Abstract
Background
The periorbital region is characterized by early visible signs of aging, including wrinkles, fine lines, and skin laxity. While surgical procedures such as blepharoplasty have traditionally been used to address these changes, minimally invasive aesthetic treatments such as polynucleotides (PNs), botulinum toxin, and hyaluronic acid (HA) fillers are increasingly preferred due to lower risks and shorter recovery times. Although these treatments are widely used, real-world data on the efficacy and safety of such combination protocols remain limited.
Objective
To assess the time course and safety of a comprehensive holistic rejuvenation procedure using highly crosslinked HA-based fillers, PNs, and letibotulinumtoxinA in the extended periorbital region.
Materials and Methods
In this prospective, non-interventional study, 34 participants with a mean age of 41.2 ± 11.4 years received an extended periorbital treatment comprising injections of an HA-based filler at Visit 1, polynucleotide at Visit 1, 2 and 3 and letibotulinumtoxinA at Visit 3 (Week 6). A mean total of 1.38 ± 0.37 cc HA-based filler was administered per patient. Skin wrinkling in the periorbital region was assessed using VISIA skin analysis, while glabellar line severity and midface volume deficit were evaluated using the Facial Wrinkle Scale (FWS) and Midface Volume Deficit Severity Scale (MVDSS), respectively. Assessments were performed by the principal investigator at baseline, week 8, and week 22.
Results
VISIA analysis showed no statistically significant change in periorbital wrinkling at Week 8 (+1.6% vs baseline) and by Week 22 (−5.1%). Mean FWS scores improved from 2.9 at baseline to 1.6 at Week 8 and 2.4 at Week 22, while MVDSS scores improved from 2.6 at baseline to 1.1 at Week 8 and remained improved at 1.3 at Week 22; all changes from baseline were statistically significant. Two non-serious injection site reactions (5.9%) were reported.
Conclusion
This study describes the real-world time course of a multimodal approach targeting muscle activity, volume loss, and skin quality in the extended periorbital region. Larger, longer and ideally controlled studies are required to characterize the safety and efficacy of such staggered multimodal treatment approaches.
Keywords: LetibotulinumtoxinA, hyaluronic acid, polynucleotides, holistic periorbital rejuvenation, volume deficit, skin wrinkling, glabellar lines
Introduction
The periorbital region is one of the first facial areas to exhibit visible signs of aging and is therefore a common focus for aesthetic treatments. Although traditionally defined by the bony orbit, the clinically relevant periorbital region extends well beyond these anatomical borders, reaching from the medial eyebrow and forehead midline across the crow’s feet to the lateral, cranial midface and mid-zygoma, with this broader definition reflecting how age-related changes affect adjacent aesthetic units and inform a more holistic treatment approach. Age-related changes in this region include loss of skin elasticity and hydration, leading to wrinkles, fine lines, and skin laxity, which may result in a tired or aged appearance.1–4 Traditionally, surgical procedures such as blepharoplasty were used to address these changes. However, particularly among patients who are not surgical candidates or wish to delay surgery, the risks and recovery time inherently to surgical procedures have increased the demand for minimally invasive treatment approaches.5,6
In this context, several non-surgical modalities are commonly used to address different aspects of periorbital aging: Polynucleotides have been shown to improve skin elasticity, firmness, and hydration, helping to reduce wrinkles and enhance skin quality in the eyelid and periorbital area.7,8 Polynucleotides are characterized as long-chain fragments of highly purified DNA, which are used to improve skin quality rather than provide volumization. After intradermal placement, they can bind water and restore hydration of the extracellular matrix. Over the longer term, the PN HPT ingredient replenishes tissue pools of nitrogen bases and nucleotide precursors through passive hydrolysis.9 The resulting availability of nucleotide precursors has been associated with tissue repair processes and improvements in skin quality, including indirect effects on fibroblast proliferation and the synthesis of collagen and elastin.8,10 In the thin periorbital skin neither a neuromodulator nor a volumizing filler addresses dermal quality itself, which is the rationale for including a polynucleotide as the skin-directed component. In addition, glabellar lines (commonly referred to as “frown lines”), resulting from repetitive contraction of the procerus and corrugator supercilii muscles, can be effectively treated with neuromodulator injections such as letibotulinumtoxinA, which aim to temporarily relax the muscles and ultimately create a smoother appearance.11–13 Furthermore, loss of midfacial volume can also contribute to an increasingly aged appearance of the periorbital region. HA-based fillers have been reported to be able to restore such volume deficit, thereby providing structural support to the midface and indirectly improving the appearance of the periorbital area.14–16
By addressing different layers inflicted in the multicausal aging process, the combination of these procedures would allow for a comprehensive and synergistic approach to periorbital rejuvenation: Polynucleotides aim for the most superficial layer, the skin, by enhancing elasticity and hydration; neuromodulators target the underlying muscles and affect the dynamic aspect of aging in that region, while HA fillers can be used to effectively augment volume lost during the natural aging process.17,18 Energy-based alternatives including non-ablative laser or radiofrequency improve skin texture but at the same time do not address dynamic muscle activity or volume loss. Hence, injectable modalities were selected since all three components of periorbital aging can be addressed within one treatment course. Despite the well-established use and efficacy of these treatments, the available evidence relates almost exclusively to their isolated application. Randomized trials have established the efficacy of letibotulinumtoxinA for glabellar lines,13 of volumizing HA fillers for midface volume deficit,19,20 while prospective series have described improvements in periorbital skin quality after polynucleotide injection.8 What has not been characterized in the literature, however, is whether these effects are reproduced when the three modalities are combined in a staged treatment approach, administered sequentially at different time points and targeting distinct anatomical structures as in routine practice, how the changes evolve given their divergent onset and duration of action, and whether instrument-based and investigator-rated measures agree. This non-interventional study was therefore designed to document the real-world time course and tolerability of such staged protocol.
Materials and Methods
Study Sample/Patient Cohort
This non-interventional, observational study imposed no randomization, predefined treatment protocols, or interventions beyond those forming part of routine clinical care, with all treatments delivered in the course of standard practice. Product selection, respective dosing and the decision to treat were made by the treating physician’s discretion on clinical grounds and independently of the study. For the scopes of this research initiative, no visit, assessment or procedure was added beyond the routine follow-up appointments. This study was conducted to assess the outcomes and safety of a holistic extended periorbital treatment comprising injections of HA-based filler (Saypha® volume plus Lidocaine), polynucleotides (PolyPhilTM eye which was marketed under the name PhilArt Eye before 2025) and letibotulinumtoxinA (Letybo®). Eligible individuals were those presenting for routine treatment at the clinic who met the general requirements for the procedure. Enrolment took place within the setting of standard clinical care, and written informed consent was obtained prior to any treatment. Inclusion required that each of the following conditions be fulfilled: (1) aged 18 years or older at the time of treatment; (2) presented with at least mild periorbital aging including skin wrinkling, frown lines at maximum frown and midface volume deficiency as assessed by the investigator; (3) had a stable medical condition with no uncontrolled systemic disease; and (4) provided signed informed consent and agreed to routine follow-up visits at 8 weeks and 22 weeks. Exclusion criteria comprised: (1) pregnancy or breastfeeding; (2) diagnosis of a neuromuscular disorder such as myasthenia gravis or Eaton–Lambert syndrome; (3) known impairment of blood coagulation; (4) the presence of eyelid ptosis; (5) known allergy to botulinum toxin or human albumin (blood protein); (6) active infection or inflammation at the intended injection sites; and (7) treatment with botulinum toxin in the glabella within the 16 weeks preceding study enrolment; (8) HA- Filler treatment in the midface or periorbital area within the last 6 months; (9) patients with a history of autoimmune disease or who are receiving immunotherapy; (10) a history of hypersensitivity to hyaluronic acid, lidocaine hydrochloride or other amide type local anaesthetics; (11) a history of fish product allergy.
A total of 34 subjects were enrolled in this study, of which 29 were female and 5 were male. Mean age was 41.2 ± 11.4 years [range: 24–65 years]. All patients were treated in accordance with regional laws, good clinical practice, and the Declaration of Helsinki. The study received a positive vote from the Ethics Committee of Vienna under the reference number EK 23–208-0124. Prior to study inclusion, all participants gave written informed consent for treatment, for the acquisition, scientific use and publication of their data and photographs. As all treatments formed part of routine care and no procedure was performed for study purposes, no additional study-related risks were imposed. Participation could be withdrawn at any time without further consequence for future treatments.
Treatment Approach
The treatment targeted the extended periorbital region, including the glabellar area, upper midface, and infraorbital region. Doses and injection points were selected according to established clinical routine and adapted to each patient’s anatomy, with the aim of evenly modulating muscle activity and achieving a pleasing aesthetic result while preserving a natural appearance and unimpaired facial expression. The order and spacing of the three modalities follow established clinical routine. The HA-based filler was administered first to provide structural correction on which the subsequent more superficial treatments build. Polynucleotides were given in three sessions at three-week intervals, corresponding to the routine treatment cycle for this product and the expected cumulative improvement in skin quality over repeated treatment sessions. LetibotulinumtoxinA was administered at Visit 3 (Week 6).
Injection Procedure
All injections were administered at a single centre by three medical doctors experienced in facial injectable procedures. Product application adhered to the manufacturers’ instructions for use and to a predefined set of injection planes and injection points for each product; letibotulinumtoxinA and polynucleotide doses were fixed for all participants, and only the HA filler volume was adapted to individual anatomy. The combination procedure consisted of:
-
1)
HA-based filler (Croma-Pharma GmbH, Leobendorf, Austria). The commercially available highly cross-linked HA injectable gel implant is contained in a 1 cc syringe. Up to 6 mL was used in total per patient, upon the treating physician’s discretion. The product was applied in the subcutaneous and supraperiosteal planes in the zygomaticomalar, anteromedial cheek and submalar region. Administration of the HA-based filler was performed at Visit 1.
-
2)
Polynucleotides (distributed by Croma-Pharma GmbH, Leobendorf, Austria). The commercially available long-chain polynucleotide solution is contained in a 2 cc syringe. For each treatment session, one syringe was used, with 1 cc for each side. The treatment session was repeated three times in total. The product was applied via intradermal micro-injections in the periorbital area, including the upper eyelid, the lateral canthal area and the lower eyelid. Polynucleotide treatments were performed at Visit 1, Visit 2 (Week 3) and Visit 3 (Week 6).
-
3)
LetibotulinumtoxinA (Croma-Pharma GmbH, Leobendorf, Austria). Each commercially available 50 U vial was diluted with 1.25 mL of sterile 0.9% sodium chloride (9 mg/mL) solution to yield 4 U per 0.1 mL. The glabellar complex was treated with five intramuscular (i.m.) injections of 4 U each, corresponding to a total dose of 20 U per patient. The injection points comprised two sites in each corrugator supercilii muscle (one into the medial and one into the lateral corrugator) and one site in the procerus muscle. LetibotulinumtoxinA was administered at Visit 3 (Week 6).
A schematic overview of the treatment protocol and assessment schedule is depicted in Figures 1 and 2.
Figure 1.
Schematic overview of the study design, illustrating the treatment schedule (Visits 1–3) and the assessment time points (baseline, Week 8, Week 22). PE = primary endpoint (change in VISIA periorbital wrinkling score [%] at Week 8 compared with baseline, assessed on site by the principal investigator; SE&S = Secondary effectiveness and Safety Assessments: VISIA skin analysis (periorbital wrinkling [%], FWS (glabellar line severity), MVDSS (midface volume deficit); standardized VECTRA® (M3 photography), and adverse events (AE), monitored throughout the study).
Abbreviations: HA, Hyaluronic Acid; PN, Polynucleotides.
Figure 2.
Participant flow through the study.
Abbreviations: PN, polynucleotides; HA, hyaluronic acid; FWS, Facial Wrinkle Scale; MVDSS, Midface Volume Deficit Severity Scale.
Clinical Severity Grading
The change in skin wrinkling in the periorbital region was assessed using VISIA Skin analysis.21 VISIA does not report an absolute wrinkle count but a percentile score comparing the analyzed area with an age-, sex- and skin-type-matched normative database. Scores run from 0% to 100% and a higher value denotes a “better aesthetic result”, so an increase from baseline indicates aesthetic improvement and a decrease indicates aesthetic worsening. Oblique left and right images were acquired and the reported value is the mean of the two. The primary endpoint of this study is the change in skin wrinkling in the periorbital region, expressed in % points relative to baseline, at Week 8, as assessed by VISIA skin analysis. The severity of glabellar lines was assessed dynamically using the FWS ranging from 1 to 4 (ie, “none” to “severe”) and the MVDSS, a 5-point scale ranging from 0 to 4 (ie, “none/minimal” to “very severe”) for the assessment of midfacial volume deficit. The FWS is more commonly reported on a 0 to 3 numbering; in the present study the same four photonumeric grades were recorded as 1 to 4, so that scores are shifted by one point relative to the conventional numbering while the grade definitions remain unchanged. All FWS values reported here follow the study-center-proprietary 1 to 4 numbering. To maintain consistency, the principal investigator carried out all gradings in person at baseline, at the 8-week visit, and at week 22. At every visit, standardized images were acquired with the VECTRA® M3 3D imaging system (Canfield Scientific Inc., Parsippany, NJ, USA). (Figures 3–4) The assessment time points follow routine practice: patients are reviewed two weeks after neuromodulator injection, which corresponds to Week 8 and also falls after completion of all three polynucleotide sessions, while Week 22 corresponds to the common 16-week re-treatment interval. VISIA periorbital wrinkling was pre-specified as the primary endpoint because it reflects the assessment used in routine practice and is instrument-based; the investigator-rated FWS and MVDSS were designated secondary endpoints, corresponding to the validated photonumeric scales.
Figure 3.
Representative VISIA photographs of a 46-year-old patient at baseline (left), Week 8 (middle), and Week 22 (right).
Figure 4.
Representative VISIA photographs of a 29-year-old patient at baseline (left), Week 8 (middle), and Week 22 (right).
Statistical Analysis
A target sample size of 34 participants was planned for this non-interventional study. As no formal hypothesis testing was intended, the sample size was not derived from a power calculation but from precision considerations: assuming a standard deviation of approximately 15 percentage points for the primary endpoint (ie, change in VISIA periorbital wrinkling score from baseline), 34 participants were expected to yield a two-sided 95% confidence interval with a half-width of approximately 5 percentage points for the mean change. This was considered sufficient to characterize the time course of the holistic periorbital rejuvenation procedure in the study population. Descriptive statistics were used to summarize all data collected. The safety set comprised every participant who had been administered at least one of the investigational products (letibotulinumtoxinA, polynucleotides, HA-based filler), and all safety evaluations were conducted within this population. Performance endpoints were analyzed descriptively using an observed-case approach. For each endpoint and time point, all available non-missing observations were included. For change-from-baseline analyses, subjects were included if both the baseline value and the respective post-baseline value were available. Statistical significance of changes from baseline was inferred from the two-sided 95% confidence intervals, with intervals excluding zero considered indicative of a statistically significant change. Analyses were performed using SPSS Statistics Version 27 (IBM, Armonk, NY, USA).
Results
Study Population
A total of 34 subjects were enrolled in this study, of which 29 (85.3%) were female and 5 (14.7%) were male. Mean age was 41.2 ± 11.4 years [range: 24–65 years]. Mean body weight was 66.3 ± 11.9 kg (n=32), mean height 168.6 ± 6.1 cm, and mean BMI 23.2 ± 3.4 kg/m2 [range: 18.6–35.1]. Five participants did not complete all planned visits and were classified as lost to follow-up (n=2) and drop-outs (n=3), resulting in a total of 29 participants completing all study follow-ups. Two participants discontinued before Visit 3 and did not receive letibotulinumtoxinA; both had experienced an injection site reaction. Three further participants discontinued after the Week 8 assessment. The flow of participants is shown in Figure 2. The mean total HA-based filler volume administered at baseline was 1.38 ± 0.37 cc [range 1.00–2.00] per patient, whereas letibotulinumtoxinA and polynucleotides were administered in standardized doses in all participants: letibotulinumtoxinA at 20 U to the glabellar complex across five injection points, and PN at 1 mL per eye per session, corresponding to 6 mL in total across three treatment sessions.
VISIA Skin Analysis
At Week 8, mean VISIA wrinkling score was 69.2% ± 25.2 compared with 68.2% ± 24.3 at baseline. The mean change from baseline was +1.6% ± 15.8 [95% CI: −4.1% to 7.3%] with the CI including 0 and thereby not meeting the primary endpoint. At Week 22, mean VISIA wrinkling score was 65.3% ± 26.8, with a mean change from baseline of −5.1% ± 16.2 [95% CI: −11.2% to 1.1%], a numerical decrease relative to baseline (Table 1 and Figure 5).
Table 1.
Table Summarizing the VISIA Skin Wrinkling (%) Score Over the Study Period
| Baseline | Week 8 | Week 22 | Week 8 vs Baseline | Week 22 vs Baseline | |
|---|---|---|---|---|---|
| N | 34 | 32 | 29 | 32 | 29 |
| Mean ± SD | 68.2% ± 24.3 | 69.2% ± 25.2 | 65.3% ± 26.8 | 1.6% ± 15.8 | −5.1% ± 16.2 |
| 95% CI Mean | 61.0%, 79.7% | 58.7%, 76.6% | 55.1%, 75.5% | −4.1%, 7.3% | −11.2%, 1.1% |
| Median | 79.0% | 81.8% | 74.5% | 2.5% | −3.0% |
| Q1, Q3 | 46.1%, 86.9% | 48.0%, 87.9% | 46.8%, 88.0% | −4.4%, 10.3% | −15.5%, 2.0% |
| Min, Max | 16%, 97% | 10%, 95% | 13%, 96% | −35%, 37% | −35%, 34% |
Figure 5.
Box-plot graphs showing the periorbital wrinkling score (%) over the study period, assessed by VISIA Skin Analysis.
Facial Wrinkle Scale
The mean FWS score was 2.9 ± 0.7 at baseline, 1.6 ± 0.7 at Week 8, and 2.4 ± 0.8 at Week 22. The mean change from baseline was −1.3 ± 0.8 [95% CI: −1.6 to −0.9] at Week 8 and −0.5 ± 0.7 [95% CI: −0.8 to −0.2] at Week 22, with both confidence intervals excluding zero implying statistical significance (Table 2 and Figure 6).
Table 2.
Table Summarizing the FWS Score Over the Study Period
| Baseline | Week 8 | Week 22 | Week 8 vs Baseline | Week 22 vs Baseline | |
|---|---|---|---|---|---|
| N | 34 | 32 | 29 | 32 | 29 |
| Mean ± SD | 2.9 ± 0.7 | 1.6 ± 0.7 | 2.4 ± 0.8 | −1.3 ± 0.8 | −0.5 ± 0.7 |
| Median | 3 | 2 | 2 | −1.0 | 0.0 |
| Q1, Q3 | 2, 3 | 1, 2 | 1, 3 | −2.0, −1.0 | −1.0, 0.0 |
| Range | 2–4 | 1–3 | 1–4 | −3.0–0.0 | −2.0–0.0 |
| 95% CI Mean | 2.6, 3.2 | 1.4, 1.9 | 2.1, 2.7 | −1.6, −0.9 | −0.8, −0.2 |
Figure 6.
Box-plot graphs showing the Facial Wrinkle Scale (FWS) score over the study period, assessed by the investigator.
Midface Volume Deficit Severity Score
The mean MVDSS score was 2.6 ± 0.6 at baseline, 1.1 ± 0.2 at Week 8, and 1.3 ± 0.5 at Week 22, with a mean change from baseline of −1.5 ± 0.5 [95% CI: −1.7 to −1.3] at Week 8 and −1.3 ± 0.6 [95% CI: −1.5 to −1.1] at Week 22, with both confidence intervals excluding zero implying statistical significance (Table 3 and Figure 7).
Table 3.
Table Summarizing the MVDSS Score Over the Study Period
| Baseline | Week 8 | Week 22 | Week 8 vs Baseline | Week 22 vs Baseline | |
|---|---|---|---|---|---|
| N | 34 | 32 | 29 | 32 | 29 |
| Mean ± SD | 2.6 ± 0.6 | 1.1 ± 0.2 | 1.3 ± 0.5 | −1.5 ± 0.5 | −1.3 ± 0.6 |
| Median | 3 | 1 | 1 | −1.5 | −1.0 |
| Q1, Q3 | 2, 3 | 1, 1 | 1, 1.5 | −2.0, −1.0 | −2.0, −1.0 |
| Range | 2–4 | 1–2 | 1–3 | −2.0, −1.0 | −2.0, 0.0 |
| 95% CI Mean | 2.4, 2.8 | 1.0, 1.2 | 1.1, 1.5 | −1.7, −1.3 | −1.5, −1.1 |
Figure 7.
Box-plot graphs showing the Midface Volume Deficit Severity Score (MVDSS) over the study period, assessed by the investigator.
Safety Results
Across the safety analysis set, two non-serious adverse events (AEs) were reported, corresponding to an overall incidence of 5.9%. Both events were local injection site reactions, and occurred in patients who had not yet received letibotulinumtoxinA, as both discontinued participation prior to Visit 3 (Week 6). No adverse device effects (ADEs), serious adverse events (SAEs), or serious adverse device effects (SADEs) were reported. One female patient experienced an injection site nodule (“bump”) in the midface region, identified at the Week 3 follow-up visit, approximately three weeks after midface HA-based filler and periorbital polynucleotide administration and attributed to the HA-based filler injection, classified under the System Organ Class (SOC) General disorders and administration site conditions with a relationship to the investigational product assessed as Possible. Another female patient experienced an injection site hematoma in the periorbital region on the day of the baseline visit, immediately following midface HA-based filler and periorbital polynucleotide administration and attributed to the polynucleotide injection, also classified under the SOC General disorders and administration site conditions with a causality likewise assessed as Possible. Both events resolved without permanent sequelae and neither required additional medical intervention, although both affected participants discontinued before Visit 3.
Discussion
This non-interventional study evaluated the outcomes of a comprehensive approach to extended periorbital rejuvenation comprising letibotulinumtoxinA, an HA-based filler for midfacial volumization, and a polynucleotide-based skin treatment using a mean total of 20 U of letibotulinumtoxin A, 1.38 cc of HA-based filler and 6 cc of polynucleotides. These procedures target different anatomical and physiological components of facial aging across the glabella, upper midface, and periorbital skin, including dynamic muscle activity, structural volume loss, and skin quality, reflecting the interrelated aesthetic units that define the extended periorbital region. The present findings provide insight into the real-world time course of changes following such multimodal treatment approach.
The primary endpoint, the change in periorbital wrinkling assessed by VISIA at Week 8, was not met: the mean change of +1.6% showed a 95% confidence interval including zero, with the same applying at Week 22. The significant improvements were therefore limited to the secondary, investigator-rated outcomes and should be interpreted in that light. Clinical assessments showed measurable changes across several outcome measures during the follow-up period. Improvements were observed in the mean scores of FWS and MVDSS at Week 8 compared with baseline, indicating reductions in wrinkle severity and midface volume deficit shortly after treatment. Although some attenuation of effect was observed at Week 22, the mean scores remained lower than baseline values. Changes in VISIA skin wrinkling measurements were less pronounced over time, which may reflect variability in imaging-based wrinkle assessment. Factors such as lighting conditions and patient positioning may influence the results.21 In addition, VISIA-based wrinkle assessment may show greater variability as the system is capable of capturing subtle skin surface appearance, including intra- and inter-day fluctuations that naturally occur. By contrast, clinical rating scales are more commonly used in studies since they are validated, widely accepted, and easy to integrate into routine study workflows.
The observed pattern of changes is consistent with the distinct mechanisms of the three product categories investigated herein. The highly crosslinked HA-based filler administered at baseline provides immediate structural volume restoration in the midface, indirectly supporting the periorbital region through replenishing of the underlying soft-tissue scaffold. The pronounced and durable MVDSS improvements at both follow-up time points (ie, Week 8 and Week 22), with mean changes of −1.5 and −1.3, respectively, are consistent with the known longevity of cross-linked HA fillers, which typically maintain volumetric effect over several months.19 Although the present observation was limited to 22 weeks, longer-term data have shown sustained midface volumization in 77% of patients at 52 weeks post-injection, suggesting the effect is likely to persist well beyond the present follow-up window.20 Polynucleotides were administered across three sessions at Weeks 0, 3, and 6, thereby – in theory – exerting cumulative effects on dermal fibroblasts and progressively enhancing skin quality.10,22 LetibotulinumtoxinA, administered at Week 6, was the most recently introduced modality at the time of the Week 8 assessment, which equals to only two weeks post-injection. Neuromodulator onset typically occurs within three to seven days, with peak effect expected around two weeks post-injection; accordingly, the marked FWS improvement observed at Week 8 is temporally consistent with letibotulinumtoxinA reaching near-maximal neuromodulatory activity at the time of assessment.13,23 By contrast, the Week 22 assessment falls at sixteen weeks post-injection, a time point at which neuromodulator effects are known to attenuate, providing a biologically plausible explanation for the partial FWS recovery observed between Week 8 and Week 22, with a mean score of 1.6 vs 2.4, respectively. In sum, the differential temporal trajectories are potentially compatible with the distinct mechanisms of the three modalities investigated in the combined approach. However, without a control group or single-modality comparison arms, this remains speculation rather than a demonstration of mechanistic effect.
Since the three modalities were administered at different time points, the Week 8 assessment simultaneously captures the HA filler at eight weeks post-injection, PN following completion of its full three-session protocol, and letibotulinumtoxinA at only two weeks post-administration. This temporal heterogeneity makes it difficult to attribute changes at any individual assessment time point to a single modality in isolation; however, it mirrors the staged treatment approach routinely applied in clinical practice and therefore contributes to the real-world relevance of the present findings. The study population consisted predominantly of women with a mean age of 41.2 years presenting with mild-to-moderate periorbital aging at baseline, a demographic that is representative of those most commonly seeking minimally invasive periorbital rejuvenation.24 Younger patients with less advanced baseline changes may exhibit smaller absolute improvements compared with older populations; still, early intervention with a multimodal approach may also serve to delay further progression of periorbital aging.
The real-world, non-interventional design of this study is an important methodological strength, enabling the evaluation of treatment outcomes under routine clinical conditions without the constraints of an interventional protocol. However, several limitations should be acknowledged. The absence of a control group means that observed changes cannot be definitively attributed to the treatment alone, as the possibility of spontaneous variation cannot be excluded. Without a comparator no causal inference is possible, and regression to the mean, seasonal variation and observer expectation cannot be separated from a treatment effect. The single-center design and the predominantly female study population limit the generalizability and external validity of findings to broader and more heterogeneous patient groups. Follow-up attrition resulted in a reduction from 34 participants at baseline to 29 at Week 22, and the staggered combination approach precludes estimation of the independent contribution of each individual modality to the overall outcome. Further, attrition was not randomly distributed: the two participants who discontinued before Visit 3 were those who experienced an injection site reaction. Furthermore, the periorbital wrinkling endpoint as measured by VISIA is among the more variable parameters of this imaging system, and the wide interindividual range of scores observed across time points reflects substantial patient heterogeneity. In retrospect, this parameter may not have been the optimal primary endpoint since it is not specific to the indication treated by any single modality, and the validated clinical scales used as secondary endpoints proved considerably more responsive and reflective of the treatment results obtained herein. Despite these limitations, the present findings contribute to the growing body of real-world evidence supporting multimodal approaches to extended periorbital rejuvenation. Future studies with larger, more diverse populations, longer follow-up periods, and ideally control arms would help clarify the durability of results and better delineate the individual contribution of each modality to the overall aesthetic outcome.
Conclusion
While periorbital wrinkling measured by VISIA did not change significantly at Week 8 or Week 22, this single-arm observational cohort showed that investigator-rated glabellar line severity and midface volume deficit both improved significantly at Week 8; the midface improvement persisted at Week 22 whereas the glabellar improvement partially regressed, a pattern that follows the differing durations of action of the modalities administered. Two mild, transient injection site reactions occurred and no serious adverse events were recorded. Larger prospective clinical trials paired with in-vitro studies are needed to better understand the proportional influence of each modality in such combined treatment approaches.
Funding Statement
This was a non-interventional study of products used routinely in the clinic, which would have been administered irrespective of the study. This investigator-initiated study received financial support from Croma-Pharma GmbH under an agreement with H&P Ambulatorien Betriebs GmbH (Yuvell), which acted as the study sponsor and was responsible for study management and conduct. Treatment decisions were accordingly independent of study participation and all treatments formed part of routine clinical care. The aim of this publication is not to promote any individual product but to describe a multimodal treatment approach for the extended periorbital region combining three product categories that address complementary anatomical concerns.
Disclosure
None of the other authors listed has any commercial associations or financial disclosures that might pose or create a conflict of interest with the methods applied or the results presented in this article.
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