Injectable hyaluronic acid (HA) formulations have long been a cornerstone of aesthetic practice. Yet formulators continue to refine their compositions, and one of the most actively discussed directions is the addition of glycerol. At first glance, this ingredient may seem purely cosmetic — it is well known as a humectant in topical products. In the context of injectables, however, glycerol takes on an entirely different and more significant role.

Glycerol: more than a humectant

Glycerol is a simple trihydric alcohol with pronounced hydrophilicity and low systemic toxicity. It holds GRAS (Generally Recognized as Safe) status and is widely used in medicine and pharmaceuticals as a solvent, stabilizer, and moisturizing agent.

Crucially, glycerol is an endogenous compound: it participates in cellular metabolism, linking lipid and carbohydrate pathways, and can serve as a carbon source, contribute to carbohydrate regeneration, and support ATP production. This endogenous nature underpins its high biocompatibility and explains the growing interest in glycerol as a functional component of injectable formulations.

Glycerol transport through aquaporins

Glycerol can only enter cells through specialized protein channels called aquaglyceroporins. In the skin, the most prevalent is aquaglyceroporin-3 (AQP3). When AQP3 is deficient in keratinocytes, cell viability is compromised: the skin becomes markedly dry, and epithelialization slows considerably [2]. In the dermis, AQP3 supports the metabolic activity of fibroblasts by facilitating matrix synthesis and cell migration — both critical determinants of tissue repair [3]. In adipose tissue, a related channel, aquaglyceroporin-7 (AQP7), regulates glycerol transport and adipocyte energy balance, thereby ensuring adequate lipid metabolism [4].

It is important to note that alongside aquaglyceroporins, the skin also expresses aquaporins that are selective for water only — meaning a substantial share of water transport occurs through pathways entirely independent of glycerol. At concentrations typical of aesthetic formulations (up to 20 mg/mL / 2%), the transport system's capacity remains well above saturation: water molecules, being smaller, pass through the pores significantly faster than glycerol. Once inside the cell, glycerol is rapidly incorporated into metabolic pathways, freeing the channels for incoming molecules. Experimental data further suggest that at physiological doses, glycerol may upregulate AQP3 expression — supporting, rather than competing with, water transport [1].

The dual role of glycerol: metabolic agent and osmotic regulator

In the context of injectable formulations, it is essential to distinguish two independent roles of glycerol—each operating at a different level and serving a distinct purpose.

As a metabolic agent, glycerol enters cells via AQP3 channels, where it is incorporated into membrane lipid synthesis and energy metabolism, providing cells with the substrate needed for division and active function. This is particularly relevant in the context of repair: glycerol delivery supports the viability and functional activity of keratinocytes and fibroblasts in the injection zone.

As an osmotic regulator, glycerol acts where HA cannot reach — inside cells. While HA binds water in the extracellular matrix (extracellular hydration), glycerol maintains osmotic pressure and retains water intracellularly (intracellular hydration). This division of responsibility ensures a balanced distribution of fluid between tissue compartments. It reduces the risk of localized edema — an unwanted effect that frequently accompanies the use of single-component HA products.

It is precisely this combination of two functions — cellular nourishment and fine-tuned water balance regulation — that makes glycerol a physiologically unique partner for HA, rather than merely an auxiliary excipient.

What else changes when glycerol meets HA

Beyond osmoregulation and metabolic support, the addition of glycerol confers additional properties to injectable HA formulations, as described by Kleine-Börger et al. [1].

Glycerol forms a stable protective hydration shell around HA molecules, creating a barrier that impedes access of hyaluronidases and reactive oxygen species (ROS) to the polymer chain. As a result, HA degradation slows, extending its duration of action in the tissue. In addition, glycerol acts as an effective protein stabilizer: it helps maintain the correct spatial configuration of collagen fibers [5], reinforcing the dermal scaffold and increasing the resistance of matrix proteins to mechanical stress during skin stretching.

The concentration question: where is the safety boundary?

The effects described above are only achieved within a specific concentration range. When glycerol content in the formulation exceeds 5%, osmotic homeostasis is disrupted. An excessive osmotic gradient draws water out of cells, leading to dehydration and cellular dysfunction. High glycerol concentrations alter lipid bilayer fluidity and trigger intracellular metabolic stress. Widespread cell death from osmotic shock releases damage-associated molecular patterns (DAMPs), initiating sterile inflammation with edema, erythema, and pain. High glycerol content also substantially increases product viscosity, impairing microcirculation and lymphatic drainage at the injection site and prolonging tissue recovery.

There is, therefore, a well-defined therapeutic window for glycerol-containing injectables — and staying within its optimal boundaries is a fundamental requirement for both safety and clinical efficacy [1].

Product categories and their characteristics

HA-based formulations containing glycerol are represented in two main categories.

Biorevitalizers contain unmodified (non-cross-linked) high-molecular-weight HA at concentrations of 1–2%. Here, glycerol serves as a key functional partner: it provides rapid tissue hydration, protects cells from osmotic stress, and supports their metabolic activity. These products are indicated for skin restoration in cases of significant dehydration — including post-photoaging recovery — and for treatment of delicate anatomical areas such as the neck, décolletage, and periorbital zone. They are particularly well-suited for patients prone to edema.

Fillers and skin boosters based on cross-linked HA (2–2.2%) incorporate glycerol as a manufacturing additive introduced during production. It increases gel plasticity, promotes smooth tissue integration, and provides additional stabilization of the HA polymer chain. Depending on the degree of cross-linking and HA concentration, these products are used for both superficial revitalization and correction of moderate-depth wrinkles. In both cases, the presence of glycerol helps maintain local hydration at the injection site and reduces the risk of adverse post-procedural reactions.

Conclusion

The combination of HA and glycerol in injectable formulations represents a physiologically sound approach — not a marketing strategy. Two substances with distinct mechanisms of action complement each other: HA provides structural support and extracellular hydration, while glycerol regulates intracellular water balance, sustains cellular metabolism, and stabilizes the dermis's protein architecture. At optimal concentrations (up to 20 mg/mL / 2%), glycerol integrates organically into the skin's natural hydration and osmoregulation mechanisms without disrupting water transport through the aquaporin system. This "intelligent" hydration balance is especially valuable when treating patients prone to puffiness, in restoration protocols, and when injecting anatomically challenging zones. For the practicing skincare specialist, understanding these mechanisms provides a solid, evidence-based rationale for product selection and protocol design.

References

1. Kleine-Börger L., Hofmann M., Kerscher M. Microinjections with hyaluronic acid in combination with glycerol: how do they influence biophysical viscoelastic skin properties? Skin Res Technol 2022; 28(4): 633–642.
2. Bollag W.B., Hill W.R., Chen Z.J., Zhang J. Aquaporin-3 in the epidermis: more than skin deep. Am J Physiol Cell Physiol 2020; 318(6): C1144–C1153.
3. Cao C., Sun Y., Healey S. et al. EGFR-mediated expression of expression is involved in human skin fibroblast migration. Biochem J 2006; 400(2): 225–234.
4. Skowronski M.T., Bhat S., Hemann E.S. et al. AQP7 is localized in capillaries of adipose tissue, cardiac and striated muscle: implications in glycerol metabolism. Am J Physiol Renal Physiol 2007; 292(3): F956–965.
5. Wen X., Shi Z., Lu P. et al. In vivo skin optical clearing by glycerol solutions: mechanism. J Biophotonics 2010; 3(1–2): 44–52.