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. 2023 Mar 11;16(3):431.
doi: 10.3390/ph16030431.

A Safe-by-Design Approach for the Synthesis of a Novel Cross-Linked Hyaluronic Acid with Improved Biological and Physical Properties

Sabrina Sciabica  1 , Riccardo Barbari  1 , Riccardo Fontana  2 , Giovanni Tafuro  3 , Alessandra Semenzato  4 , Daniela Traini  5   6 , Dina M Silva  6 , Larissa Gomes Dos Reis  6 , Luisa Canilli  7 , Massimo Terno  7 , Peggy Marconi  2 , Anna Baldisserotto  1 , Silvia Vertuani  1 , Stefano Manfredini  1
Affiliations

A Safe-by-Design Approach for the Synthesis of a Novel Cross-Linked Hyaluronic Acid with Improved Biological and Physical Properties

Sabrina Sciabica et al. Pharmaceuticals (Basel). .

Abstract

Hyaluronic acid (HA) is a polymer with unique biological properties that has gained in interest over the years, with applications in pharmaceutical, cosmetic, and biomedical fields; however, its widespread use has been limited by its short half-life. Therefore, a new cross-linked hyaluronic acid was designed and characterized using a natural and safe cross-linking agent, such as arginine methyl ester, which provided improved resistance to enzymatic action, as compared to the corresponding linear polymer. The antibacterial profile of the new derivative was shown to be effective against S. aureus and P. acnes, making it a promising candidate for use in cosmetic formulations and skin applications. Its effect on S. pneumoniae, combined with its excellent tolerability profile on lung cells, also makes this new product suitable for applications involving the respiratory tract.

Keywords: arginine; bioactivity; cosmeceutical; cross-linking; hyaluronic acid; lung; skin.

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Conflict of interest statement

The authors declare no conflict of interest. The company had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; nor in the decision to publish the results.

Figures

Figure 1
Figure 1
Schematic synthesis of the cross-linked HA-Arg.
Figure 2
Figure 2
1H-NMR profile of cross-linked HA–Arg and native HA.
Figure 3
Figure 3
Thermograms of the native HA and HA-Arg.
Figure 4
Figure 4
SEM images of HA (panels a1, a2) and HA–Arg (panels b1, b2). SEM scale bar: 20 µm (panels a2, b1, b2), 30 µm (panel a1).
Figure 5
Figure 5
Swelling degree percentage of HA–Arg obtained in PBS at different pH values and in water. Each value is the average of three independent measurements (mean ± StDev).
Figure 6
Figure 6
The trend of viscosity values (panel a), G′ and G″ moduli (panel b), complex moduli (G*) (panel c), and damping factor (tan δ) (panel d).
Figure 7
Figure 7
DVS isotherms of two cycles of moisture sorption and desorption of HA and HA-Arg.
Figure 8
Figure 8
Antimicrobial activity of HA, Arg, and HA–Arg, against P. acnes. Bacterial growth was quantified by OD600 using a spectrophotometer. Data are the mean of 3 independent experiments performed in triplicate (mean +/− SD); ns p ≥ 0.1; * p < 0.1; *** p < 0.001; **** p ≤ 0.0001 (TWO WAY ANOVA followed by Dunnett post test).
Figure 9
Figure 9
Antimicrobial activity of HA, Arg, and HA–Arg, against S. aureus. Bacterial growth was quantified by OD600 using a spectrophotometer. Data are the mean of 3 independent experiments performed in triplicate (mean +/− SD); ns p ≥ 0.1; **** p ≤ 0.0001 (TWO WAY ANOVA followed by Dunnett post test).
Figure 10
Figure 10
Antimicrobial activity of HA, Arg, and HA–Arg against S. pneumoniae. Bacterial growth was quantified by OD600 using a spectrophotometer. Data are the mean of 3 independent experiments performed in triplicate (mean +/− SD); ns p ≥ 0.1; *** p < 0.001; **** p ≤ 0.0001 (TWO WAY ANOVA followed by Dunnett post test).
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