In their practice, cosmetologists often come across injectable products based on hyaluronic acid, which are subject to various modifications. These can be products for mesotherapy, biorevitalization, volumetric correction, and so on. To attract the attention of specialists, marketers often talk about the resistance of these compositions to biodegradation, which is achieved by using various types of hyaluronic acid (HA) crosslinks. In this article, we will look at what “crosslinking” is and what modifications can be made to biopolymers to achieve their optimal bioavailability.
Types of chemical interactions
Before diving into the variety of crosslinks and modifications of HA, let us consider the main points from the point of view of chemistry. It is customary to distinguish two types of interactions between substances – chemical and physical. Their main difference is that during physical interaction, the spatial structure of the substance changes, and in the case of chemical interaction, it is possible to obtain a new substance with a different composition and properties. Let us analyze this statement with concrete examples.
Physical interaction can be of two types: intramolecular and intermolecular. For example, the DNA molecule is shaped like a helix. Such a structure is formed due to the formation of hydrogen bonds between different parts of one biopolymer molecule to obtain a new, mobile spatial form. In this case, no new substance is formed – the structure of the molecule, that is, the number of atoms in it, remains unchanged, but instead of a straight chain, we observe a helix.
Fig. 1. The structure of the DNA molecule is a densely packed double helix formed by physical interaction (hydrogen bonds)
In the case of intermolecular interactions, it is still more interesting. It is known that collagen molecules can be packed into various spatial structures as layers, coils, etc. This occurs precisely due to the formation of a network of hydrogen bonds between several biopolymer molecules.
Now consider chemical interactions. For the behavior of a chemical reaction, it is not enough just to bring atoms or molecules together and the appearance of a physical interaction between them (which is true for hydrogen bonds). In this case, more serious processes and forces are involved, affecting the structure of the substance and leading to the production of new molecules. Therefore, during the burning of brightly colored organic substances, only dark ash can be obtained.
Fig. 2. Pharaoh's Serpent chemical reaction means burning of a tablet of calcium gluconate
In the case when biopolymer molecules are interconnected not only by physical, but also by chemical bonds, for example, during the formation of disulfide bridges between keratin molecules, a fundamentally new chemical substance is formed. Keratin is the main structural protein of hair, responsible for its strength, smoothness and elasticity. When heated or exposed to chemicals in the keratin molecule, the disulfide bridges are destroyed, which leads to brittleness and dryness of the hair.
How is crosslinking different from modification?
Now that we have figured out the differences between chemistry and physics, let us talk about ways to change the structure of HA, as well as what these chemical changes are used for in cosmetology.
From the point of view of polymer chemistry, cross-linking polymerization is the process of formation of molecular bridges (crosslinks) between molecules. Modification is the transformation of one molecule into another by introducing various agents.
Fig. 3. The reaction for obtaining cross-linked hyaluronan: the active groups of HA molecules are marked in red, the cross-linking agent is marked in green, the resulting cross-link is in blue.
The simplest analogy that comes to mind is sewing. In the case of chemical crosslinking, we take one piece of tissue (one biopolymer molecule), another piece of tissue (a molecule of the same or a different polymer), and a thread (the third molecule is a crosslinking agent). At the output, we get a complex structure with new mechanical properties (dress).
Speaking of modification, it is easiest to imagine embroidery. We take one piece of tissue (biopolymer molecule), a beautiful thread (any other molecule that allows us to achieve the properties we need), and again create a completely new substance (embroidered fabric).
If we return to chemistry, then it is worth noting an important difference between these processes. Cross-linking is one of the types of polymerization that is increasing the size of the molecule using monomers, which, in our case, are HA molecules. In turn, the modification reaction cannot be considered polymerization, since there is no interaction of monomers. Beads – molecules – substituents, forming a chemical bond with its active centers, are placed on an already existing biopolymer, like on a thread.
Based on the facts presented above, we can conclude that when carrying out these reactions, we will obtain macromolecules with different properties. The products obtained in the course of the transformations described above will differ in resistance to biodegradation, viscosity, bioavailability and other properties. Moreover, depending on the purpose of use, you should carefully approach the composition of the drugs used.
Types of hyaluronic acid crosslinks
Cosmetologists rarely meet with modified HA – such reactions require a significant investment of time and production capacity. Therefore, most manufacturers grind dry or mix several substances in solution. For example, HA and vitamin C, with the production of associates – molecular complexes, where the molecules are connected only by hydrogen bonds. Calling it a full-fledged modification or cross-linking is incorrect. In this case, we are talking about the appearance of physical interaction without the formation of new molecules.
When HA is dissolved in water, a viscous gel is formed due to the formation of a large number of hydrogen bonds, which, when injected into the skin, is easily biodegraded. In this form, HA is found in products for mesotherapy and biorevitalization. It is logical to assume that for the volumetric correction of aesthetic imperfections, when the high viscosity of the drug and the lasting result are important, it is impossible to manage simply by dissolving HA in water.
In this case, a change in the chemical structure of the biopolymer is carried out, carrying out cross-linking and achieving complication of the drug structure with the help of cross-linking agents – substances that form bridges between hyaluronan molecules. This is a complex multi-stage process leading to the formation of a dense structure.
The most common cross-linking agents are: butanediol diglycidyl ether, or BDDE, divinyl sulfone, bicarbodiimide, etc. They have a different structure, but a similar ability to form cross-links between HA molecules. During the reaction, the crosslinking process can be carried out both once and repeatedly. Such manipulations will affect the final density, viscosity and stability of the resulting gel.
Among products for contour plastics based on HA, it is customary to single out monophasic and biphasic fillers.
Fig. 4. Scheme for obtaining a biphasic filler obtained by cross-linking hyaluronan with a cross-linking agent BDDE, and then placed in non-cross-linked HA
Their main difference is that monophasic fillers contain only crosslinked hyaluronan, while biphasic ones also contain a certain amount of non-crosslinked HA. This step is justified for several reasons:
· Biphasic fillers are less likely to cause allergic reactions. This is because when the drug enters the deep layers of the skin, biodegradation begins with uncrosslinked HA, identical to the natural analogue, and the immune system does not recognize the injected filler as something foreign.
· For a similar reason, biphasic fillers have a more pronounced and lasting effect compared to monophasic counterparts. The primary degradation of biphasic fillers begins precisely with uncrosslinked fragments, which makes it possible to prolong the effect of the correction of imperfections.
Conclusion
The modern market of products for aesthetic cosmetology offers a whole range of products to combat age-related changes, as well as to correct certain aesthetic imperfections. A competent approach to the choice of the drug will allow the specialist to achieve success in his work, and help to achieve a high level of satisfaction with the results of his work. In this article, some issues of chemistry and physics have been considered, which will allow a comprehensive and reasonable approach to the selection of basic tools for successful routine practice.
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