmometer (Beijing Yasen Boke OM819).
To evaluate support performance, 0.5 mL aliquots of both the PLLA-b-PEG/HA filler and the PLA facial filler were injected into the intermediate layer of cellulose-based artificial skin (Suzhou HVHA Medical Technology Co. Ltd.). The specimens were placed in petri dishes to maintain moisture and incubated at a constant room temperature of 24°C for 15 h. The samples were then observed for shape retention and any signs of material collapse.
A 0.5 mL aliquot of PLLA-b-PEG/HA filler was injected into the fascial layer of fresh ex vivo rabbit skin. To simulate the mechanical stress of facial muscle movement, the injection site was subjected to three full twisting cycles mimicking a 2 N torsional compressive force. The material was then inspected for deformation.
Twenty-eight 4-month-old Japanese white rabbits (14 males and 14 females; body weight: 2.2–2.5 kg) were obtained from Beijing Longan Experimental Animal Breeding Center (Beijing, China). The animals were housed under controlled conditions (temperature: 23°C ± 3°C; relative humidity: 40%–70%; 12-h light/12-h dark cycle) and provided with standard laboratory chow and purified water ad libitum. Following a 1-week acclimatization period, the rabbits were randomly assigned to 7 groups (4 rabbits/group; 2 males and 2 females), corresponding to predefined observation time points: 4, 12, 26, 38, 52, 78, and 104 weeks. All experimental procedures were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC).
Anesthesia was induced via intramuscular administration of Xylazine compound (0.1 mL/kg) combined with Tiletamine-Zolazepam (0.1 mL/kg), and maintained with isoflurane (Qingdao Orbiepharm Co. Ltd., Qingdao, Shandong, China) in a sterile operating room. The parietal region of the rabbits was shaved, and the skin was disinfected sequentially with alcohol and iodophor. Using a 27-gauge needle, subcutaneous injections (0.5 mL per site) were administered at the precise midpoint of the parietal bone (defined as the intersection of the interaural and interocular lines).
At 4, 12, 26, 38, 52, 78, and 104 weeks post-injection, biopsies containing the cranial epidermis, subcutaneous tissue, and underlying parietal bone were harvested from the injection sites under anesthesia, with care taken to preserve tissue architecture. Control tissue samples were harvested from non-implanted regions using the same method. The excised tissues were fixed in 10% neutral-buffered formalin. Osseous components were decalcified prior to paraffin embedding. Full-thickness 4-μm sections were cut along the sagittal plane, centered on the implantation site.
Sections were stained with hematoxylin and eosin (H&E), Masson's trichrome, Alcian blue, and Picrosirius red. Picrosirius red-stained sections were imaged using a polarizing microscope (Ci-S, Nikon Corporation, Tokyo, Japan) to differentiate type I and type III collagen, while other sections were examined under a standard light microscope (BX63, Olympus, Tokyo, Japan). Quantitative analysis of collagen and HA content in the implantation region was performed using Image Pro Plus 6.0 (Media Cybernetics, Bethesda, MD, USA).
Statistical analyses and graphical visualization were performed using GraphPad Prism 10 (GraphPad Software, San Diego, CA, USA). In vivo data are expressed as the mean ± standard error of the mean (SEM), with each condition replicated a minimum of three times. Differences across multiple groups were assessed using one-way analysis of variance (ANOVA), while unpaired t-tests were used for pairwise comparisons. A p-value of < 0.05 (p < 0.05) was considered statistically significant.
We reviewed the records of 15 East Asian adult subjects (age range 22–64 years, 13 females and 2 males) who underwent periorbital rejuvenation with PLLA-b-PEG/HA filler. These subjects sought treatment for tear trough hollowing and related periorbital aging changes. Inclusion criteria comprised adults aged 18 to 65 years presenting with clinically appreciable infraorbital volume deficits. Severity was classified as moderate to severe (grades 2–3) according to the Allergan Infraorbital Hollows Scale (AIHS). Furthermore, these individuals had not received any other periocular treatments within the preceding year. Exclusion criteria included a history of allergy to PLLA or HA, active skin infection or inflammation in the target area, bleeding disorders or anticoagulant use that could not be paused, pregnancy or lactation, recent (< 12 months) surgery or trauma to the periorbital area, or inability to complete follow-up visits. All treatments were performed by a single experienced injector (dermatologist) following a standardized protocol. The same treating injector also completed the investigator-rated Global Aesthetic Improvement Scale (I-GAIS), whereas AIHS scoring was performed by one blinded independent physician reviewer.
The injection procedures adhered to a standardized protocol tailored to the specific anatomical deficits of each patient. To address the multi-layered etiology of periorbital aging, treatment was stratified into three distinct anatomical targets: the deep infraorbital, the sub-orbicularis oculi, and the pretarsal region (Table 1 and Figure 1).
| Injection site | Injection layer | Entry point | Instrument | Technique | Unilateral dose (mL) | Key procedural notes |
|---|---|---|---|---|---|---|
| Deep Infraorbital | Supraperiosteal | Lateral Orbital Thickening (LOT), Orbicularis Retaining Ligament (ORL), and Tear Trough Ligament (TTL) | 30G or 29G Needle | Small Bolus | 0.3–2.0 | Place strictly on the supraperiosteal plane to provide support |
| Sub-orbicularis Oculi | Primarily in the sub-orbicularis/deep soft-tissue plane, with limited superficial subcutaneous refinement when needed | Intersection of the lateral canthus line and the horizontal line extending from the alar base | 27G or 25G Cannula | Fanning/Linear threading | 0.3–2.0 | Target the palpebromalar groove and the lateral transition zone adjacent to the tear trough; avoid overly superficial placement |
| Pretarsal Fullness (“Aegyo-sal”) [5] | Subdermal | A few millimeters lateral to the lateral canthus, close to the lower lash line. | 27G Cannula | Linear threading | 0.3–1.0 | Start with the central portion, followed by the lateral and medial areas; inject slowly to define the extent of pretarsal fullness. This region should be approached as a selective, non-routine treatment area |
We captured standardized, high-resolution photographs at baseline and at the 1, 3, and 6-month follow-up visits using a digital single-lens reflex camera (Canon EOS 5D Mark IV, Canon Inc., Tokyo, Japan). The primary efficacy endpoint was defined as the proportion of subjects achieving a ≥ 1-grade improvement from baseline on the 5-point AIHS at 6 months post-treatment [22]. To ensure objectivity, AIHS scores were assessed by one blinded, independent physician reviewer.
Secondary efficacy endpoints included the Global Aesthetic Improvement Scale (GAIS). The treating injector completed the Investigator-rated GAIS (I-GAIS) and the subjects completed the subject-rated GAIS (S-GAIS) at 1, 3, and 6 months. Additionally, subjects rated their satisfaction on a 5-point Likert scale (1 = Very Dissatisfied to 5 = Very Satisfied) at 3 and 6 months.
Clinical safety follow-up was extended for all subjects to 12–14 months after treatment. We documented all treatment-emergent adverse events (TEAEs), specifically noting their nature, severity, and duration. During the extended safety follow-up period, we paid specific attention to delayed nodules, granulomas, persistent contour irregularities, prolonged edema, and other late adverse events. In a subset of subjects, additional standardized photographs obtained at 12–14 months were available for descriptive review; however, these images were not incorporated into the prespecified efficacy analysis and were used only as ancillary visual safety documentation.
Statistical analysis was performed using GraphPad Prism 10 software (GraphPad Software, San Diego, CA, USA). Continuous data were expressed as mean ± standard deviation (SD). The change in AIHS scores from baseline to each follow-up point was analyzed using the Friedman test followed by Dunn's multiple comparisons test. GAIS and satisfaction data were presented as frequencies and percentages. A p-value of < 0.05 was considered statistically significant.
SEM analysis revealed that the PLLA-b-PEG microspheres presented a spherical morphology and homogeneous size distribution. In contrast, microspheres of the PLA facial filler exhibited morphological irregularities, characterized by a heterogeneous size profile: a subset featured a larger diameter (~50 μm), while another subset had a diameter of < 10 μm. These PLLA-b-PEG microspheres were subsequently integrated with HA hydrogel utilizing specific mixing technology to fabricate the PLLA-b-PEG/HA filler (Figure 2A). Scanning electron microscopy micrographs demonstrated uniform dispersion of the microspheres within the gel matrix, with no evidence of aggregation or clumping (Figure 2B). Correspondingly, the PLLA-b-PEG/HA filler exhibited consistent and smooth injectability (Figure 2C).
The PLLA-b-PEG/HA filler and a commercial control HA hydrogel were subjected to immersion in saline for 5 min. After removing excess water, the PLLA-b-PEG/HA filler showed minimal water uptake and negligible swelling, whereas the commercial control hydrogel adsorbed substantial water, resulting in marked volume expansion (Figure 2D). Osmolality determination of the PLLA-b-PEG/HA filler via an osmolometer yielded a value of 302 mOsmol/kg, which was comparable to physiological osmolality.
Additionally, 0.5 mL of the PLLA-b-PEG/HA filler injected into an artificial skin model exhibited no height reduction over a 15-h period, indicating robust supportive capacity. In contrast, the PLA facial filler displayed a 50% reduction in height, thereby demonstrating inadequate support (Figure 2E). Following the injection of the PLLA-b-PEG/HA filler into the fascial layer of rabbit skin and subsequent vigorous twisting of the skin for three cycles, the filler retained its anatomical position and original shape without significant displacement or deformation (Figure 2F). These properties of high support and deformation resistance are crucial for providing a stable, predictable, and long-lasting correction in a mobile anatomical region like the periorbital area.
Over the 104-week study period, the subcutaneous fibrous connective tissue in the control group displayed a physiologically normal architecture, with no pathological aberrations observed in cutaneous histology; the content, proportion, and spatial arrangement of collagen fibers remained consistent with physiological baselines.
Following implantation of the PLLA-b-PEG/HA filler, no overt abnormalities were identified on the cutaneous surface at the implantation site, and the implant-induced tissue elevation persisted for up to 78 weeks. Pathological assessments revealed mild inflammatory responses within 12 weeks post-implantation, accompanied by a modest deposition of newly formed fibrous connective tissue. From 26 to 78 weeks post-implantation, the magnitude of the inflammatory response at the implantation site increased moderately—yet remained non-severe—while the volume of newly formed fibrous connective tissue increased substantially; concurrently, the implanted microspheres were observed to undergo gradual fragmentation. By 104 weeks post-implantation, the inflammatory response had exhibited progressive attenuation and returned to baseline levels comparable to the normal (blank control) tissue, though a considerable quantity of newly formed fibrous connective tissue persisted (Figure 3).
Notably, in comparison to the control tissue, the periosteum in the implanted group demonstrated local thickening; however, no structural disorganization or excessive hypertrophy was observed (Figure 4A). Simultaneously, the density of newly formed capillaries at the implantation site was significantly elevated, and this angiogenic effect was sustained until the complete degradation of the microspheres (approximately 104 weeks). Masson's trichrome staining illustrated a gradual accumulation of collagen fibers post-implantation, which reached a peak at 52 weeks and was maintained through 78 weeks (Figure 4B). Alcian blue staining revealed that the HA at the implantation site underwent progressive degradation and became nearly undetectable by 52 weeks (Figure 4C). Picrosirius red staining indicated a subtle elevation in the proportion of type III collagen throughout the experimental period. Although this increment lacked statistical significance in most instances, it suggested a benign adaptive process (Figure 4D).
A total of 15 subjects (13 female, 2 male) with a mean age of 48.5 ± 8.2 years were included in the retrospective analysis. Baseline characteristics are summarized in Table 2. All subjects presented with moderate-to-severe infraorbital hollowing, with a mean baseline AIHS score of 2.47 ± 0.5. The mean injection volume was 1.05 ± 0.15 mL per side.
| Characteristic | Value |
|---|---|
| Age (years), Mean ± SD | 48.5 ± 8.2 |
| Gender, n (%) | |
| Female | 13 (86.7%) |
| Male | 2 (13.3%) |
| Ethnicity, n (%) | |
| East Asian | 15 (100%) |
| Fitzpatrick skin type, n (%) | |
| II | 5 (33.3%) |
| III | 8 (53.3%) |
| IV | 2 (13.3%) |
| Baseline AIHS Score, Mean ± SD | 2.47 ± 0.52 |
| Baseline AIHS Grade, n (%) | |
| Grade 2 (Moderate) | 8 (53.3%) |
| Grade 3 (Severe) | 7 (46.7%) |
Treatment with the PLLA-b-PEG/HA filler resulted in a statistically significant and clinically meaningful improvement in infraorbital hollowing, as assessed by a blinded independent reviewer using the AIHS [23]. The Friedman test revealed a significant change in AIHS scores across the study time points (p < 0.0001). Post hoc analysis confirmed that AIHS scores at 1, 3, and 6 months were all significantly improved compared with baseline (Dunn's multiple comparisons test, p < 0.001 for all). This improvement is visualized in Figure 5A. The box plot analysis shows a marked downward shift in the median AIHS score from 2.0 at baseline to 1.0 at all post-treatment follow-up points. This indicates that the initial correction achieved at 1 month was well-maintained through the 6-month period. The primary efficacy endpoint was met, with 93.3% (14 of 15) of subjects achieving at least a 1-grade improvement on the AIHS at the 6-month follow-up. Representative clinical photographs illustrating this aesthetic improvement are shown in Figure 6. In a subset of representative cases, localized lower-lid fullness was observed in the first 2–3 mm below the lower eyelid after treatment. In the present study, this finding was interpreted descriptively as pre-tarsal augmentation rather than a formal efficacy endpoint. Because this region is anatomically delicate and visually prominent, such fullness may have implications for injection pattern design and warrants cautious, highly individualized treatment planning.
Subject- and treating injector-assessed GAIS ratings demonstrated high levels of aesthetic improvement that remained stable over time (Figure 5B). The improvement rate, defined as the proportion of subjects with a GAIS score of ≤ 3 (“Improved” or better), was 100% at 1 month and 93.3% at both 3 and 6 months for subject and investigator. A Cochran Q test confirmed that these improvement rates did not change significantly over the 6-month follow-up period for either the subjects (p = 0.368) or the investigators (p = 0.223). Furthermore, a Wilcoxon matched-pairs signed-rank test was performed at each time point to compare subject and investigator ratings. No statistically significant difference was found at 1 month (p = 0.125), 3 months (p = 0.317), or 6 months (p = 0.250), indicating strong concordance between the subjects' perceived improvement and the investigators' clinical assessment.
Patient-reported outcomes suggested generally positive satisfaction with the treatment. At the 6-month visit, 14 out of 15 subjects (93.3%) reported being “Satisfied” or “Very Satisfied.” These high satisfaction scores matched the improvements seen in the objective AIHS and subjective GAIS evaluations [24].
The PLLA-b-PEG/HA filler showed a good safety record and all subjects tolerated the procedure well. Adverse events were mild, temporary, and only occurred at the injection site. Three subjects (20.0%) noted tenderness, two (13.3%) had local swelling, and one (6.7%) experienced minor bruising. These reactions resolved naturally without any medical treatment [22]. Symptoms usually peaked within the first 48 h. Tenderness and swelling disappeared in 3 to 5 days, and the single case of bruising faded within a week.
All 15 subjects completed extended clinical safety follow-up through 12–14 months after treatment. No serious or late-onset complications, including nodules, granulomas, persistent edema, or progressive contour irregularities were documented during this extended safety period.
Injectable rejuvenation in the periorbital region poses unique challenges due to the area's extremely thin skin, complex anatomy, and dynamic muscle activity [25]. The clinical hesitation to use traditional PLLA here stems from inherent material limitations rather than mere historical caution. Because conventional PLLA is hydrophobic, the particles tend to aggregate if the reconstitution process is not perfect [26] Following injection, these clumps can provoke an intense foreign body reaction characterized by multinucleated giant cells and dense fibrosis [27]. Thicker tissue might conceal mild inflammation, but the infraorbital area is too delicate to hide such changes. In this region, even minor lumps under the skin can appear as clear nodules or uneven contours. The literature frequently documents these issues [17, 18, 28-30]. Therefore, practitioners generally view traditional PLLA as a risky choice for treating the tear trough [15].
The core characteristic of the PLLA-b-PEG/HA material is the covalent modification of the PLLA backbone with hydrophilic poly (ethylene glycol) (PEG) segments. This structural design influences particle–tissue interactions and helps reduce the inflammatory response often observed with pure PLLA [30, 31]. The manufacturing process creates amphiphilic microspheres with a smooth surface and a precise size range of 20–45 μm. Previous studies show that increased surface hydrophilicity improves the compatibility of the particles with the hydrogel carrier and promotes more homogeneous dispersion within the gel matrix [21]. This property supports even suspension of the particles within the gel and reduces clumping or settling issues often seen with hydrophobic materials [16]. In the present study, these characteristics were reflected in the relatively consistent extrusion force and the uniform distribution observed under SEM.
The physicochemical characterization in the present study showed that the material exhibited high support capacity and resistance to deformation. In a highly mobile anatomical zone subject to constant dynamic muscle activity, such properties may be advantageous, as they could help the filler better maintain its configuration under repetitive mechanical stress. In this context, the gel may contribute to structural support for tear trough correction and to a more stable treatment result over time. In addition, the observed mechanical stability, together with the formulation's opacity and physiological osmolality, may help reduce the risk of migration, visible blue-gray discoloration, and post-injection edema [32, 33]. However, these potential clinical implications should be interpreted cautiously, as the present study did not directly evaluate in vivo material dynamics in treated infraorbital tissue.
Beyond physical support, the biological interaction between the implant and the host tissue drives the fundamental regenerative mechanism. Our 104-week preclinical assessment provides insights into this process (Figure 3). Unlike the aggressive foreign body reaction seen with irregular particles, the PLLA-b-PEG microspheres elicited a mild, controlled inflammatory response. Pathological assessment showed that inflammation remained non-severe throughout the study and progressively attenuated to baseline levels by week 104. This controlled microenvironment facilitates tissue remodeling. This is consistent with our previous findings [16]. Notably, we observed an increase in the density of newly formed capillaries at the implantation site. Existing literature suggests that such neovascularization is critical for establishing a healthy tissue bed and preventing fibrotic encapsulation, thereby ensuring the longevity of the aesthetic correction [34]. Furthermore, while the HA component underwent progressive degradation and became nearly undetectable by week 52, the deposition of new collagen fibers peaked at this same time point and remained high through week 78 (Figure 3B). This temporal pattern aligns with the concept of compensatory volume replacement described in biostimulator research: as the carrier gel absorbs, the newly formed autologous tissue provides structural continuity, maintaining the implant-induced elevation [35, 36].
Clinically, this specific biological behavior translated into a favorable and extended safety profile. AIHS scores improved early and remained stable throughout the 6-month efficacy follow-up, while subject- and treating injector-reported GAIS also supported sustained aesthetic improvement during this period. Importantly, all subjects additionally underwent clinical safety follow-up through 12–14 months, during which no nodules, granulomas, persistent edema, or progressive contour irregularities were documented. This extended safety observation strengthens the interpretation that the product may address a major concern associated with biostimulatory materials in the periorbital region [20].
Notably, in some representative cases, localized fullness in the immediate subciliary/pretarsal region was visible after treatment. Although this appearance may be aesthetically desirable in selected East Asian patients seeking enhancement of pretarsal fullness [5], it also highlights that this area should not be treated routinely. Rather, injection in this region should be conservative, low-volume, and limited to carefully selected patients, because excessive augmentation may alter lower-eyelid contour and affect the preferred injection strategy.
We must acknowledge several limitations in this study. First, the design was retrospective, and the sample size was small. We also did not include a control group for comparison. Regarding the animal experiments, we relied only on tissue analysis to observe structural changes. We did not investigate the specific molecular mechanisms involved. In the clinical cohort, formal efficacy assessment was limited to 6 months, although all subjects underwent extended clinical safety follow-up to 12–14 months. Additional photographs at 12–14 months were available only in a subset of subjects and were reviewed descriptively rather than analyzed as formal efficacy endpoints. Moreover, no imaging examinations, including ultrasound and magnetic resonance imaging (MRI), were conducted during the extended follow-up period; therefore, subclinical tissue characteristics in the treated area and imaging-based assessment of product-related tissue reactions and volume changes could not be evaluated. Finally, although the same material platform has been reported to demonstrate 12-month effectiveness and safety in other facial indications [19, 20], such findings provide only indirect support and cannot replace direct long-term efficacy and imaging evidence in the infraorbital region. Future studies should focus on prospective, randomized trials with larger sample sizes, longer standardized efficacy follow-up, and objective tools such as high-frequency ultrasound to more precisely characterize long-term tissue responses in the periorbital region.
This study demonstrated that the PLLA-b-PEG/HA gel maintained favorable effectiveness throughout the 6-month efficacy follow-up and showed a favorable safety profile during the extended 12- to 14-month safety follow-up. The modification of PLLA microspheres with PEG increased particle hydrophilicity. This improvement allowed the particles to spread evenly within the tissue and reduced the risk of nodules, a common issue with standard PLLA in this delicate area. Our results support a dual-action mechanism. First, the HA carrier provides immediate structure and support. Second, the microspheres encourage the growth of new tissue and blood vessels. By combining volumizing capacity with acceptable tissue compatibility, this material may represent a promising option for periorbital rejuvenation.
Weibin Chen led the study design and performed injections on the study subjects. Guojie Lei, Xia Lou, Qi Wang, and Fang Yang provided assistance in the study. Kun Zhang: Provided rheological data, resources, and supervision. Tong He: Methodology, investigation (animal studies), data curation, writing – original draft, writing – review and editing. Guangyu Chen and Yang Ling drafted the initial paper and conducted data analysis under the guidance of Shiwei Wang. All authors approved the final version of the manuscript.
The authors have nothing to report.
The authors have nothing to report.
Animal experiments were conducted in compliance with Ethics Committee guidelines (IACUC No. YXKT2022L010) from Beijing YongXin Kangtai Technology Development Co. Ltd. The retrospective clinical study was conducted in accordance with the principles of the Declaration of Helsinki. Due to the retrospective nature of the analysis of anonymized patient data, the requirement for specific informed consent for this study was waived by the Institutional Review Board, as initial treatment consent included provisions for the use of data for research purposes.
Weibin Chen hereby authorizes Journal of Cosmetic Dermatology to use the accompanying images of this article for the publication of the paper titled ‘Cross-linked Sodium Hyaluronate Filler Containing Poly-L-Lactic Acid-b-Poly(ethylene glycol) Microspheres for Periorbital Rejuvenation: A Multimodal Assessment of Physicochemical, Preclinical, and Clinical Performance’.
The authors declare no conflicts of interest.
The data underlying this article will be shared by the corresponding author upon reasonable request.
