Injections of native hyaluronic acid (HA) remain the gold standard for improving skin quality, supported by a robust evidence base. However, modern aesthetic medicine seeks synergy: combining HA with amino acids promises not only deep hydration but also active tissue regeneration. The primary challenge lies in the uniqueness of each formulation. Varying concentrations, active ingredient profiles, and protocols make it impossible to extrapolate results from one commercial product to another directly. Nevertheless, understanding the general mechanisms of these agents is critical for clinical practice.

This topic is the focus of a recent systematic review and meta-analysis by Mosteirin M. et al., published in the Journal of Cosmetic Dermatology in early 2026 [1].

Study design and structure

The authors analyzed data from 11 clinical studies (2014–2024) that used HA in combination with amino acids (AA) in adult patients. The meta-analysis included randomized controlled trials (RCTs) and prospective cohort studies. The observation period ranged from 1.4 to 12 months. Outcomes evaluated included wrinkle dynamics (WSRS), aesthetic improvement (GAIS), dermal thickness, and biostimulatory potential (EGF expression).

Comparative analysis of products and protocols

The table below summarizes key studies included in the review, demonstrating the diversity of approaches and compositions united by the "HA + amino acids" concept.

Table. Key studies included in the review

Key meta-analysis results: efficacy and histology

The study confirmed the dual-action concept: immediate hydration via HA and long-term remodeling via AA. To evaluate the effect, the authors used the Mean Difference (MD) — the average difference between "before" and "after" states.

Biostimulation and EGF

Histological tests showed a sharp increase in the number of cells expressing epidermal growth factor (EGF). In key studies [4–6], the number of EGF-positive cells increased from a baseline of 10 ± 2 to 220 ± 12 per field of view, confirming the activation of the skin's regenerative potential.

Dermal structure

Ultrasound scanning and histology recorded significant thickening of the dermal layer: MD = −0.42 mm. This growth was accompanied by an increase in the density of type I and III collagen fibers.

Synergy mechanism and antioxidant protection

Amino acids such as glycine and proline constitute approximately 57% of the amino acid profile of collagen and are critical substrates for its biosynthesis. However, their role extends beyond being "building blocks." The inclusion of AA in HA formulations helps reduce oxidative stress and improve fibroblast survival. According to the study, this occurs through the neutralization of reactive oxygen species (ROS) and the chelation of transition metal ions—iron and copper—which catalyze oxidative processes. Thus, amino acids act as a "metabolic shield": they not only stimulate neocollagenesis but also protect cells and newly synthesized fibers from degradation caused by free radicals and external aging factors. Furthermore, using AA (e.g., lysine) to stabilize HA reduces the risk of cytotoxicity associated with traditional crosslinking agents, creating an optimal environment for tissue regeneration.

Aesthetics

• GAIS: Marked improvement on the Global Aesthetic Improvement Scale at 3 months: MD = 3.13, p < 0.00001.
• WSRS: A statistically significant reduction in Wrinkle Severity Rating Scale scores: MD = 2.15, p < 0.0001. This indicates that, on average, wrinkle depth decreased by more than 2 points on a standard scale—a highly significant clinical result.

Safety

No serious adverse events (SAEs) were identified. Typical reactions (edema, erythema, tenderness) were transient and resolved spontaneously. Statistical analysis showed no significant difference in the frequency of side effects between combined formulations and control groups. However, due to extreme data heterogeneity (I² = 94%) and differences in complication-reporting protocols, the authors caution against interpreting these figures with caution.

Statistical limitations and "pitfalls"

Extreme heterogeneity

Despite positive findings, the authors urge caution due to the high heterogeneity index (I²), which measures how similar (or dissimilar) results are across combined studies.

• 0%: Perfect consistency
• <25%: Low heterogeneity (reliable data)
• 50–75%: Moderate to high heterogeneity
• >75%: Very high heterogeneity

In this study, the index for aesthetic improvement (GAIS) was I² = 99%. This means results varied wildly across clinics and authors. This extreme heterogeneity arose because:

• Different products were used (e.g., HA + 3 amino acids vs. HA + 10 amino acids + vitamins).
• Different anatomical zones were treated (temples, malar area, and full face).
• Results were often evaluated subjectively (GAIS scale).

Geographic and author bias

Nearly half of the studies (5 of 11) were conducted in Italy, and a significant portion of the work was conducted by a single research group (Scarano et al.), which may limit the external validity of the data.

Quality of evidence

According to the GRADE system, the quality of evidence for aesthetic scales and safety was rated as "very low," while for wrinkles and cellular activity, it was rated as "moderate."

Future perspectives

The combination of HA and amino acids (particularly glycine, proline, and lysine) represents a promising vector for the development of biorevitalizers. These formulations do more than replenish moisture; they create conditions for neocollagenesis and reduced oxidative stress. The future of this field lies in standardizing protocols and developing products with controlled-release actives, ensuring predictable, long-lasting rejuvenation results.

References

1. Mosteirin M., Ardila A.G., Calomarde R.G., Mariscal G. Efficacy and safety of amino acid-enriched hyaluronic acid in facial rejuvenation: a systematic review and meta-analysis. J Cosmet Dermatol 2026; 25(3): e70741. DOI: 10.1111/jocd.70741
2. Guo Y. Wei W., Wang H. et al.  Effect of a new hyaluronic acid hydrogel dermal filler cross-linked with lysine amino acid for skin augmentation and rejuvenation. Aesthet Surg J 2023; 44(1): NP87–NP97. 
3. Guo Y., Li P,. Wei W. et al. Safety and efficacy of the amino acid crosslinked hyaluronic acid in the treatment of temple hollowing. Asian J Surg 2024: S1015-9584(24)02414-X.
4. Scarano A., Amuso D., Amore R. et al. Malar augmentation with Hyaluronic acid enriched with glycine and proline: a clinical evaluation. J Biol Regul Homeost Agents 2021; 35(2 Suppl. 1): 187–194. 
5. Scarano A., Rapone B., Amuso D. et al. Hyaluronic acid fillers enriched with glycine and proline in eyebrow augmentation procedure. Aesthetic Plast Surg 2022; 46(1): 419–428.
6. Scarano A., Qorri E., Sbarbati A. et al. The efficacy of hyaluronic acid fragments with amino acid in combating facial skin aging: an ultrasound and histological study. J Ultrasound 2024; 27(3): 689–697.
7. Iannitti T., Morales-Medina J.C., Coacci A., Palmieri B. Experimental and clinical efficacy of two hyaluronic acid-based compounds of different cross-linkage and composition in the rejuvenation of the skin. Pharm Res 2016; 33(12): 2879–2890. 
8. Siquier-Dameto G., Boadas-Vaello P., Verdú E. Intradermal treatment with a hyaluronic acid complex supplemented with amino acids and antioxidant vitamins improves cutaneous hydration and viscoelasticity in healthy subjects. Antioxidants (Basel). 2024; 13(7): 770.
9. Ayatollahi A., Samadi A., Barikbin B. et al. Efficacy and tolerability of a hyaluronic acid-based extracellular matrix for labia majora rejuvenation and augmentation: a pilot study. Cureus 2024; 16(4): e58970.