Hyaluronic Acid Knowledge

What are the crosslinkers for cross linked hyaluronic acid dermal filler?

What are cross linked hyaluronic acid dermal filler?

The duration of natural hyaluronic acid in the human body is very short. Generally, it will be degraded into water and carbon dioxide by the hydrolase in the human body very soon. 

To prolong the maintenance time of hyaluronic acid, cross-linking agents are introduced into the production process of hyaluronic acid. By reacting hyaluronic acid with a cross-linking agent, the cross-linked hyaluronic acid gel is produced, which is very popularly used in the aesthetic field.

The cross linking process of cross linked hyaluronic acid dermal filler

As we mentioned above, natural hyaluronic acid is very easy to be absorbed. The structure of natural hyaluronic acid is linear. There is no intersection between the molecular chains. It’s in liquid form. Please check photo below:

non cross linked hyaluronic acid

For the above reasons, we introduced crosslinker into the production process of dermal filler. The red and blue parts in the circular frame are the molecular chains of hyaluronic acid, and the yellow linear particles (cross-linkers) added are the cross-linking agents. After adding the cross-linking agent, the texture of hyaluronic acid also changed significantly, from liquid to gel.

cross linked hyaluronic acid dermal filler

The addition of a cross-linking agent makes hyaluronic acid complete the transformation from liquid to gel. It unites the molecules of hyaluronic acid. On the one hand, it strengthens the supporting force (hardness and elasticity) of hyaluronic acid. On the other hand, it prolongs the duration of HA. See photo below

What are the crosslinkers for cross linked hyaluronic acid dermal filler?

The cross-linking agent used in most cross linked hyaluronic acid dermal filler currently on the market is BDDE. Its cross-linking ability is attributed to the reactivity of the epoxy groups at both ends of the molecule. Under alkaline (pH>7) conditions, these epoxy groups preferentially react with the most accessible primary alcohols in the hyaluronic acid skeleton to form ether bond connections.

The stability of the ether bond (compared to the ester or amide bond) is one of the reasons why BDDE cross-linked hyaluronic acid can be used clinically for up to 1 year or more. Furthermore, BDDE has significantly lower toxicity than other cross-linking agents (such as DVS), is biodegradable, and has been well studied. All these factors have contributed to BDDE becoming the industry standard crosslinker.

Cross-linking degree and cross-linking agent

Relations between the amount of crosslinker and cross linked extent

The degree of cross-linking is related to the amount of cross-linking agent. The more crosslinker is put in, the higher the degree of cross-linking of hyaluronic acid. 

The degree of cross-linking determines the viscoelasticity of the cross-linked hydrogel particles. Viscoelasticity is mainly characterized by elastic modulus and viscous modulus. The elastic deformation reflects the solid state of the material, and the viscous deformation reflects the liquid state of the material. The gel is a typical semi-solid substance.

Below is a table with a comparison of gel properties with different cross-linking degree ratios



Elastic Modulus(Pa)

Viscous modulus(Pa)

Cross-linked degree 1




Cross-linked degree 2

x +0.018



Cross-linked degree 3

x +0.036



Cross-linked degree 4

x +0.054



Cross-linked degree 5

x +0.072



We can see from the above table that as the amount of cross-linking agent increases, the growth rate of elastic modulus is much greater than the growth rate of viscous modulus. In other words, as the amount of cross-linking agent increases, the gel becomes more solid. Plastic surgeons’ most direct feeling is that these cross linked hyaluronic acid dermal fillers are relatively “hard” and difficult to push. So how to solve this problem?

Solutions to solve hardness of the gel

Manufacturers generally take the following measures to reduce pushing force:

(1) Add softener. Softener serves to dilute the hydrogel, lubricate the needle tube and needle, and increase the fluidity of the hydrogel.

(2) Reduce the particle size of hydrogel. So we see that some cross linked hyaluronic acid dermal fillers with a high degree of cross-linking have extremely small gel particles, and you can barely feel the presence of the particles when you twist them with your hands. Such tiny particles greatly reduce the damping coefficient of the needle tube and needle. However, even so, doctors still feel the injection was difficult.

(3) Neutralize the highly cross-linked hydrogel with non-cross-linked hyaluronic acid. Non-cross-linked hyaluronic acid stays in the human body for a very short time and cannot participate in shaping and filling. Manufacturers often add non-cross-linked hyaluronic acid just to change the viscous state of the high cross-linking degree, to lubricate, and to change the feeling of the injection.

Relations between duration and cross linked degree

It’s not that the higher the degree of cross-linking, the longer or better it stays in our body.

Cross linked hyaluronic acid dermal filler is a hydrogel formed by reacting sodium hyaluronate with a small amount of chemical cross-linking agent and then combining with water.

The molecular biological basis of histocompatibility is the consistency of the filler with human biological macromolecules. Sodium hyaluronate has no species specificity. All biological sodium hyaluronates have a linear structure composed of disaccharide units glucuronic acid and glucosamine, with the same molecular composition and structure.

Cross linked hyaluronic acid dermal filler is a change in the original molecular structure. According to the principle of tissue compatibility, sodium hyaluronate molecules are artificially modified. The smaller the modification, the better the tissue compatibility. It is important to note that the degree of modification of modified hyaluronic acid is inversely proportional to tissue compatibility.

The cross-linking degree of hyaluronic acid from most manufacturers is between 1 and 2%. This is because the cross-linking degree of the cross-linking agent BDDE (1,4-butanediol diglycidyl ether) is safe in the human body if it is between 1 and 2%.

The cross-linking degree of Tri Aqua cross linked hyaluronic acid dermal filler has always been kept below 1%.

Medical experiments have proven that after hydrolysis of hyaluronic acid with a cross-linking degree of less than 1%, BDDE fragments can enter the normal metabolic cycle and be excreted from the body.

Advantages of Tri Aqua cross linked hyaluronic acid dermal filler

The safety and reliability of Tri Aqua cross linked hyaluronic acid dermal filler comes from its exclusive two-site cross-linking technology.

  1. Thorough response

Double-site cross-linking can double the chance of BDDE reacting with hyaluronic acid than single-site cross-linking. Therefore, the dosage of BDDE in Tri Aqua dermal filler is the lowest, and the residual amount of BDDE is extremely low, basically close to the complete reaction.

2. Safety

Using dual-site cross-linking technology, the link between BDDE and hyaluronic acid is more closely combined than single-site cross-linking. Since the cross-linking agent reacts very thoroughly with hyaluronic acid, there is no stimulation from free cross-linking agents, and the probability of inflammatory reactions is extremely low.

3. Long-lasting effects

When single-site cross-linked BDDE reacts with hyaluronic acid, there will be a hanging phenomenon, and the tail end will be in a free state, which will increase the chance of being decomposed. Two-site cross-linked hyaluronic acid has two sites of cross-linking between the cross-linking agent and hyaluronic acid. The combination is stronger and less likely to produce free ends. The linked hyaluronic acid is twisted and folded more tightly and is more resistant to hydrolysis, so it can last much longer.

4. High viscoelasticity

Since the two links between the cross-linking agent and the hyaluronic acid are in non-planar and different phases, the linked gel molecules present a twisted and folded structure, which not only retains the internal space but also has high density, so makes the viscoelasticity very good.

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