Clinical safety of a low-modification hyaluronic acid filler (MoD 2%) for facial rejuvenation

Abstract

Background

The degree of modification (MoD) of hyaluronic acid (HA) fillers reflects the extent of chemical cross-linking of native HA chains. Lower MoD values correspond to reduced cross-linker content and potentially more physiological behavior, but may also shorten filler longevity. Recent work on HA filler chemistry suggests that cross-linking intensity and impurity load contribute to delayed inflammatory reactions, nodules, and granulomas.

Objectives

To evaluate the long-term safety and clinical performance of a low-MoD (2%) HA filler (Volonic Light, Volonic Co., Ltd., Korea) over 24 months, focusing on the incidence of granulomas, nodules, and delayed inflammatory reactions, as well as durability and patient-reported satisfaction.

Methods

In this prospective, single-center, single-arm cohort study, n = 60 adults underwent facial rejuvenation with a monophasic, lidocaine-containing HA filler with MoD 2% (Volonic Light; Volonic Co., Ltd., Korea). Injections targeted fine lines and contours in the mid- and superficial dermis.

Results

Across 60 patients and 24 months of observation, no clinically apparent granulomas, delayed-onset nodules, or persistent inflammatory reactions were observed at any time point. Early post-injection events included transient edema (24/60, 40.0%) and ecchymosis (9/60, 15.0%), which resolved spontaneously within 7–10 days.

Conclusions

In this single-center, single-arm cohort (n = 60), a low-MoD (2%) HA filler was not associated with clinically apparent granulomas or delayed-onset nodules during 24 months of follow-up, and showed a predictable, near-complete clinical resolution of effect by 2 years.

Introduction

Hyaluronic acid (HA) fillers are among the most widely used injectables for aesthetic soft tissue augmentation, owing to their biocompatibility, reversibility (e.g., dissolution with hyaluronidase), and favorable safety profile. Nevertheless, adverse events such as delayed inflammatory reactions, nodules, and foreign body granulomas are well documented, with reported granuloma incidences for HA fillers in the range of approximately 0.02–0.4%.1, 2, 3, 4

Although rare, these complications can be challenging to manage and may significantly affect patient satisfaction and confidence in minimally invasive procedures.^2,5,6 Management is typically individualized and depends on timing and clinical phenotype (e.g., noninflammatory nodules vs delayed inflammatory reactions). A commonly recommended approach includes careful assessment (and imaging when indicated), exclusion of infection/biofilm, and stepwise treatment. For HA fillers, hyaluronidase is widely used to dissolve product in cases of overcorrection, palpable irregularities, delayed nodules, and selected inflammatory complications.⁴

Modern HA fillers are manufactured by chemically cross-linking native HA with reagents such as 1,4-butanediol diglycidyl ether (BDDE), which prolongs in vivo longevity by increasing resistance to enzymatic and oxidative degradation.^5,7,8

The degree of modification (MoD) is a quantitative parameter describing the ratio of modified HA disaccharide units (carrying mono- and double-linked BDDE residues) to native disaccharide units.^7,8

Higher MoD values typically yield fillers with greater firmness and longevity but also signify a higher total amount of chemically modified HA and bound cross-linker.^5,7,8

Recent work has suggested that cross-linking intensity, residual BDDE, and other impurities may influence the risk of delayed inflammatory reactions.^5,6,9,10 Filler granulomas and delayed-onset nodules (DONs) are increasingly understood as complex events involving the filler’s physicochemical properties, host immune reactivity, injection technique, and potential biofilm formation.^2,3,5,6 In this context, low-MoD fillers—which use substantially lower proportions of cross-linker—are of growing interest as they may combine acceptable durability with a more physiological degradation profile.

Volonic Light (Volonic Inc., Korea) is a monophasic HA filler designed for fine lines and superficial facial rejuvenation. The manufacturer promotes it as a high-purity filler with minimal residual BDDE and endotoxin, produced through a proprietary purification process (VolWaPRO™). In the present study, we focus on a formulation characterized by a MoD value of 2%, placing it in the low-modification category compared with many conventional fillers.^5,7,8

Conceptually, a low MoD may confer several potential advantages:

• •Reduced cross-linker burden per unit volume;
• •Closer resemblance to native HA’s degradation and turnover;
• •Lower propensity for long-lasting foreign body responses and granuloma formation;
• •More predictable and complete resorption within a finite time frame (e.g., ≤2 years).

However, low-MoD fillers must still achieve sufficient mechanical integrity and persistence to justify their use in aesthetic practice.

The primary aim of this prospective cohort study was to evaluate the long-term safety of a low-MoD (2%) HA filler over 24 months, with a particular emphasis on the incidence of granulomas, delayed nodules, and delayed inflammatory reactions. Secondary aims were to document aesthetic performance, duration of effect, and patient satisfaction as measured by the Global Aesthetic Improvement Scale (GAIS) at 6 months.

Materials and methods

Study design and setting

This was a prospective, single-center, observational cohort study conducted at a private aesthetic clinic. The study adhered to the principles of the Declaration of Helsinki. All patients provided written informed consent for treatment and use of anonymized data and photographs for research and publication.

Patients

Eligible participants were adults aged 25–60 years seeking minimally invasive facial rejuvenation with HA fillers. Inclusion criteria were:

• •Clinical indication for treatment with a fine-line filler (e.g., perioral lines, fine nasolabial folds, early marionette lines, tear troughs, or contour refinement);
• •Fitzpatrick skin type I–IV;
• •No facial HA injections in the preceding 12 months in the targeted area.

Exclusion criteria included:

• •Known allergy to HA, lidocaine, or BDDE;
• •History of autoimmune or granulomatous disease;
• •Active infection or inflammation at the injection site;
• •Pregnancy or breastfeeding;
• •Use of systemic immunosuppressants or anticoagulants.

A total of 60 patients were enrolled and treated. Demographic data, medical history, and previous aesthetic treatments were recorded at baseline.

Filler characteristics

The investigational product was Volonic Light, a lidocaine-containing HA filler manufactured by Volonic Co., Ltd. (Korea). It is described as a monophasic HA gel produced from non-animal stabilized HA, designed for mid-to-superficial dermal injection for fine lines and subtle contouring.

For this formulation, the MoD (degree of modification)—defined as the stoichiometric ratio of BDDE-modified disaccharide units (mono- and double-linked) to total HA disaccharides^7,8—was specified as 2% by the manufacturer. In the context of the literature, this places the filler at the low end of cross-linking levels, as many conventional HA fillers exhibit substantially higher total MoD and cross-link density.^5,7,8

Injection techniques

All injections were performed by a single experienced injector (board-certified anatomical and aesthetic physician) to minimize technique-related variability. The filler was administered using 30 G needles or 25 G cannulas, depending on anatomical site and clinical indication.

Typical target planes were:

Mid-dermis for fine rhytids (e.g., perioral lines).

Deep dermis or superficial subcutis for contour refinement (e.g., tear troughs, early marionette lines, lateral canthal fine lines).

Injection techniques included linear threading, serial puncture, and small aliquots via fanning. Injection volumes per area were conservative (e.g., 0.1–0.3 mL per line or subunit), with total volumes per session tailored to individual needs (usually 1.0–2.2 mL).

Topical anesthetic cream (lidocaine-based) was offered but not mandated; the filler itself contained lidocaine for intra-procedural comfort. No prophylactic antibiotics were routinely used.

Follow-up schedule

Patients were scheduled for follow-up visits at:

• •2 weeks (early safety and touch-up if needed);
• •6 months;
• •12 months;
• •18 months;
• •24 months.

At each follow-up, standardized photographs were taken, and clinical examination of all treated sites was performed, with specific attention to:

• •Palpable nodules or induration;
• •Asymmetry;
• •Tyndall effect;
• •Delayed inflammatory signs (erythema, edema, warmth, tenderness);
• •Evidence of granulomatous reactions (firm, sometimes cystic nodules, often delayed).^2,3,10

Representative clinical photographs from two patients are presented as a composite (Figure 1A–D).

Figure 1.

(A) Patient 1 before treatment (baseline). (B) Patient 1 after treatment (follow-up). (C) Patient 2 before treatment (baseline). (D) Patient 2 after treatment (follow-up). Composite clinical photographs from two representative patients treated with low-MoD (2%) hyaluronic acid filler (Volonic Light).

In addition, in a representative case, high-frequency ultrasound images of the lip were obtained at 6 months and 24 months post-injection for qualitative documentation of persistence and resorption (Figure 2A and B).

Figure 2.

(A) Lip ultrasound 6 months after injection. (B) Lip ultrasound 24 months (2 years) after injection demonstrating no sonographically visible residual filler. Ultrasound images are provided for qualitative illustration and were not used as quantitative endpoints. Composite high-frequency ultrasound images of the lip obtained after Volonic Light injection in a representative case.

Outcome measures

Safety outcomes

Primary safety outcomes:

• •Incidence of granulomas (clinically suspected and/or biopsy-confirmed foreign body granuloma);
• •Incidence of delayed-onset nodules (DONs) persisting >4 weeks after onset;
• •Incidence of delayed inflammatory reactions (e.g., tender, swollen nodules or edematous plaques occurring ≥4 weeks post-injection).

Secondary safety outcomes:

• •Early adverse events (bruising, edema, pain, injection-site erythema);
• •Need for hyaluronidase or other medical interventions;
• •Serious adverse events related to filler treatment.

Aesthetic performance and durability

At each follow-up, the treating investigator evaluated aesthetic outcomes qualitatively (improved, unchanged, worsened) and estimated persistence of volume or line correction using prespecified categories (>75%, 50–75%, 25–50%, <25% of the initial effect) based on standardized photographs and clinical examination. Independent blinded ratings and objective volumetric measurements (e.g., 3D imaging or systematic ultrasound volumetry) were not performed.

Global aesthetic improvement scale (GAIS) and satisfaction

At 6 months, both investigator and patients independently rated global facial aesthetic improvement using the GAIS:

• •3 = Very much improved
• •2 = Much improved
• •1 = Improved
• •0 = No change
• •−1 = Worse

Patients additionally completed a simple satisfaction scale (very satisfied, satisfied, neutral, dissatisfied, very dissatisfied) relating to the treated regions at the 6-month visit.

Statistical analysis

Given the exploratory nature of this single-arm cohort, analyses were primarily descriptive. Categorical data are presented as counts and percentages; continuous data as mean ± standard deviation (SD). For selected proportions (including key safety endpoints), exact (Clopper-Pearson) 95% confidence intervals (CIs) were calculated. No formal hypothesis testing or a priori power calculation was performed.

Results

Patient characteristics

Sixty patients (52 women, 8 men) completed at least 24 months of follow-up. Mean age at baseline was 39.2 ± 7.8 years (range 27–56), and mean BMI was 22.1 ± 2.4 kg/m². Common treatment areas included perioral lines (72%), early nasolabial folds (65%), tear troughs (40%), lateral canthal lines (38%), and early marionette lines (30%). Approximately 45% had received previous HA fillers in other facial regions more than 12 months prior; none had a history of filler granulomas or delayed nodules.

Early adverse events

Early post-injection effects were typical for HA fillers:

Transient edema in treated areas: 24/60 (40.0%; 95% CI, 27.6–53.5)

Localized ecchymosis: 9/60 (15.0%; 95% CI, 7.1–26.6)

Mild injection-site pain or tenderness: 18/60 (30.0%; 95% CI, 18.8–43.2)

All early events resolved spontaneously within 7–10 days without intervention. No cases of vascular occlusion, skin necrosis, or immediate hypersensitivity reactions were observed.

Long-term safety: granulomas, nodules, and delayed reactions

Over the full 24-month observation period, no clinically apparent granulomas were detected (0/60; 0.0%; exact 95% CI, 0.0–5.9%). There were also no delayed-onset nodules persisting beyond 4 weeks (0/60; exact 95% CI, 0.0–5.9%) and no episodes consistent with delayed inflammatory reactions at treated sites (e.g., tender swollen nodules appearing months after injection). Safety outcomes were based on clinical examination and patient-reported symptoms; routine imaging or biopsy was not performed.

A small number of transient, noninflamed palpable irregularities (subtle “lumps” or firmness) were noted in 4 patients (4/60, 6.7%; 95% CI, 1.8–16.2%) within the first 6 weeks; all were mild, asymptomatic, and resolved spontaneously or with gentle massage and minor touch-up injections. None persisted beyond 3 months and none required hyaluronidase.

No patients required systemic corticosteroids, antibiotics, or other systemic treatments for filler-related complications during the study.

Aesthetic performance and durability

At 6 months, the majority of patients were judged to have maintained a substantial component of the initial correction:

• •75% of initial effect: 50% of patients
• •50–75%: 35%
• •25–50%: 15%
• •<25%: 0%

Between 12 and 18 months, gradual softening and volume loss were observed in almost all patients. By 24 months, the investigator judged that treated sites had largely or completely returned to baseline in all patients, with no palpable residual gel nodules or focal induration. Clinically, the filler appeared to have undergone near-complete degradation within 2 years, consistent with expectations for a low-MoD, low-cross-linker HA gel.^5,7,8

Representative clinical before/after outcomes from two patients are shown in the composite Figure 1A–D.

In a representative case, lip ultrasound at 6 months demonstrated qualitative persistence (Figure 2A), whereas at 24 months the ultrasound demonstrated qualitative absence of sonographically visible residual filler (Figure 2B).

GAIS and patient satisfaction at 6 months

At the 6-month follow-up:

Investigator GAIS

• •Very much improved (3): 35%
• •Much improved (2): 48%
• •Improved (1): 15%
• •No change (0) or worse (−1): 2%

Mean GAIS (investigator): 2.1 ± 0.6

Patient GAIS

• •Very much improved (3): 38%
• •Much improved (2): 50%
• •Improved (1): 10%
• •No change or worse: 2%

Mean GAIS (patient): 2.2 ± 0.5

On the satisfaction scale, 54% of patients reported being very satisfied, 34% satisfied, 10% neutral, and 2% dissatisfied (no “very dissatisfied” responses). Dissatisfaction was generally related to conservative volume choices or rapidly evolving aging changes rather than specific product complaints.

Discussion

This prospective 24-month, single-center cohort study evaluated a low-modification (MoD 2%) HA filler in 60 patients. No clinically apparent granulomas, delayed-onset nodules, or delayed inflammatory reactions were observed during follow-up, and patient-reported outcomes at 6 months were generally favorable. These findings suggest a potentially favorable long-term safety profile in this limited cohort, but rare events cannot be excluded and confirmatory comparative studies are needed.

MoD, cross-linking, and safety

The MoD of a BDDE-cross-linked HA filler quantifies the fraction of HA disaccharide units that have been chemically modified—either mono- or double-linked by BDDE.^7,8

This parameter, together with related metrics such as cross-linking degree (CrD) and total-MoD (T-MoD), helps characterize the structural density and potential persistence of the filler network.^5,7,8

Higher MoD and cross-link density are generally associated with firmer, more cohesive gels and increased resistance to enzymatic degradation, but they also entail greater cumulative exposure to chemically modified HA and residual cross-linker.^5,7, 8, 9 Recent reviews have highlighted that highly cross-linked fillers may show prolonged persistence and, in some cases, a greater propensity for delayed inflammatory reactions or foreign body granulomas—especially when injected in large boluses or in high-risk sites.1, 2, 3^,5,6,10

By contrast, low-MoD fillers like the one evaluated here (MoD 2%) are expected to:

• •Behave closer to native HA in terms of biodegradation and remodeling.
• •Carry a reduced amount of chemically bound BDDE per unit volume.
• •Potentially present fewer long-lived antigenic or foreign body stimuli.

In our cohort, the absence of clinically apparent granulomas or delayed nodules over 24 months is compatible with the hypothesis that lower chemical modification may reduce long-lived inflammatory stimuli. However, granulomas after HA fillers are rare (≈0.02–0.4%),1, 2, 3 and this study (n = 60) is underpowered to detect low-incidence events. With 0 events in 60 patients, the exact 95% CI for granuloma incidence is 0.0–5.9%, underscoring the risk of type II error for rare complications. For example, to have an 80% probability of observing at least one event if the true incidence were 0.1%, approximately 1609 subjects would be required.

Duration of effect and complete resorption

One concern with lowering MoD is acceleration of filler breakdown, potentially limiting clinical utility.^5,7,8 In this study, aesthetic benefit remained clearly apparent in most patients at 6 months, with >75% of the initial effect judged preserved in half the cohort. Between 12 and 18 months, the effect gradually diminished, and by 24 months treated sites were clinically indistinguishable from baseline, with no palpable residual nodules or irregularities.

Representative clinical outcomes (Figure 1A–D) and illustrative ultrasound images (Figure 2A and B) qualitatively support this time-limited behavior, including the absence of sonographically visible residual filler at 24 months in the illustrated case.

This finite lifespan may actually be advantageous from a safety standpoint. Reviews of HA filler behavior in vivo indicate that highly cross-linked products can persist far longer than originally anticipated—sometimes several years—especially when injected deeply or in high volumes.^1,3,5,10, 11, 12

While longevity is often desirable, persistent depot material may act as a substrate for delayed inflammatory reactions or infection, and can complicate correction if aesthetic trends or patient preferences change.^{2,3,5,6,11,12}

In contrast, a low-MoD filler that reliably resorbs by around 2 years offers a balance between meaningful aesthetic duration and long-term safety. If complications arise, standard hyaluronidase protocols can still be used to accelerate degradation.^13,14

GAIS and patient satisfaction

The high GAIS scores and satisfaction rates at 6 months indicate that reduced cross-linking did not compromise clinical impact in the short to medium term. Mean GAIS >2 (between “much improved” and “very much improved”) from both investigator and patient perspectives supports the filler’s effectiveness for fine-line correction and light contouring.

In real-world practice, patients often value natural-looking, soft results that integrate well with dynamic facial movement. Low-MoD gels tend to be less stiff and more tissue-adaptive than heavily cross-linked fillers, which may be particularly appropriate for superficial lines and dynamic zones.^5,6,7,8 The favorable GAIS and satisfaction data in this series are consistent with these expectations.

Context with current literature on HA filler complications

Comprehensive reviews highlight that delayed inflammatory reactions and soft tissue granulomas following HA filler injection are multifactorial. They can be triggered by infection, biofilm, systemic immune activation (including post-vaccination or post-viral events), and filler impurities or degradation fragments.1, 2, 3^,5,6,10, 11, 12 Large-bolus injections, repeated procedures in the same site, and high cross-linker loads have all been implicated as potential contributors.^3,5, 6, 7^,10

Our study adds to this body of evidence by describing the benign course of a low-MoD, low-cross-linker, high-purity filler over 24 months without delayed inflammatory events in a moderate cohort size. While it cannot isolate MoD as the sole protective factor, it supports the hypothesis that lower chemical modification and optimized purification (e.g., minimized residual BDDE, endotoxin)^5,9 may help reduce the long-term inflammatory burden of HA fillers.

Limitations

This study has several limitations. First, it is a single-center, single-arm observational cohort without a comparator filler, so direct conclusions about relative safety versus standard/high-MoD products cannot be drawn. Second, the sample size (n = 60) is modest for very rare events such as granulomas; with 0/60 events, the exact 95% CI still allows an incidence up to 5.9%, indicating potential type II error. Third, outcome assessments were not blinded and were performed by the treating investigator, which may introduce bias for subjective endpoints such as GAIS and persistence categories. Fourth, persistence and volumetric effects were assessed semi-quantitatively using clinical examination and standardized photographs; objective volumetric methods (e.g., 3D photography or systematic ultrasound volumetry) were not used. Finally, no formal power calculation or hypothesis testing was prespecified; analyses were primarily descriptive.

Moreover, the cohort consisted predominantly of relatively healthy, middle-aged individuals with modest treatment volumes. Results may not generalize to older patients, those with comorbidities (including autoimmune conditions), patients receiving very high injection volumes, or those undergoing repeated procedures in the same anatomical zones over many years. GAIS and satisfaction were formally assessed only at 6 months; additional time points could provide a more complete longitudinal view of patient perception.

Future directions

Future research should consider:

Comparative trials of low-MoD versus standard/high-MoD fillers in matched anatomical sites.

Larger multicenter cohorts to better estimate true incidence of granulomas and delayed nodules with low-MoD products.

Integration of MoD, cross-link density, and impurity profiling into risk stratification models for filler selection.

Objective volumetric assessments (e.g., 3D photography or ultrasound) to quantify time-dependent degradation.

Such work would help refine filler choice based not only on rheology and lifting capacity, but also on long-term immunologic safety and degradation behavior.

Conclusion

In this 24-month prospective, single-arm cohort (n = 60), treatment with a low-MoD (2%) hyaluronic acid filler (Volonic Light) was not associated with clinically apparent granulomas, delayed nodules, or delayed inflammatory reactions. With 0/60 granulomas, the exact 95% CI for granuloma incidence was 0.0–5.9%, so rare events cannot be excluded. Aesthetic improvement and patient satisfaction at 6 months were favorable, and clinical effect diminished with near-complete resorption by 24 months.

Overall, these findings support the feasibility of a low-MoD approach for fine-line correction and subtle facial contouring, while emphasizing the need for larger, controlled and preferably multicenter studies incorporating comparator fillers, blinded outcome assessment, and objective volumetry to establish robust evidence-based guidance on long-term safety and durability.

Funding

The authors received no financial support for the research, authorship, or publication of this article. No manufacturer or commercial entity was involved in study design, data collection, analysis, or writing.

Informed consent

Informed consent was obtained from all participants, with full disclosure of the study’s purpose, risks, and confidentiality. Photographs were obtained under standardized conditions, and patients provided consent for anonymized publication.

Author contributions

Conceptualization: Kyu-Ho Yi, Jovian Wan. Writing—Original Draft Preparation: Kyu-Ho Yi, Soo-Bin Kim. Writing—Review & Editing: Kyu -Ho Yi, Jovian Wan, Soo-Bin Kim, Olena Sydorchuk. Supervision: Kyu-Ho Yi, Olena Sydorchuk. All authors have reviewed and approved the article for submission.