Italian Expert Consensus on Poly(ethylene glycol) Diglycidyl Ether-Crosslinked Hyaluronic Acid Hydrogels for Facial Aesthetics: Product Selection, Injection Techniques, and Safety

Abstract

Background: Hyaluronic acid (HA) hydrogels are the most widely used injectable fillers for facial rejuvenation. A new generation of HA fillers crosslinked with poly(ethylene glycol) diglycidyl ether (PEGDE) has been developed to enhance cohesiveness, tissue integration, stability, and longevity while minimizing swelling and immunogenicity. Owing to their distinct viscoelastic properties, PEGDE-crosslinked HA fillers may require product-specific selection and adapted injection techniques. Objective: The objective of this study is to provide practical, expert-based recommendations for the safe and effective use of PEGDE-crosslinked HA hydrogels in facial aesthetic treatments. Methods: A multidisciplinary panel of nine Italian experts in aesthetic medicine, each with more than 15 years of experience using HA fillers, developed consensus recommendations based on clinical practice and available evidence. A pre-meeting questionnaire informed structured discussions during a face-to-face meeting held in Paris in January 2024. The nominal group technique was applied, with consensus defined as agreement by at least 80% of panel members. Results: Consensus was reached on product selection, injection planes, delivery devices, techniques, and typical treatment volumes for PEGDE-HA hydrogels across multiple facial regions, including the forehead, temples, midface, nasolabial folds, chin, jawline, and lips. Recommended injection techniques included microbolus, macrobolus, and retrograde linear threading, with placement ranging from superficial subcutaneous to supraperiosteal planes depending on the anatomical area and clinical indication. Typical injection volumes generally ranged from 0.1 to 0.5 mL per side. Optional ultrasound mapping was considered beneficial in selected high-risk or superficial procedures to improve anatomical safety. Conclusions: These expert consensus recommendations provide practical guidance for clinicians using PEGDE-crosslinked HA hydrogels in facial rejuvenation. Tailoring product characteristics to injection depth, technique, and regional anatomy may help optimize clinical outcomes and procedural safety. Future research priorities include prospective comparative studies with other crosslinking technologies, standardized reporting of adverse events, long-term outcome registries, and further evaluation of ultrasound-guided injection strategies.

1. Introduction

Over the past three decades, since the introduction of hyaluronic acid (HA) hydrogels for aesthetic use, both their composition and manufacturing techniques have evolved substantially, contributing to progressive refinements in facial rejuvenation approaches [1,2,3]. Today, HA remains the most widely used injectable filler material worldwide [4], largely due to its established clinical performance, reversibility, and favorable safety profile reported across a broad range of indications [5]. Ongoing innovation within aesthetic medicine continues to drive the development of new HA-based technologies aimed at improving handling characteristics, durability, and predictability of clinical outcomes and patient satisfaction [6].

HA hydrogels are composed predominantly of water (approximately 95%) and 0.5–3% crosslinked HA, which together confer their characteristic viscoelastic properties [7]. Variations in HA concentration, crosslinker type, and degree of crosslinking allow modulation of viscosity, elasticity, and water-binding capacity, thereby influencing lifting, shaping, and volumizing behavior in vivo [8,9]. Among recent developments, a new generation of HA hydrogels employs poly(ethylene glycol) diglycidyl ether (PEGDE) as a crosslinking agent [10]. PEGDE represents a biocompatible alternative to the more commonly used 1,4-butanediol diglycidyl ether (BDDE) [11]. Unlike BDDE, PEGDE is provided as a mixture of PEG oligomers with variable chain lengths, leading to heterogeneous spacer formation between HA chains. This heterogeneity has been associated with differences in crosslinking efficiency/kinetics and viscoelastic performance in physicochemical studies [10,11,12,13].

Experimental and in vitro studies suggest that PEGDE crosslinking may increase resistance of HA hydrogels to enzymatic degradation by hyaluronidase and may be associated with reduced exposure of antigenic sites, potentially contributing to hydrogel stability [14,15]. In addition, the incorporation of amino acids such as glycine and L-proline has been reported to support stabilization of viscoelastic and thermodynamic properties, which may help modulate post-injection swelling behavior [16].

The first PEGDE-crosslinked HA hydrogel was introduced in Italy in 2012, followed by the development of several PEGDE-HA formulations intended for a range of facial aesthetic indications (

Table 1. Overview of PEGDE-HA formulations, extrusion force, delivery devices, and recommended injection planes.

Product (PEGDE-HA)	HA Content (mg/mL)	Extrusion Force *	Needle/Cannula Gauge	Injection Plane(s) and Technique	Typical Duration (Months) **
PEGDE-HA 22 mg/mL	22	Low	25–30 G needle or 25 G cannula	Subdermal or superficial subcutaneous (refinement, lips, NLF)	6–10
PEGDE-HA 24 mg/mL	24	Low–moderate	23–27 G needle or cannula	Submucosal or superficial subcutaneous (lip contour/volume)	6–10
PEGDE-HA 26 mg/mL LR	26	Low–moderate	25–27 G cannula or needle	Subcutaneous/deep subcutaneous (forehead, cheeks, temples)	8–12
PEGDE-HA 26 mg/mL LV	26	Moderate–high	25–27 G cannula or 27–30 G needle	Supraperiosteal (forehead, temples, eyebrow contour)	10–12
PEGDE-HA 26 mg/mL + CaHA	26 + 1% CaHA	Moderate	22–25 G cannula or 27 G needle	Mid- to deep subcutaneous	10–15
PEGDE-HA 28 mg/mL	28	High	23–27 G needle or 22–25 G cannula	Supraperiosteal/deep subcutaneous	10–15
PEGDE-HA 28 mg/mL + CaHA	28 + 1% CaHA	High	23–25 G needle or cannula	Supraperiosteal/deep subcutaneous	10–15

* Extrusion force levels are relative and derived from expert consensus observations (low = soft gel, moderate = medium viscosity, high = high viscosity/greater lifting capacity). Injection depth is described as subdermal, superficial subcutaneous, deep subcutaneous, or supraperiosteal, depending on the indication. ** Typical duration values represent expert consensus estimates based on routine clinical practice and published observational data, and may vary according to facial area, injection plane, volume, and individual patient factors.

). These products are currently available in multiple markets across Europe and Asia. Due to their distinct rheological and handling characteristics, PEGDE-HA hydrogels may require product-specific selection and adaptation of injection techniques and volumes compared with other HA filler technologies, particularly for practitioners less familiar with this crosslinking approach.

To address this knowledge gap, the present consensus document was developed by a multidisciplinary panel of experienced Italian physicians with clinical experience in the use of PEGDE-crosslinked hyaluronic acid (PEGDE-HA) hydrogels for facial aesthetic indications involving the upper, mid-, and lower face. The aim of this work is to provide practical, consensus-based guidance on product selection and injection techniques, informed by available published evidence and expert clinical experience, to support procedural safety and consistent aesthetic outcomes in routine clinical practice.

1.1. Consensus Methodology

A multidisciplinary group of nine Italian experts in aesthetic medicine (seven men and two women) convened to discuss the use of PEGDE-crosslinked hyaluronic acid (PEGDE-HA) hydrogels in clinical practice. The group included two plastic surgeons (Lanfranchi, Marchetti), four dermatologists (Basso, Di Lella, Rana, Zerbinati), one general surgeon (Dell’Avanzato), one vascular surgeon (Marini), and one gynaecologist (Mazzarella). All participants had at least 15 years of experience with hyaluronic acid injectable fillers and an average of 3.5 years of experience using PEGDE-HA hydrogels (range: 1–11 years). Experts were selected based on their clinical experience with HA fillers and familiarity with PEGDE-HA hydrogels, acknowledging the inherent limitations of expert-opinion–based consensus methodologies.

A pre-meeting questionnaire was distributed to collect information on expert demographics, patient profiles, and treatment strategies, with the aim of identifying which PEGDE-HA hydrogel formulations were most frequently used for specific indications and techniques in routine practice. The results served as the foundation for structured discussions during a face-to-face consensus meeting held in Paris in January 2024, aimed at aligning and defining practical treatment recommendations.

During the meeting, the experts discussed their individual clinical experiences with PEGDE-HA hydrogels and sought consensus on general injection techniques across a range of upper, mid-, and lower-face indications. A nominal group technique was applied, whereby participants were invited to comment in a round-robin fashion, after which agreement on individual statements was assessed [7]. An initial draft was prepared by the Chair and subsequently reviewed by all panel members. Iterative feedback was incorporated until consensus was achieved and the final text validated. Consensus was predefined as agreement by at least 80% of participants. All final statements met this predefined threshold (≥80% agreement), with several reaching full agreement among panel members. A consolidated summary of the area-based recommendations, including product selection, injection planes, techniques, and typical treatment volumes, is provided in Supplementary Table S1.

1.2. Forehead

Forehead lines visible at rest may be softened using PEGDE-HA 26 mg/mL LR or PEGDE-HA 26 mg/mL LV. According to expert consensus, both formulations can also be used to address age-related flattening of the forehead curvature. Based on their handling characteristics and clinical experience, PEGDE-HA 26 mg/mL LR and PEGDE-HA 26 mg/mL LV were considered by the panel to provide sufficient structural support to counteract the compressive and shear forces generated by the frontalis muscle.

When injecting in the subcutaneous plane, a lower-viscosity formulation such as PEGDE-HA 26 mg/mL LR was preferred by the experts, whereas deeper injections were generally performed using a product with greater plasticity. For the correction of forehead lines and frontal concavity, experts reported injecting 0.2 to 0.3 mL of PEGDE-HA 26 mg/mL LR per side subcutaneously as retrograde linear threads using a 25 G cannula, typically through a single lateral entry point on each side.

PEGDE-HA 26 mg/mL LV (0.5 mL per side) was also used for this indication in expert practice. It was administered either supraperiosteally as retrograde linear threads using a 25 G cannula or via a 27 G needle inserted perpendicular to the skin, delivering five microbolus injections of approximately 0.025 mL each. Gentle massage after injection was recommended to facilitate even product distribution.

In expert experience, anesthesia by nerve block or topical anesthetic cream was generally not required for forehead injections. Injections were typically performed approximately 2 cm above the orbital rim to reduce the risk of inadvertent intravascular injection into the supratrochlear and supraorbital arteries, which ascend beneath the frontalis muscle and become more superficial in a variable manner 1.5 to 2 cm above the orbital rim. These vessels represent well-documented high-risk structures in this region, and inadvertent intravascular injection in the forehead has been associated with severe ischemic complications, including visual impairment and blindness [17].

According to expert-reported estimates from routine clinical practice, transient edema lasting 24 to 48 h was observed in approximately 20% of patients following subcutaneous injections of PEGDE-HA 26 mg/mL LR, while mild pain was reported in around 5% of cases, consistent with cannula-based techniques. Supraperiosteal injections of PEGDE-HA 26 mg/mL LV were associated with transient discomfort lasting 24 to 48 h in approximately 20% of patients, likely related to local tissue expansion in the frontal area. The duration of the aesthetic effect was typically reported by the panel to be approximately 8 to 10 months for PEGDE-HA 26 mg/mL LR and 10 to 12 months for PEGDE-HA 26 mg/mL LV, with variability depending on injection plane, volume, and individual patient factors.

1.3. Temples

The temporal region is anatomically complex and is generally considered suitable for treatment by experienced injectors. This complexity is related to the variable course of the superficial temporal artery and its branches, as well as the presence of multiple fascial planes, which have been identified as potential danger zones during filler injections [18].

According to expert consensus, the area may be subdivided into central, anterior, and temporoparietal regions, with most patients seeking temple rejuvenation requiring correction primarily in the central zone. To address volume loss, experts reported varying preferences regarding the injection plane, employing techniques targeting the supraperiosteal, interfascial, or subcutaneous layers, depending on anatomical considerations and treatment goals.

For supraperiosteal augmentation, PEGDE-HA 28 mg/mL was used in expert practice at volumes of 0.25–0.5 mL per side using a 25–27 G needle with a macrobolus technique. The needle was inserted perpendicularly until contact with the periosteum, and following aspiration, the product was slowly deposited without needle movement. PEGDE-HA 28 mg/mL + CaHA was also used for this indication; based on expert experience, its higher HA concentration was considered to provide greater structural support, allowing correction with relatively smaller volumes. Experts further reported that this formulation was perceived to be associated with prolonged clinical effect in the temple region and was not associated with clinically relevant tissue overexpansion in their experience. However, direct randomized comparative trials with other filler technologies are not available.

Using a 25 G cannula, PEGDE-HA 26 mg/mL LV (0.25–0.5 mL per side) was placed as retrograde interfascial threads in expert practice. The same cannula size was also used for retrograde subcutaneous injections of PEGDE-HA 26 mg/mL LR or PEGDE-HA 22 mg/mL (0.5 mL per side). PEGDE-HA 26 mg/mL LR was generally preferred by experts for patients with thicker skin, whereas PEGDE-HA 22 mg/mL was considered more suitable for thinner skin. In cases of marked temporal hollowing, some experts reported employing a layering technique targeting two or more tissue planes, either within the same session or during a subsequent treatment.

For anterior temple filling, experts reported using PEGDE-HA 28 mg/mL at volumes of 0.2–0.4 mL per side, injected as supraperiosteal boluses with a 27 G needle. The injection point was located approximately 1 cm above and 1 cm posterior to the frontal crest. In expert experience, injections in this region may also contribute to elevation of the lateral eyebrow. One expert reported performing ultrasound mapping prior to injection to identify vascular structures and enhance procedural safety. Ultrasound-based anatomical mapping has been proposed as a useful adjunct in high-risk regions such as the temple to reduce the risk of inadvertent intravascular injection [19].

For the temporoparietal region, the consensus recommendation was supraperiosteal retrograde injections of PEGDE-HA 28 mg/mL (0.3–0.5 mL per side) using a 25 G cannula. Slow injection of small volumes followed by gentle massage was recommended to reduce the risk of venous compression. Treatment of this area was considered by the experts to provide structural support to overlying tissues.

According to expert-reported estimates from routine clinical practice, pain or discomfort lasting 12–24 h, particularly during mastication, was observed in approximately 15% of patients treated with supraperiosteal injections in the central temple. Due to the thin skin in this region, subcutaneous injections of PEGDE-HA 26 mg/mL LR or PEGDE-HA 22 mg/mL, often performed to camouflage visible vessels, were reported to be associated with transient increased vascular visibility lasting 24–48 h in approximately 40% of cases. Treatment of the temporoparietal region was associated with mild pain or edema in approximately 10% of patients during the first 24 h, likely related to post-treatment massage.

In expert experience, treatment effects in the temple region were typically reported to persist for approximately 8–12 months, with durations of up to 12–15 months following supraperiosteal injection. Treatments in the temporoparietal area showed similar reported longevity, generally in the range of 10–15 months, with variability depending on injection depth, volume, and individual patient factors.

1.4. Eyebrow Contouring

Injections in the lateral aspect of the eyebrows may be performed to enhance contour and volume. According to expert consensus, both recommended techniques involve placement of the product in the supraperiosteal plane using a lateral entry point and retrograde injection, a strategy intended to reduce the risk of vascular injury by avoiding the supraorbital foramen. The supraorbital foramen and notch represent critical anatomical landmarks in this region, and lateral entry points have been reported to reduce the likelihood of direct vascular injury during supraperiosteal injections [20].

In the first technique, PEGDE-HA 28 mg/mL (0.1–0.2 mL per side) was injected using a 27–30 G needle to provide structural support to the retro-orbicularis oculi fat and to counteract age-related brow descent, based on expert experience. The second technique employed PEGDE-HA 26 mg/mL LR or PEGDE-HA 26 mg/mL LV (0.3–0.5 mL per side), injected with a 25 G cannula to achieve a rounded contour. After product placement, gentle upward massage was recommended to facilitate contour shaping.

According to expert-reported estimates from routine clinical practice, hematoma lasting 5–7 days was observed in approximately 2% of patients, particularly those with thin skin. With the cannula-based technique, mild edema lasting approximately 12 h was reported in around 2% of cases. The duration of the aesthetic effect was typically reported by the panel to be approximately 10–15 months following needle-based injections of PEGDE-HA 28 mg/mL and 8–12 months following cannula-based injections of PEGDE-HA 26 mg/mL LR or PEGDE-HA 26 mg/mL LV, with variability depending on injection technique, depth, and individual patient factors.

1.5. Cheekbones

To enhance the prominence of the zygomatic arch, PEGDE-HA 28 mg/mL was identified by the expert panel as the preferred formulation based on handling characteristics and clinical experience. It was administered either using a 23–25 G cannula as supraperiosteal macroboli of 0.2–0.3 mL per side, or with a 27–30 G needle using a three-point pyramidal technique with supraperiosteal bolus injections of 0.3–0.4 mL per side.

According to expert-reported estimates from routine clinical practice, the cannula-based technique was associated with transient discomfort lasting 6–12 h and pain lasting 12–24 h in approximately 10% of patients. With the needle-based technique, hematoma lasting 3–5 days was reported in approximately 15–30% of cases.

In expert experience, the duration of correction with both techniques was typically reported to be approximately 10–15 months, with variability depending on injection technique, volume, and individual patient factors. Supraperiosteal injection in the zygomatic region is supported by anatomical studies demonstrating a relatively predictable vascular anatomy at the bone level, which may reduce the risk of intravascular placement when performed using appropriate technique and low injection pressure [18,21].

1.6. Cheeks

For cheek projection and lifting, experts reported using PEGDE-HA 26 mg/mL LV injected as subdermal or superficial subcutaneous boluses of 0.1–0.2 mL per side using a 27 G needle. For cheek volumization, PEGDE-HA 26 mg/mL LR or PEGDE-HA 26 mg/mL + CaHA were selected by the panel based on skin thickness, with PEGDE-HA 26 mg/mL LR generally used in patients with thicker skin and PEGDE-HA 26 mg/mL + CaHA in those with thinner skin. Both products were administered in a retrograde manner using a 22–25 G cannula at volumes of 0.3–0.5 mL per side, with PEGDE-HA 26 mg/mL LR placed in the deep subcutaneous plane and PEGDE-HA 26 mg/mL + CaHA in the mid-subcutaneous plane. PEGDE-HA 26 mg/mL + CaHA was also used in expert practice to address superficial cheek wrinkles.

Most experts reported employing a multiplane or triple-layer approach, with PEGDE-HA 26 mg/mL LV placed in the deepest plane for projection, PEGDE-HA 26 mg/mL + CaHA in the mid-layer for volumization, and PEGDE-HA 22 mg/mL placed more superficially to refine contour irregularities, based on its favorable tissue integration characteristics observed clinically. The midface includes arterial “danger zones” (e.g., superficial midcheek and infraorbital/periosteal regions), and awareness of the infraorbital, facial/angular, and transverse facial arterial pathways is essential when choosing injection planes and technique [22].

According to expert-reported estimates from routine clinical practice, transient edema lasting up to 12 h was observed in approximately 2% of patients following subcutaneous cannula injections in the cheek area. With needle-based injections, swelling and hematoma were reported more frequently, affecting approximately 15% and 20% of patients, respectively, with durations of 5–7 days for swelling and 10–15 days for hematoma. In expert experience, the duration of the aesthetic effect for cheek treatments was typically reported to be approximately 10–12 months, with variability depending on injection technique, plane, volume, and individual patient factors.

1.7. Nasolabial (Nasogenian) Grooves

For the correction of nasolabial grooves, experts reported using three main techniques depending on the severity of the groove and skin thickness. PEGDE-HA 28 mg/mL was administered subcutaneously at volumes of 0.2–0.3 mL per side using a 30 G needle. The needle was inserted vertically, perpendicular to the skin, and the product was deposited as a series of microboli along the groove using slow injection. Experts also reported using subcutaneous retrograde injections of PEGDE-HA 26 mg/mL + CaHA at volumes of 0.2–0.3 mL per side with a 22–25 G cannula. In patients with thin skin or those requiring more superficial correction, PEGDE-HA 26 mg/mL LV or PEGDE-HA 22 mg/mL (0.2–0.5 mL per side) was injected subcutaneously using a 25 G cannula. Given the increased risk associated with superficial placement, ultrasound mapping was considered by some experts to assist in identifying relevant vascular structures.

The facial artery closely follows the nasolabial fold, and deeper injections using conservative product volumes are generally considered to be associated with a lower risk profile. The close anatomical relationship between the facial artery and the nasolabial fold has been well documented, making this region one of the most frequently reported sites of vascular adverse events following filler injections [23].

According to expert-reported estimates from routine clinical practice, supraperiosteal bolus injections in this region were occasionally associated with transient lip numbness due to local tissue expansion in this highly innervated area. Transient erythema lasting approximately 12 h was reported in around 50% of patients. In expert experience, treatment effects were typically reported to persist for approximately 10–12 months following cannula-based techniques and 10–15 months following microbolus needle injections, with variability depending on injection depth, technique, and individual patient factors.

1.8. Deep Pyriform Space

The deep pyriform space is a depression located lateral to the piriform aperture at the nasal ala that tends to enlarge with age due to maxillary recession and fat atrophy. Deep volumization in this area is intended to provide structural support to the overlying cheek fat and may contribute to the softening of nasolabial folds. According to expert consensus, supraperiosteal placement was generally favored in this region, as the angular artery typically courses more superficially. The deep pyriform space is considered a high-risk region because of the variable course of the angular artery and its connections to the ophthalmic circulation. Although the artery typically runs superficially, supraperiosteal bolus placement is generally regarded as the safer approach for deep support in this area [22,24].

Experts reported using supraperiosteal bolus injections of PEGDE-HA 28 mg/mL at volumes of 0.2–0.3 mL per side with a 27 G needle. The bolus technique was considered by the panel to allow controlled deposition of the product at this anatomical point. For less pronounced depressions, experts also reported using microbolus injections of PEGDE-HA 28 mg/mL at volumes of 0.1–0.2 mL with a 30 G needle placed in the superficial subcutaneous plane.

1.9. Chin

Treatment of the chin is commonly performed to enhance lower-face definition and to contribute to overall facial balance. According to expert consensus, PEGDE-HA 28 mg/mL was selected as the preferred formulation for chin correction based on handling characteristics and clinical experience. The injected volume was adapted to the desired degree of augmentation. In routine practice, treatments in women were more frequently focused on central chin projection, whereas in men additional lateral injections were often employed to achieve broader chin contours and increased jawline definition.

For projection of the pogonion, experts reported injecting PEGDE-HA 28 mg/mL at volumes of 0.2–0.3 mL using a 25–27 G needle as a supraperiosteal microbolus. Using the same entry point, the needle could be redirected medially and laterally to deposit additional product if required. In male patients, two entry points were typically used to allow greater lateral elongation, often employing a fan technique. Based on expert experience, men generally required approximately 30–40% higher product volumes than women. PEGDE-HA 28 mg/mL (0.2–0.3 mL) was also administered subdermally using a paramedial entry point with a 22–25 G cannula and a retrograde injection technique. Although the chin is considered a relatively low-risk region, careful attention to the location of the mental foramen and mental neurovascular bundle is required during both needle- and cannula-based injections [22].

According to expert-reported estimates from routine clinical practice, needle-based injections in the chin were associated with hematoma in approximately 2% of patients, typically resolving within 2–3 days. Pain during the first 4–6 h after injection was reported in approximately 50% of cases. With cannula-based techniques, bruising was rarely reported, while mild discomfort and pain lasting 12–24 h occurred in approximately 5–7% and 13% of patients, respectively. In expert experience, the duration of the aesthetic effect for both needle- and cannula-based techniques was typically reported to be approximately 10–15 months, with variability depending on injection depth, volume, and individual patient factors.

1.10. Marionette Lines and Labiomental Fold

Filler treatment is commonly used to address marionette lines by restoring volume and providing structural support to the overlying soft tissues. According to expert consensus, PEGDE-HA 28 mg/mL or PEGDE-HA 26 mg/mL + CaHA was used for this indication, with injections of 0.2–0.3 mL per side placed in the deep subcutaneous plane using a 22–25 G cannula. The entry point was located at the modiolus, approximately 0.5 cm above and lateral to the oral commissure. The product was administered in a fan-shaped pattern using retrograde linear threads. Gentle compression after injection was recommended to reduce the risk of hematoma formation.

For treatment of the labiomental fold, the same products were used, injecting 0.1–0.2 mL per side into the deep subcutaneous plane with a 22–25 G cannula, following the same retrograde technique. The lower facial region contains multiple arterial branches with variable depth; therefore, careful cannula-based techniques with conservative product volumes have been advocated to mitigate the risk of vascular compromise [25].

According to expert-reported estimates from routine clinical practice, mild discomfort lasting 24–48 h was observed in approximately 15–20% of patients treated in these areas, while hematoma was reported in approximately 5–7% of cases. In expert experience, the duration of the aesthetic effect was typically reported to be approximately 10–15 months, with variability depending on injection depth, volume, technique, and individual patient factors.

1.11. Jawline Definition

For jawline definition, PEGDE-HA 28 mg/mL was selected by the expert panel as the preferred formulation based on handling characteristics and clinical experience. This area was treated using two main entry points. The first was located at the mandibular angle, with the cannula advanced along the mandibular border toward the mid-jaw. The second entry point was positioned lateral to the depressor anguli oris muscle, from which supraperiosteal retrograde linear threads were deposited either toward the mandibular angle or toward the chin using a cannula.

In addition, a small bolus of 0.3–0.5 mL was sometimes placed at the mandibular angle using either a cannula or a needle, injected in the subcutaneous plane. Experts noted that jawline treatment was commonly combined with chin augmentation to support a more balanced lower-face profile and smoother contours. Some experts also reported using PEGDE-HA 26 mg/mL + CaHA to refine and contour the jawline, injecting 0.3–0.5 mL per side subcutaneously with either a cannula or a needle.

According to expert-reported estimates from routine clinical practice, hematoma occurred in approximately 20% of patients, typically resolving within 3–5 days. In expert experience, the duration of the aesthetic effect was typically reported to be approximately 10–15 months, with variability depending on injection depth, volume, technique, and individual patient factors.

Anatomical investigations of the lower face have highlighted the importance of cautious supraperiosteal or deep subcutaneous placement along the mandibular border to minimize the risk of injury to the facial and mental arterial branches [24].

1.12. Lips

Lip shape may be enhanced by defining the vermillion border. According to expert consensus, this procedure was performed using PEGDE-HA 22 mg/mL or PEGDE-HA 24 mg/mL, with a total volume of approximately 0.5 mL per side (covering both the upper and lower vermillion borders), injected in the subcutaneous plane as retrograde linear threads using a 27 G needle and a horizontal technique.

To enhance the philtral columns, experts reported using subcutaneous injections of PEGDE-HA 22 mg/mL, with a total volume of 0.4–0.5 mL, administered using either a 30 G needle or a 23–25 G cannula with a retrograde technique. For treatment of the lip body, experts generally favored lip eversion rather than excessive volumization. Depending on the degree of correction required, this approach was achieved using PEGDE-HA 24 mg/mL (total volume of 0.6 mL) or PEGDE-HA 22 mg/mL (total volume of 1.0 mL), injected in the submucosal plane using a 30 G needle with a vertical retrograde technique. The use of topical anesthetic cream or a nerve block was considered optional and dependent on local practice.

The considerable anatomical variability and frequently superficial course of the superior and inferior labial arteries underscore the need for a meticulous injection technique in lip augmentation and help explain the relatively higher incidence of bruising and vascular complications reported in this region [24].

For lip volume enhancement, PEGDE-HA 24 mg/mL at a total volume of 0.6–0.8 mL was administered in expert practice using a 23–25 G cannula as retrograde linear threads in the submucosal plane. Experts noted that PEGDE-HA 24 mg/mL was a versatile formulation suitable for treating both the lips and the perioral area within the same session, based on handling characteristics and clinical experience.

According to expert-reported estimates from routine clinical practice, pain was generally not reported and appeared to be more closely related to the injection technique than to the filler material itself. Discomfort was typically noted only in the presence of a hematoma. Several experts observed reduced procedural discomfort when using thin-walled TSK 27 G and 30 G needles, which may be attributable to reduced soft tissue trauma. Hematoma was reported in approximately 20–30% of patients following needle-based injections, whereas no hematomas were reported with cannula-based techniques. With cannula use, transient swelling lasting 1–2 days was observed in approximately 35% of cases and was attributed to the injection procedure rather than the filler material. In expert experience, the duration of the aesthetic effect for lip treatments was typically reported to range from approximately 6 to 10 months, with variability depending on technique, volume, and individual patient factors.

2. Discussion

Aesthetic practitioners have access to a wide range of hyaluronic acid (HA) filler technologies, and injectors who are new to a specific product line or facial indication may not always be familiar with the physicochemical characteristics of individual hydrogels or the injection techniques required to achieve predictable clinical outcomes. The PEGDE-crosslinked HA range utilizes an alternative crosslinking agent to BDDE, which is associated with distinct physicochemical properties that may influence handling characteristics and clinical behavior [11,13].

The present consensus summarizes expert clinical experience with PEGDE-HA fillers across a variety of facial indications and provides practical, practice-oriented guidance on product selection, injection volumes, and techniques, informed by available published evidence. During the consensus meeting, the panel also discussed the physicochemical and handling characteristics of PEGDE-HA hydrogels in the context of routine clinical use, without implying comparative clinical superiority over other filler technologies.

2.1. Injection Safety

Ensuring procedural safety is a fundamental aspect of aesthetic practice, particularly when working with crosslinked hyaluronic acid fillers. According to expert consensus, thorough anatomical knowledge, careful selection of injection planes, and controlled delivery techniques are essential components of risk mitigation strategies aimed at reducing the likelihood of intravascular injection and other adverse events. Particular attention should be given to anatomically complex or high-risk regions, including the temporal area, forehead, nasolabial fold, piriform fossa, and perioral region [22,24,25]. Numerous anatomical and clinical studies have documented the potential for severe vascular complications associated with inadvertent intravascular injection of HA fillers, underscoring the importance of meticulous technique and risk awareness in facial aesthetic procedures [17,18,19,21,24,25,26].

In selected clinical scenarios, such as superficial injections, treatment of previously injected areas, or procedures performed in anatomically high-risk zones, ultrasound mapping may be considered to assist in the visualization of vascular structures and to support procedural planning and precision [26,27]. Although not required for routine practice, ultrasound has been proposed as a useful adjunct in complex cases or in patients with altered anatomy following prior treatment [28].

Aspiration was discussed by the panel as a precautionary step commonly adopted during needle-based supraperiosteal bolus injections in areas where a stable needle position can be maintained, including the piriform fossa, temporal region, and nasal spine. When performed, aspiration is typically carried out at the initial injection using an empty syringe. However, the panel acknowledged the limitations of aspiration, including the possibility of false-negative results, and noted that aspiration is not applicable when using cannulas [29]. Accordingly, aspiration should not be regarded as a standalone safety measure, but rather as one element of a broader risk-mitigation strategy that includes detailed anatomical knowledge, conservative injection volumes, slow injection speed, and continuous patient monitoring. In line with this safety-oriented approach, Supplementary Table S1 provides a consolidated, area-based summary of product selection, injection planes and techniques, and typical treatment volumes.

To translate these principles into practical clinical guidance, the panel summarized key safety considerations in the following structured checklist. These recommendations reflect expert consensus derived from routine clinical practice and are intended to support risk mitigation rather than to replace formal training in facial anatomy, injection techniques, or complication management.

Safety checklist for PEGDE-HA injections:

• Patient selection and informed consent: Evaluate indications, prior filler history, and individual risk factors. Inform patients about expected local reactions and rare but serious vascular complications.
• Anatomical risk awareness: Apply detailed knowledge of facial vascular anatomy, particularly in high-risk areas. Consider conservative volumes and controlled deposition in regions with relevant arterial pathways.
• Plane control and incremental correction: Select injection depth based on indication and product characteristics. Use small bolus sizes and incremental correction rather than aggressive single-session volumization.
• Slow injection and low extrusion pressure: Inject slowly with minimal pressure while continuously observing patient feedback and skin perfusion.
• Appropriate choice of device and technique: Select needle or cannula according to anatomical region and target plane. Cannulas may reduce vessel crossings in selected areas, while needles may be appropriate for stable supraperiosteal bolus placement.
• Aspiration: role and limitations: If performed, aspiration should be limited to stable needle-based bolus injections and interpreted cautiously, recognizing that a negative aspiration does not exclude intravascular placement.
• Minimization of entry points and passes: Limit the number of entry points and redirections, particularly in superficial planes. Withdraw to a safe depth before changing direction.
• Optional ultrasound support: Consider ultrasound mapping or guidance in high-risk regions, superficial injections, or previously treated areas with potentially altered anatomy.
• Post-procedure instructions and follow-up: Provide clear guidance on expected post-treatment effects and warning signs of vascular compromise, with a rapid pathway for patient contact if concerns arise.
• Preparedness for vascular adverse events: Maintain a defined emergency protocol, including access to hyaluronidase and referral pathways for urgent specialist assessment when indicated.

2.2. Tissue Integration

All HA fillers function as hydrogels and act as temporary tissue scaffolds, creating a three-dimensional (3D) environment that resembles soft tissues by providing mechanical support while permitting molecular diffusion through elastic networks. The biomechanical behavior of these scaffolds is influenced by multiple factors, including HA concentration, degree of crosslinking, and the crosslinking technology employed [30].

PEGDE was selected as a biocompatible crosslinking agent for this range of products based on its established use in food, cosmetic, and medical applications. As a mixture of oligomers with varying chain lengths, PEGDE introduces heterogeneous spacer lengths between HA chains, in contrast to more uniformly crosslinked systems such as those based on BDDE [10,11,12,13]. This molecular architecture results in a less uniformly rigid three-dimensional scaffold, which may influence tissue integration characteristics and in vivo distribution of the hydrogel [31].

Histological analyses from punch biopsies obtained up to eight months after injection have demonstrated a harmonious spatial distribution of PEGDE-HA within surrounding connective tissue structures, including collagen fibers, blood and lymphatic vessels, glands, and nerves [31]. According to expert clinical experience, these histological features were associated with clinically natural-appearing outcomes. However, patient satisfaction data were not derived from standardized quantitative assessments.

2.3. Collagen Stimulation

The PEGDE-HA product range includes a formulation combining PEGDE-HA with a low (1%) concentration of calcium hydroxyapatite (CaHA) microspheres (10–12 μm in diameter) [32]. The collagen-stimulating effects described for this formulation are primarily attributable to the CaHA component, while the PEGDE-HA hydrogel serves as a volumizing and carrier matrix. CaHA microspheres provide a three-dimensional framework that supports fibroblast adhesion and may facilitate localized collagen biostimulation at the injection site.

Histological analyses of skin samples obtained from patients treated subdermally with 1 mL of PEGDE-HA 26 mg/mL + CaHA demonstrated an increase in newly formed type III collagen fibers at two months compared with untreated control tissue [33]. In addition, a 24-week post-marketing observational study involving 60 patients with mid-face volume loss reported clinically meaningful improvement following treatment with PEGDE-HA 26 mg/mL + CaHA [34]. These findings should be interpreted in the context of the observational study design and limited sample size.

2.4. Duration of Aesthetic Results

Experts noted that PEGDE-HA hydrogels produce long-lasting outcomes, typically one year or longer for most facial indications. Even in the lips, the duration was reported as 6–10 months. The longevity of PEGDE-HA is attributed to its stable crosslinking mechanism, in which the opening of the PEGDE epoxide ring reacts with HA hydroxyl groups to form C–O–C bonds, among the most chemically stable and degradation-resistant [12].

Skin biopsies taken eight months post-injection of PEGDE-HA 26 mg/mL + CaHA have confirmed the continued presence of PEGDE-HA integrated with collagen fibers [35]. In vitro studies also demonstrated slower enzymatic degradation, with maximal hyaluronidase activity reached only after 120 h [32]. Clinical investigations have reported sustained correction lasting up to two years [36].

2.5. Swelling Ratio

The swelling ratio of a hyaluronic acid filler is an important physicochemical parameter that is associated with its early volumizing behavior and is influenced by factors such as HA concentration and the degree of crosslinking. In vitro comparative studies of PEGDE- and BDDE-crosslinked HA hydrogels have shown that, at equivalent molar concentrations, PEGDE-crosslinked hydrogels exhibit a lower swelling ratio under experimental conditions [37].

The incorporation of amino acids such as L-proline and glycine in the PEGDE-HA range has been reported to support osmotic balance within the hydrogel matrix, which may contribute to modulation of post-injection swelling behavior [31]. While transient swelling related to injection trauma can occur, experts reported that PEGDE-HA fillers were generally associated with limited post-procedural edema in routine clinical practice. According to expert experience, volumizing effects were perceived as clinically predictable; however, swelling ratio data are derived from in vitro models and may not fully reflect in vivo tissue behavior.

2.6. Immunogenicity

Available experimental, histological, and observational data suggest that PEGDE-crosslinked hyaluronic acid (PEGDE-HA) hydrogels are associated with a low immunogenic potential. It has been proposed that steric masking of antigenic sites by PEGDE may reduce immune recognition; however, this mechanism is primarily supported by in vitro and mechanistic evidence [38]. To date, no cases of foreign body reactions or granuloma formation specifically attributed to PEGDE-HA have been reported in the available published literature, although long-term post-marketing surveillance data remain limited [33,36].

Immunological findings related to PEGDE-HA have also been explored in small clinical and experimental studies. In a study combining PEGDE-HA 26 mg/mL + CaHA with radiofrequency treatment, early post-procedure inflammatory markers increased transiently, while CD8 and CD20 expression decreased below baseline levels by day 21 and remained stable through day 150 [39]. These observations should be interpreted cautiously, as the study design did not allow isolation of the individual contribution of the filler and the energy-based device.

In vitro analyses have suggested that PEGDE-HA may influence polymorphonuclear leukocyte activity, including reduced migration and oxidative metabolism under experimental conditions [14]. While these findings indicate potential anti-inflammatory effects at the cellular level, their direct clinical relevance remains uncertain.

Evidence regarding the use of PEGDE-HA in patients with autoimmune conditions is limited to small prospective case series. In a study involving 15 patients with Hashimoto’s thyroiditis treated with PEGDE-HA 26 mg/mL + CaHA, no local or systemic adverse events or nodular formations were observed during 150 days of follow-up [39,40]. In a subgroup analysis, tissue samples demonstrated a reduction in CD4+ and CD8+ lymphocyte expression over time. These findings are preliminary and do not allow broad generalization regarding immunological safety in patients with autoimmune diseases.

2.7. Thermo-Resistance

Hyaluronic acid (HA) filler injections are frequently combined with energy-based treatments, such as lasers or radiofrequency, in aesthetic practice. Radiofrequency-based procedures are known to induce collagen remodeling and dermal tightening, while HA fillers primarily address volume loss [41].

Experimental and observational studies have suggested that PEGDE-crosslinked HA hydrogels exhibit structural stability when exposed to thermal and mechanical stress, which may limit degradation when used in combination with energy-based procedures [39,42,43]. These findings are primarily derived from in vitro analyses and clinical observations rather than from controlled comparative trials.

Combined treatment protocols using PEGDE-HA 26 mg/mL + CaHA together with infrared or radiofrequency energy have been evaluated in observational clinical studies. These studies reported improvements in skin elasticity and hydration at follow-up time points of up to 150 days in women with facial laxity, accompanied by histological findings such as increased fibroblast activity and angiogenesis [39]. Similar combined approaches have also been explored in non-facial indications, including urogenital rejuvenation in women with vaginal laxity [41].

According to expert clinical experience, the use of radiofrequency in combination with PEGDE-HA fillers was not associated with an apparent reduction in filler persistence or clinical performance. These observations support the practical compatibility of PEGDE-HA fillers within multimodal treatment strategies, although high-level comparative evidence remains limited.

2.8. Limitations

This consensus document is primarily based on expert opinion rather than pooled quantitative patient-level data, which may introduce inherent subjectivity. In addition, the recommendations are informed by clinical experience and selected published studies, while randomized head-to-head comparative trials between PEGDE-crosslinked HA fillers and other crosslinking technologies are currently lacking. Reported adverse event rates are derived mainly from expert clinical experience and observational data rather than from standardized epidemiological analyses.

The expert panel represented a limited number of practitioners from a single geographic region, which may affect the generalizability of the recommendations. Furthermore, variability in injection technique, patient anatomy, and treatment indications may influence clinical outcomes and limit the direct applicability of specific recommendations.

These limitations emphasize the need for further high-quality clinical research and indicate that the guidance presented should be interpreted within the context of individual clinical judgment and evolving scientific evidence.

3. Conclusions

PEGDE-crosslinked hyaluronic acid (HA) hydrogels represent a distinct category of HA fillers with physicochemical characteristics that may influence handling properties, tissue distribution, and clinical behavior. This expert consensus provides practical, area-specific guidance on product selection, injection planes, techniques, and safety considerations for facial aesthetic applications, based on collective clinical experience and currently available evidence.

The recommendations presented herein are derived from expert opinion supported by mechanistic, histological, and observational data. As such, they are intended to inform clinical practice rather than to establish definitive comparative efficacy or safety claims. Interpretation of these recommendations should take into account the methodological constraints inherent in consensus-based guidance.

Further research is warranted to strengthen the evidence base for PEGDE-crosslinked HA fillers. Future investigations should prioritize prospective comparative studies, standardized reporting of adverse events, long-term outcome registries, and quantitative correlations between rheological parameters and clinical outcomes. Additional evaluation of ultrasound-assisted injection techniques may further refine safety strategies, particularly in anatomically high-risk regions.