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Review

Full Face Tailored Treatments Using Hyaluronan Dermal Fillers: Biophysical Characterization for Safe and Effective Approaches

by
Beatriz Molina
1,
Domenico Romano
2,
Michela Zazzaron
3,
Eyal Kramer
4,
Clara Cigni
5,
Franco Grimolizzi
5 and
Gilberto Bellia
5,*
1
Medikas Clinic, Somerset, Bristol BA16 0HY, UK
2
Private Practice, 20122 Milan, Italy
3
Private Practice, 31056 Roncade, Italy
4
Esthetics Medicine Clinic, Tel Aviv 61503, Israel
5
IBSA Farmaceutici Italia Srl, 26900 Lodi, Italy
*
Author to whom correspondence should be addressed.
Cosmetics 2024, 11(4), 144; https://doi.org/10.3390/cosmetics11040144
Submission received: 11 June 2024 / Revised: 6 August 2024 / Accepted: 12 August 2024 / Published: 22 August 2024
Browse Figures
Versions Notes

Abstract

:
Hyaluronic acid (HA)-based dermal fillers are among the most popular non-invasive facial aesthetic treatments. To ensure an effective and safe treatment experience, knowledge of their biophysical and rheological characteristics, such as: HA concentration, molecular weight (MW), G′, and the degree of cross-linking is essential. Products with a higher MW, G′, and degree of cross-linking are more suitable for promoting volume and lift. Dermal fillers with a lower MW, G′, and degree of cross-linking can produce a soft filling effect that regulates hydration and elasticity. This review discusses how these rheological characteristics can inform treatment choice and their effects on clinical outcomes. The Aliaxin® line of HA dermal fillers, which are tailored to different clinical applications due to their rheological characteristics, highlights that extensive knowledge of the product can provide very safe and effective procedures for patients, whilst respecting their natural facial aesthetics. This review discusses studies using Aliaxin® dermal fillers for volumizing and hydrating treatments and fillers that can be used for lip augmentation. Treatment with Aliaxin® was overall very effective, with no reported adverse events. A full facial treatment using tailored dermal fillers may be a future approach to achieve an effective and safe harmonized and natural aesthetic.

1. Introduction

The field of aesthetic medicine faces many clinical, but also cultural and ethical, challenges [1]. Aesthetic medicine aims to improve patient well-being by targeting wrinkles and/or correcting imperfections, alongside maintaining respect and understanding for the patient’s own unique facial anatomy and characteristics. Minimally invasive, safe, and effective dermal fillers continue to grow in demand within the field of aesthetic medicine [2,3,4]. Respecting the natural physiognomy of the face is becoming easier to achieve due to hyaluronic acid (HA)-based treatments that are more efficient, safe, and less invasive, due partly to the natural role HA plays within the skin [5]. According to the International Society of Aesthetic Plastic Surgery, HA-based dermal fillers are among the most used non-surgical treatments worldwide [2].
HA is a naturally occurring linear polysaccharide found in the skin and throughout the body. It has a high ability to bind and retain water and is essential for many key biological processes including cell signaling, wound repair, and regulating the extracellular dermal matrix [5,6]. Due to these properties, HA-based products are now at the forefront of many medical treatments and aesthetic applications [5].
The HA in dermal fillers is often modified by covalently cross-linking HA polymer chains to form an HA hydrogel to extend its life within tissues [3,7]. The cross-linking process can vary depending on different factors, including chemical cross-linking molecules, HA concentration, HA molecular weight (MW), and reaction time [4]. Thus, differences in the extent of cross-linking, along with other biophysical and rheological characteristics, can create fillers that behave in different ways, and this translates to the way they are used in clinical practice [4]. Clinicians are now focused on creating a tailored full face treatment approach for their patients. Using hydrogels with different characteristics is fundamental to achieving the optimal outcome across areas of concern and injection points [4,8,9]. In recent years, patients are not solely focused on product efficacy but also on safe and respectful treatments. Therefore, the understanding of product safety and receiving informed consent is vital in the doctor–patient relationship [1]. To create an effective and safe treatment experience, it is essential that the practitioner has knowledge of the biophysical characteristics of dermal fillers and for which indication the dermal filler should be used.
The aim of this review is to highlight the importance of this knowledge and to create a link between the biophysical characterization and rheological properties of HA hydrogels and clinical outcomes. Here we describe this knowledge using the Aliaxin® line of dermal fillers, commercialized by IBSA Farmaceutici Italia Srl, which can be tailored to different areas of concern for full soft tissue facial restoration. This review aims to demonstrate that extensive product knowledge has provided many safe and effective aesthetic procedures for patients, whilst respecting their natural facial characteristics.

2. Methods

The review was conducted by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Although the methodology for the review was planned, an official protocol for the study was not prepared.
A systematic search of the literature was performed, with no restriction by date, until 15 February 2024. Only articles in the English language were included. References found were then compiled into EndNoteTM 20 (Clarivate Analytics LLC., Philadelphia, PA, USA), and duplicates were removed. One reviewer checked the articles found to confirm that validity was met and sufficient information was provided. Moreover, the National Institute of Health (NIH) Quality Assessment Tool for Before-After (Pre-Post) Studies with no control group was used to evaluate the quality of articles and their associated risk of bias.
Finally, study or case series design, patients’ characteristics, efficacy, and safety data were extracted from full texts into tables in Microsoft® Excel® for Microsoft 365 MSO, Version 2403 (Microsoft Corporation, Redmond, WA, USA).

3. HA Dermal Filler In Vitro Characterization

3.1. Cross-Linking Reaction and Rheological Characteristics of HA Dermal Fillers

The Aliaxin® line of dermal fillers are all cross-linked using 1,4-butanediol diglycidyl ether (BDDE), a popular method used for most commercial HA dermal fillers to create a stable covalent ether linkage [10]. The product line consists of six formulations: Aliaxin® Essential Volume (AEV), Aliaxin® Fine Lines (AFL), Aliaxin® Global Performance (AGP), Aliaxin® Lips Volume (ALV), Aliaxin® Shape and Restore (ASR), and Aliaxin® Superior Volume (ASV) [4,11,12,13,14,15,16,17]. Despite having the same HA concentration (25 mg/mL), Aliaxin® fillers present different physico-chemical properties. In this context, the understanding of the rheological characteristics of the fillers is fundamental. These parameters can dictate the use of HA-based dermal fillers in clinical practice [18,19] and their characterization is therefore essential to understand the differences between available products and reach the desired clinical outcome.
Our review here describes the cross-linking reaction and rheological characteristics as the basis of Aliaxin® fillers.

3.1.1. BDDE Cross-Linking

The reaction with BDDE under alkaline conditions creates a stable covalent ether link between HA hydroxyl groups and epoxide groups of the cross-linker, producing a three-dimensional network of HA polymer chains [10]. In the reaction, nucleophilic groups of HA react with the epoxide groups of BDDE, forming derivatives of 1,4-butanediol di-(propan-2,3-diolyl)ether (BDPE), finally resulting in the cross-linkages of the HA chains [10]. However, BDDE can be present in different chemical states at the end of the cross-linking reaction: the fully reacted cross-linker (reaction with HA occurred on both ends of the molecule); the pendant cross-linker (reaction with HA occurred on one end only); the residual cross-linker (the BDDE molecule has not reacted with HA) [20]. Over the past years, several discussions highlighted the mutagenic potential of unreacted BDDE which is thought to be the result of the reactive nature of the epoxide groups. Although unreacted BDDE has been found to be toxic in a Drosophila model [21], a definitive carcinogenic effect has not been proved in mice or humans. However, the FDA set a limit (<2 parts per million (ppm)) as the total amount of unreacted BDDE in dermal fillers to avoid any potential risk [20]. For the Aliaxin® line of dermal fillers, this is achieved through their high-quality production process that meets the FDA regulatory requirements. As previously mentioned, the cross-linking reaction ends in the formation of different hydrogels commonly recognized as HA cross-linked dermal fillers. Different reaction conditions, such as HA MW, quality of the cross-linkers, and reaction time, can create hydrogels with different characteristics [3,10]. These characteristics can be described using rheological characterization, including measures such as measure of elasticity (G′) and measure of viscosity (G″) [3]. Moreover, since these products display different biophysical and rheological characteristics, they can be tailored for different clinical applications.

3.1.2. Rheology

The rheological characterization of HA hydrogels is vital for understanding a product’s clinical indication. Rheology describes the behavior of a hydrogel, such as its ability to flow and integrate within tissues and its capacity to resist deformation [3]. The most important biophysical and rheological data are represented by: HA concentration, MW, G prime (G′), tan delta (tan δ), cohesivity, and degree of cross-linking. An overview of the biophysical and rheological characteristics of the Aliaxin® line is reported in Table 1 and further discussed in the following sections.
Among rheological parameters, G′ is also defined as the storage/elastic modulus and represents a measurement of the elastic modulus of a gel or its ability to return to its original shape when subjected to dynamic forces (unit of measurement: Pascal (Pa)). Therefore, it is a measure of the hydrogel’s elasticity and thus its capacity to resist deformation, such as the stress occurring during facial movements. The higher the G′, the higher its elasticity and resistance to deformation, creating a more stable product following its injection [4,23,24]. Products with different G′ are used to target different areas and tissue layers of the face (Figure 1). Products with a low G′ are used for superficial tissue layers such as the dermis and promote hydration and enhance the skin quality, whereas products with a low-medium G′ are used for deeper layers such as the superficial and deep fat layers to correct fine lines and increase volume [25]. Products with a high G′ can instead be used for lifting and contouring of the face [25].
Aliaxin® fillers display different G′. Among them, ASR and AFL are the hydrogels with the lowest G′ (39 Pa and 45 Pa, respectively) [14,16], AGP and ALV are medium-G′ gels (95 Pa and 107 Pa, respectively) [12,17], while AEV and ASV are the fillers of the Aliaxin® line with the highest G′ (162 Pa and 295 Pa, respectively) [9,15].
On the other hand, G″ or loss/viscous modulus measures the energy lost on shear deformation through internal friction [unit of measurement: Pascal (Pa)]. It is a measure of the hydrogel’s viscosity and ability to flow while deformed, which is often low since dermal fillers are not subjected to high levels of deformation within the tissues [25].
Another less-known parameter is the complex viscosity (η*), a combination of both G′ and G″ defined as the measure of the resistance to deformation when shear stress is applied (unit of measurement: Pascal-second (Pa-s)). It corresponds to the resistance to flow during the injection. A representation of the rheological curves of Aliaxin® fillers is shown in Figure 2A,B. In particular, the complex viscosity measured at different frequencies (Hz) is here shown for an example of low-, medium-, and high-G′ fillers of the Aliaxin® line (ASR, AGP, and AEV, respectively). Calculation of the complex viscosity confirms AEV as one of the most rigid, viscoelastic, and viscous hydrogels, followed by AGP and then by ASR, the less rigid and viscous one [19].
Tan δ is a measure of the ratio between the elastic and viscous properties of the hydrogel (G″/G′). It measures whether a filler is more elastic (solid/gel behavior) or more viscous (liquid behavior). The lower the tan δ, the higher the elastic elements (G′) of the hydrogel [23,24]. A lower tan δ indicates a higher elasticity and storage modulus (G′) [23]. The ideal tan δ value for a filler varies from 0.1 to 0.6 and its value is usually inversely proportional to the G′ one.
ASR and AFL have the lowest G′ and highest tan δ and are used for superficial dermal corrections and promoting hydration, such as improving fine lines and wrinkles around the mouth and forehead [4,14,16]. ASV and AEV have a higher G′ and are used for injection into deeper tissues to improve facial structure and the appearance of severe wrinkles [4,13,15,22,26]. A summary of the Aliaxin® line and their G′ and tan δ scores are shown in Figure 2C.
Finally, cohesivity is another fundamental parameter which describes the integrity of the hydrogel—the more uniform the integration of a product with the surrounding tissue without disintegration, the more natural the result that can be achieved [11].
Hydrogel cohesivity can be measured using different approaches; however, one of the best methods is performed using the Gavard–Sundaram cohesivity scale ranging from grade 1 (fully dispersed) to grade 5 (fully cohesive) [26].
All the products of the Aliaxin® line have a high cohesivity score, as determined by the Gavard–Sundaram cohesivity scale, across different G′ and tan δ results (Table 1). This score indicates full cohesion, meaning that optimal integrity without unwanted gel migration is achieved following the injection of Aliaxin® fillers [4]. On the other hand, fillers obtained using different technologies can display a lower cohesivity grade, meaning that optimal integrity is not guaranteed and unwanted gel migration can occur [27].

3.2. Mechanical and Hydrating Ability of HA Dermal Fillers

HA polymers of different MW have distinct functions related to their biological activities. Low-MW HA of <10 kDa is involved in proinflammatory activation, those with medium MW of 100–<500 kDa have mild inflammatory properties, and an MW of ≥500 can promote anti-inflammatory and antioxidant activities and can increase skin hydration [28,29,30].
Moreover, MW can also create differences in the cross-linking reaction and thus the mechanical characteristics of the hydrogel. Indeed, the structural and physicochemical properties of cross-linked HA also depend on its molecular weight. Studies reported that the increase in the molecular weight of HA chains could lead to the reinforcement of the three-dimensional network of the polymer, resulting in an increase in the solution viscosity and viscoelasticity [28]. This has been demonstrated by different experimental settings proving a clear connection between the viscosity and both molecular weight and concentration [31]. In connection, another study also demonstrated that the hydrodynamic properties of cross-linked HA also depend on the molecular weight [32].
The Aliaxin® products are equally concentrated, but each product contains a unique composition of HA MWs (Table 1). For example, ASR contains three HA MWs (500, 1000, and 2000 kDa) [4], while the others contain two, such as AEV (1000 and 2000 kDa).
Thanks to these compositions and different molecular weight, Aliaxin® products also show different mechanical and hydration properties. Indeed, products containing higher-MW HA have longer HA chains, which increases interactions between the chains due to the formation of weak hydrogen bonds [5]. This creates a three-dimensional structure between the HA chains that promotes a higher viscosity and a mechanical volumizing effect following the use of an HA hydrogel product [5,11,29]. Examples of these products in the Aliaxin® line are AEV and ASV. Alternatively, products with a lower molecular weight cannot create three-dimensional networks between chains that are as strong, but instead can form interactions with water, promoting hydration and a higher ability to spread within the tissues [11,29,33]. Examples of these Aliaxin® products include AFL and ASR.
In addition to the product’s MW, the pure mechanical or hydrating properties of HA dermal fillers can be derived from additional in vitro characterization, such as cross-linking degree [10]. This parameter can influence the behavior of the hydrogels in terms of their mechanical or hydration properties. Scientific literature describes how the mechanical and physical properties of the cross-linked fillers could be dependent on the cross-linking degree [10]. Some studies suggested that the cross-linking can increase the HA hydrogel strength and the elastic contribution. This phenomenon can then modulate the viscoelastic properties of HA cross-linked fillers [34,35]. Although the mechanism is not fully understood, it has been suggested that a too-high cross-linking degree could even potentially affect the biocompatibility of the HA hydrogels [10]. To fully investigate the correlation between viscoelastic properties and cross-linking degree of hydrogels, it is therefore of fundamental importance to have clear methods and definitions for the cross-linking parameters. Several different calculations and definitions for the degree of cross-linking exist within the literature, and four main terms have been proposed that describes the formation of HA hydrogels using BDDE [10].
Of these terms, the most appropriate is the degree of modification (MoD), which is defined as the stoichiometric ratio between the sum of mono-linked and double-linked residues and HA disaccharide units, as follows [10]:
MoD = nlinked cross-linkers/nHA disaccharides
A hydrogel with a low MoD describes a low total change and the product will more closely resemble the original intact HA polymers [10].
In Table 1, the cross-linking degree of the Aliaxin® line has been adapted to a grading scale (from 1 to 5) for ease of understanding—the higher the score, the more cross-links have been formed. ASR has the lowest grade of cross-linking, and AEV and ASV the highest.
Certain products, such as AGP and AEV, have the same molecular weights but differences in their G′ and cross-linking degree. This demonstrates that the complete set of biophysical and rheological parameters should be considered to fully characterize each product for different clinical indications (Table 1) [4].
The hydration capacity of HA hydrogels is often inversely related to the G′ and the cross-linking degree, with ASR exhibiting the highest water-absorbing capacity and lowest cross-linking degree and ASV showing the lowest water-absorbing capacity and the highest cross-linking degree. However, all Aliaxin® products demonstrate a high swelling capacity compared to other commercial HA dermal fillers produced using different technologies, such as NASHA, Vycross, and CMP [4,18]. The high swelling capacity may be due to the higher level of insoluble HA found within Aliaxin® hydrogels [4]. The insoluble fraction is important—two fillers may be equally as concentrated in HA but have varying levels of insoluble HA, which is responsible for the filler’s firmness, ability to take up water, and resist degradation and, therefore, producing different outcomes [4].

4. HA Dermal Fillers’ Clinical Application

4.1. Clinical Studies and Regulatory Framework

With the wide increase in HA dermal fillers in different aesthetic medicine applications, it has become pivotal to establish a consensus regarding fillers’ development and regulatory approval. Globally, dermal fillers are nowadays classified as class III medical devices, and they are therefore subjected to the International Standardization Organization (ISO) and country-dependent medical device regulations to evaluate their efficacy and safety [36]. Moreover, clinical trials and post-marketing surveillance evaluations are gaining a crucial importance to evaluate HA fillers’ performances. The following section of the review investigates the clinical trials and regulatory requirements as well as post-marketing real data evidence.

4.1.1. Regulatory Requirements

Although dermal fillers are globally recognized as class III medical devices due to their in vitro characteristics and metabolism in the human body, different regulations currently exist in different countries [36].
In Europe, Medical Device Regulation (MDR) (EU) 2017/745 Article 61 and Annex XIV requirements should be fulfilled for the approval of a dermal fillers [37]. EU MDR 2017/745 lists the requirements for fillers’ safety in terms of risk management and clinical evaluation regarding product safety and efficacy, elucidating the technical and performance information needed [37].
In the US, fillers’ commercialization is strictly regulated by the Food and Drug Administration (FDA) Code of Federal Regulations (CFR) Title 21, Chapter I, Subchapter H on Medical Devices. This regulation considers the fillers as implants, due to the fact they are injected and remained into the body for 30 days or more [38]. The FDA requests that each device must demonstrate standalone safety and effectiveness through pre-clinical and clinical evidence and strictly regulates the intended use for each filler implant [38].
The National Medical Products Administration (NMPA) also evaluates dermal fillers as class III medical devices in China and therefore their commercialization is evaluated through the Medical Devices Supervision and Administration Regulation (MDSAR) [39]. Similarly to the FDA, the NMPA also considers fillers as facial implants.
On the other hand, in Australia hyaluronic acid and its derivatives are listed in Schedule 4 of the Poison Standard and therefore they are allowed for injection and considered as class III medical devices through the Therapeutic Goods (Medical Devices) Regulation 2002 (Schedule 2) [40].

4.1.2. Clinical Trials

As discussed in the previous section, HA MW, degree of cross-linking, and other rheological characteristics can aid in the selection of the correct product or products depending on the aesthetic goals of the patients. These parameters can also inform the injection site and tissue target. Although in vitro characterization provides fundamental knowledge to choose the right administration, it is still fundamental to collect clinical studies’ data to prove HA fillers’ efficacy and safety in human subjects. To fully compare the product efficacy during clinical studies, a further standardization of the desired clinical outcomes is foreseeable for the future.
Fillers’ efficacy can be proved using aesthetic scales, for example, evaluating wrinkles and facial volume severity like the wrinkle severity rate scale (WSRS) [41] and facial volume loss scale (FVLS) [42] as well as using the global aesthetic improvement scale (GAIS). Moreover, several instrumental analyses can be performed using 3D cameras to quantify the improvements after the use of dermal fillers [43]. For example, two open-label, single-center clinical studies demonstrated both clinical (WSRS and FVLS) and instrumental improvements after injection with ASV and AEV at different timepoints [44,45]. Instrumental analysis (3D camera volume measurement) has also been used to evaluate the amelioration of lip volume after treatment with ALV during another open-label, single-center clinical study [46].

4.1.3. Tissue Integration and Safety

In addition to effective and long-lasting treatments, there is also a high demand for safe treatments that respect the natural facial physiognomy of the patients.
Although HA-based fillers are considered injectable with a very high safety profile due to the intrinsic nature of HA, some common adverse events (AEs) have been associated with the use of fillers in the scientific literature [47,48,49]. The most associated AEs are usually mild events which spontaneously resolve within few days like edema and bruising. However, other uncommon AEs have been reported in the literature and involved inflammatory reactions, like granulomas, angioedema, skin induration, and delayed complications such as swelling and lumps or nodules [50,51]. These AEs can be due to several variables, such as patient anamnesis, product characteristics, and injection techniques used for the treatment [50]. Granuloma represents a protracted inflammatory response to a foreign substance resulting in palpable nodules under the skin, which can create a consistent discomfort for patients [52]. The management of these AEs usually includes the use of drugs such as dexamethasone and colchicine to reduce inflammatory reactions [53] and cause filler degradation; in this context, HA-based fillers are considered temporary products that can be degraded using hyaluronidase compared to the synthetic ones that cannot be easily dissolved [53].
It is important to note that fillers’ characteristics are crucial factors for the appearance of such AEs; for example, some HA dermal filler products that claim longer-lasting results due their higher G′ can induce a higher number of patients to experience nodules or granulomas, especially in sensitive areas such as lips [47,48,49]. Post-marketing surveillance reported 195 delayed complications following the use of high-G′ HA-based dermal fillers within a five-year period. Of these adverse events, 71.8% were nodules, 21.5% hypersensitivity, and 6.7% granulomas [47]. This could be because highly viscous and low-cohesion hydrogels can be perceived more easily as a foreign body by the immune system, leading to unwanted side effects. Similarly, biostimulatory molecules used to obtain a volumizing effect, such as injectable poly-L-lactic acid which exerts its effect through a subclinical inflammatory response, could also lead to a higher number of inflammatory reactions such as nodules and granulomas [54]. On the other hand, the Aliaxin® product line consists of different formulations specifically developed to ensure natural outcomes and to be respectful of patients’ anatomy and physiology. Clinical studies performed using Aliaxin® fillers not only demonstrated a long-term efficacy but also an excellent safety profile with non-serious AEs reported up to 9–12 months [43,45,46]. A clinical study also demonstrated excellent long-term safety and efficacy outcomes up to 18 months after treatment with ALV and AFL [55]. Moreover, Aliaxin® fillers are temporary fillers based on HA. In this context, the literature has demonstrated that these products are usually degraded after 1 year by endogenous hyaluronidase [53], ensuring a high safety profile compared to synthetic semipermanent and permanent fillers.

4.2. HA Dermal Filler Treatments and Clinical Experiences

Different clinical applications can be found for HA fillers with different characteristics. For example, Aliaxin® products with a higher G′ are more suitable for deeper tissue integration to achieve a higher degree of facial sculpting, and products with a lower G′ are better suited to superficial wrinkles and improving skin hydration [4,11,18,34]. Table 2 shows the most relevant clinical applications and experiences for each Aliaxin® filler.

4.2.1. Volumizing Treatments Using Aliaxin® Dermal Fillers

Several studies have used Aliaxin® dermal fillers, specifically ASV and AEV, for volumizing treatments around the mid-face and nasolabial folds. These products are most suitable for volumizing and facial sculpting via mechanical lifting due to their higher degree of cross-linking and higher G′. Their indication is more suited for deeper tissue injection [19].
An open-label, single-center trial analyzed the volumizing effect of ASV on the mid-face, which can often suffer volume loss due to age-related changes in the facial bone, fat, dermis, and epidermis [44]. This can lead to skin sagging and deepening of nasolabial folds. The study was conducted over six visits for a total of 9 months, with 20 healthy middle-aged female patients, and used instrumental evaluation and photographic evidence to measure and document mid-facial volume. Injections were performed using needles (25–27 G), or a cannula (25 G, 40 mm) for deeper injection at the lateral zygomatic bone level. A touch-up treatment was performed 3–4 weeks after the first injection. ASV provided a clinically significant high-volumizing effect after the first injection, which was maintained and even increased as the study progressed. This has been demonstrated by the findings proving that the improvement of facial volume is statistically significant (p < 0.001) 6 months after treatment and still observable 9 months after [44]. All injections were very well tolerated, and no patients experienced any undesirable effects [44].
Volumizing fillers have also been effective for the correction of nasal imperfections, as demonstrated by a retrospective case series that utilized AEV together with botulinum toxin [62]. This case series selected 48 patients wishing to improve their nasal shape. Of these patients, 42 patients were satisfied with the procedure after an 8–12-month follow-up (p < 0.05) [62]. This study demonstrated a move towards non-surgical minimally invasive interventions, in which volumizing facial dermal fillers can play an important role. HA dermal fillers can be useful for preserving the height of the nose, which is often a challenge with rhinoplasty. The reversibility of this procedure may also be attractive to some patients [62].
AEV has also been well tolerated and effective in reducing the appearance of nasolabial folds, a major sign of facial aging [45]. This study compared AEV with and without lidocaine, a local anesthetic, in 27 female volunteers over four weeks. Two injection techniques were used in combination: a single injection with a 27 G × 19 mm needle in the periosteal level of the nasal base, and a linear retrograde injection with a 27 G × 13 mm needle into the deep dermis. Clinical and instrumental evaluation of the filling activity of the nasolabial folds demonstrated that both groups had a very significant reduction in wrinkle severity. This has been demonstrated by both clinical evaluation (mean reduction of wrinkle severity rate scale (WSRS): 33.3%; Wilcoxon test p < 0.001 for both preparations) and by instrumental analysis, for skin roughness reduction (−36% without and −32% with lidocaine; both p < 0.001 vs. baseline) and wrinkle depth reduction (−41% without and −31% with lidocaine; both p < 0.001 vs. baseline) [45]. For practitioners that prefer to use some local anesthetic, this study provides evidence to suggest that lidocaine can be mixed with Aliaxin® dermal fillers without any significant alterations to clinical outcomes [45].

4.2.2. Contouring Treatments with “Soft” Aliaxin® Dermal Fillers

Aliaxin® dermal fillers with a low G′ and a lower cross-linking score can be used to promote hydration in areas of the face that require soft shaping. One such area of concern is the tear trough area, which can become thin due to loss of fat and weakening of ligaments around the eye during the aging process [61].
The use of ASR was investigated in a retrospective case series in 58 female patients with a complete infraorbital hollow, which is not commonly addressed with aesthetic treatments due to the delicate nature of the area [61]. Strategic positioning of the product using a 25 G × 50 mm cannula inserted into the inner canthus and a linear retrograde superficial injection to introduce 0.1 mL microdroplets produced a significant improvement (p < 0.05) in the skin smoothness, texture, and color of the area without any unwanted adverse events, including swelling or blue discoloration known as the Tyndall effect [62]. The facial rejuvenation and hydration effects of ASR can also be attributed to its biological properties due to different HA molecular weights, promoting neocollagenesis and biorestructuring of the dermal architecture [4]. Hydration and the restoration of lost volume in this sensitive area mean that surgical procedures in this sensitive facial region can be avoided [61].
AGP has been investigated in several studies to treat superficial wrinkles and nasolabial folds. Due to the high molecular weight of AGP, it requires injection straight into the nasolabial fold or wrinkles [57,58,59]. A single-center, open-label study assessed the appearance of nasolabial folds after 3 and 6 months following a single injection of AGP in 30 female patients [57]. Changes to nasolabial folds and skin elasticity were measured instrumentally and clinically assessed with photographs at each visit. There was a significant reduction (p < 0.05 using Friedman test) in the appearance of nasolabial folds, but no significant changes in skin elasticity and hydration [57].
A retrospective, multicenter observational study in 25 women also demonstrated aesthetic improvements with AGP [59,63]. Comparing photographs and profilometric measurements using confocal microscopy, 80% of patients showed “exceptional improvement” at 4 and 6 months following treatment (p < 0.05) [59,63].
One randomized study in 30 patients investigated the use of AGP, followed by a non-cross-linked HA dermal filler a month later to target moderate-to-severe wrinkles, versus just AGP alone [58]. The combination treatment significantly improved the wrinkle severity rating scale score across areas including the nasolabial folds, upper lips, periorbital area, and cheeks compared with just using AGP alone [58]. Skin hydration, elasticity, and trans-epidermal water loss were also significantly improved (p < 0.0001) in the combination therapy group, suggesting a further biological effect of utilizing linear HA in dermal filler products [58]. There were no reported adverse events related to the products across these studies [57,58,59]. Animal studies have also reported a good AGP tolerability macroscopically and histologically [64].

4.2.3. Treating the Lips Using Aliaxin® Dermal Fillers

The lips are an area of the face in demand for aesthetic improvements. An understanding of the location and depth of the superior and inferior labial arteries is important to ensure the safe and effective delivery of lip filler injections [65]. Studies have confirmed that these arteries may vary in position and depth, but the most common location is the submucosal plane between the orbicularis oris muscle and the oral mucosa, followed by the intramuscular and subcutaneous plane [65,66,67]. The artery in the lower lip is also likely to be more superficial compared to the upper lip [65].
Dermal filler injections in locations that are highly mobile and highly sensitive, such as the lips, can increase the chances of developing adverse events such as delayed onset nodules [32,68]. This highlights the need for proven safe treatments, using knowledge of the anatomy of the lips and an understanding of the filler rheological properties to select and deliver the best treatment for the patient.
ALV is a filler with low tan δ value and good elastic properties, which is important for reshaping the lips and creating natural volume (Table 1). In a clinical series with 10 patients followed over 22 weeks, ALV demonstrated a consistent result over time, although not significant, delivering good volume enhancement with excellent definition of the lips and perilabial area [60]. There were no reported adverse events—only two patients experienced slight edema following treatment [60]. In an open-label clinical trial with 23 female patients, ALV was also able to significantly improve lip volume, both clinically (p < 0.05; Wilcoxon test) and instrumentally (p < 0.05; ANOVA paired t-test), without any adverse events for each timepoint over a 6-month period [47].
A clinical case series with nine female patients used either ALV or AFL for lip treatments [56]. Due to the lower viscosity and degree of cross-linking, AFL is more suited to patients requiring hydration or definition of the lips. Four patients received AFL and five received ALV using the author’s own technique of injecting into the mid-dermis at four sites: two in the top lip and two in the bottom lip, using a multilinear, retrograde fanning technique [56]. Patients were clinically assessed from 6 to 18 months post-treatment. All patients reported excellent lip sensitivity and integration of the HA filler into the labial mucosa as well as a significant improvement (p < 0.05) in the patient and doctor satisfaction after treatment, demonstrating them to be highly satisfied with the cosmetic outcome. None of the patients presented with edema or any other relevant adverse events [56]. An older open-label study published in 2012, during the first years of AFL clinical use, investigated the effects of AFL in 46 female patients for the augmentation and rejuvenation of the lips and perioral area [57]. Patients were asked to rate the results based on their degree of satisfaction. After 3 months, 88% of patients were satisfied or very satisfied with their treatment result, and after 6 months, this number dropped to just over half [57]. The treatment was also very well tolerated [57].

5. Conclusions and Future Perspectives

Using the Aliaxin® line of HA dermal fillers, this review has highlighted the importance of understanding the biophysical and rheological properties of dermal fillers for their optimal use.
Importantly, healthcare practitioners should be able to compare the rheological parameters of the different products currently available. However, when comparing different products, it is also crucial to consider that the chosen experimental settings during the biophysical and rheological characterization consistently vary the results. A lack of standard conditions and differences in experimental parameters can affect results and create difficulties when comparing products. Indeed, it has been demonstrated that different experimental conditions like applied forces, temperature, and humidity can notably change the rheological measurements [19]. Since the rheological parameters are currently measured using different conditions due to a lack of harmonization, this is a current limitation to comparing different fillers produced with different technologies. Therefore, specific investigations using the same experimental settings are vital to have a comprehensive knowledge of HA-based fillers. In this regard, a study comparing various commercialized BDDE-cross-linked HA hydrogels, including ASV, has provided a direct comparison across products within the same experimental setting [23]. In this study, ASV was found to have the most concentrated HA and the highest cohesivity but a lower G′ compared to other similar products [23]. This direct comparison demonstrated the importance of rheological characterization for advising clinical use, as these parameters were shown not to correlate with chemical data such as HA structural modifications and degree of branched HA [23].
Investigating the in vitro characteristics is not only fundamental to understand how the product is produced but also to select the right administration and clinical use for the filler. In this context, clinical studies and real-world evidence represent a fundamental aspect to assess fillers’ efficacy and safety. In this context, a major effort to standardize the clinical outcomes and requirements when these products are evaluated is also necessary for the future.
Therefore, further publications that elucidate fillers’ production and rheological characterization, as well as post-marketing surveillance data, are therefore advisable and recommended from all producers. These data will indeed allow clinicians to evaluate the best and safest approach for their patients.
Selecting the correct product tailored to the facial area of concern and location can indeed improve both clinical outcomes and safety, leading to natural but effective facial rejuvenation.
For example, products with a higher degree of cross-linking, higher MW, higher G′, and lower tan δ are more suitable for a deeper subdermal injection to promote volume, lift, and structure. Dermal fillers that contain lower-MW HA and have a lower degree of cross-linking and G′, and a higher tan δ, can produce a soft filling effect that increases hydration and elasticity [4]. These characteristics also directly impact the recommended injection technique and application site. The G′ in Aliaxin® products are lower than other types of dermal fillers, promoting safe tissue integration and a natural look.
Due to the different characteristics of these products, it would be interesting to explore a full facial treatment using multiple Aliaxin® products in the future, with the aim to achieve a harmonized and natural look. This can provide the patient with targeted support, lift, and volume, along with effective full facial softening.

Author Contributions

Conceptualization, B.M., D.R., M.Z. and E.K.; methodology, B.M., D.R., M.Z. and E.K.; writing—original draft preparation, C.C., F.G. and G.B.; writing—review and editing, B.M., D.R., M.Z. and E.K.; visualization, all authors. All authors have read and agreed to the published version of the manuscript.

Funding

Medical writing was supported by IBSA Farmaceutici Italia Srl.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study.

Acknowledgments

Medical writing support was provided by Anna Sanniti.

Conflicts of Interest

B.M., D.R., M.Z. and E.K. declare no conflicts of interest. C.C., F.G. and G.B. are currently employees of IBSA Farmaceutici Italia Srl.

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Cosmetics 11 00144 g001
Figure 1. Placement of injectable HA cross-linked fillers in different facial layers based on G′ values.
Figure 1. Placement of injectable HA cross-linked fillers in different facial layers based on G′ values.
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Figure 2. Rheological parameters and characterization of the Aliaxin® HA hydrogels. (A) Complex viscosity values (η*) of ASR, AGP, and ASV calculated using the frequency sweep tests [4]. (B) Complex viscosity values (η*) of ASR, AGP, and ASV calculated at 0.159, 0.7, and 2 Hz [19]. (C) Schematic representation of G′ and tan δ scores of the Aliaxin® fillers. AEV, Aliaxin® Essential Volume; AFL, Aliaxin® Fine Lines; AGP, Aliaxin® Global Performance; ALV, Aliaxin® Lips Volume; ASR, Aliaxin® Shape and Restore; ASV, Aliaxin® Superior Volume; G′, G prime; HA, hyaluronic acid; tan δ, tan delta.
Figure 2. Rheological parameters and characterization of the Aliaxin® HA hydrogels. (A) Complex viscosity values (η*) of ASR, AGP, and ASV calculated using the frequency sweep tests [4]. (B) Complex viscosity values (η*) of ASR, AGP, and ASV calculated at 0.159, 0.7, and 2 Hz [19]. (C) Schematic representation of G′ and tan δ scores of the Aliaxin® fillers. AEV, Aliaxin® Essential Volume; AFL, Aliaxin® Fine Lines; AGP, Aliaxin® Global Performance; ALV, Aliaxin® Lips Volume; ASR, Aliaxin® Shape and Restore; ASV, Aliaxin® Superior Volume; G′, G prime; HA, hyaluronic acid; tan δ, tan delta.
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Table 1. Biophysical and rheological characteristics of the Aliaxin® HA hydrogels.
Table 1. Biophysical and rheological characteristics of the Aliaxin® HA hydrogels.
Aliaxin®
Hydrogel		Total HA (mg/mL)MW (kDa)G′ (Pa)Tan δCohesivityCross-Linking Score
AEV251000, 20001620.1555/5 [4,11,13]
AFL25500, 1000 450.4053/5[4,16,19]
AGP251000, 2000950.2354/5[4,12,19]
ALV251000, 2000 1070.2154/5[17,22]
ASR25500, 1000, 2000390.5152/5[4,14,19]
ASV2523002950.1245/5[11,15,19]
AEV, Aliaxin® Essential Volume; AFL, Aliaxin® Fine Lines; AGP, Aliaxin® Global Performance; ALV, Aliaxin® Lips Volume; ASR, Aliaxin® Shape and Restore; ASV, Aliaxin® Superior Volume; G′, G prime; HA, hyaluronic acid; MW, molecular weight; Mw, weight average molar mass; Pa, pascal; tan δ, tan delta.
Table 2. Clinical applications of the Aliaxin® line existing literature.
Table 2. Clinical applications of the Aliaxin® line existing literature.
Aliaxin® HydrogelClinical OutcomeReferences
AEVVolumizing treatment for the mid-face (cheeks and cheekbones), nasolabial folds, and chin[4,19,45]
AFLHydrating treatment for the lips and marionette lines[4,19,55,56]
AGPHydrating and soft shaping treatment for nasolabial folds and superficial wrinkles, including the mouth, forehead, and glabellar wrinkles[4,19,57,58,59]
ALVVolumizing treatment for lips[46,55,60]
ASRHydrating and soft shaping treatment for nasolabial folds and superficial wrinkles, including the mouth, forehead, and glabellar wrinkles[4,19,61]
ASVVolumizing treatment for the mid-face (cheeks and cheekbones), facial contours, very deep wrinkles, nasal imperfections[23,44,57]
AEV, Aliaxin® Essential Volume; AFL, Aliaxin® Fine Lines; AGP, Aliaxin® Global Performance; ALV, Aliaxin® Lips Volume; ASR, Aliaxin® Shape and Restore; ASV, Aliaxin® Superior Volume.
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Molina, B.; Romano, D.; Zazzaron, M.; Kramer, E.; Cigni, C.; Grimolizzi, F.; Bellia, G. Full Face Tailored Treatments Using Hyaluronan Dermal Fillers: Biophysical Characterization for Safe and Effective Approaches. Cosmetics 2024, 11, 144. https://doi.org/10.3390/cosmetics11040144

AMA Style

Molina B, Romano D, Zazzaron M, Kramer E, Cigni C, Grimolizzi F, Bellia G. Full Face Tailored Treatments Using Hyaluronan Dermal Fillers: Biophysical Characterization for Safe and Effective Approaches. Cosmetics. 2024; 11(4):144. https://doi.org/10.3390/cosmetics11040144

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Molina, Beatriz, Domenico Romano, Michela Zazzaron, Eyal Kramer, Clara Cigni, Franco Grimolizzi, and Gilberto Bellia. 2024. "Full Face Tailored Treatments Using Hyaluronan Dermal Fillers: Biophysical Characterization for Safe and Effective Approaches" Cosmetics 11, no. 4: 144. https://doi.org/10.3390/cosmetics11040144

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