Hybrid Collagen Stimulators

What Are Hybrid Collagen Stimulators?

In hybrid collagen stimulators, hyaluronic acid (HA) gel is combined in the same syringe with a substance that stimulates collagen production and given as a single injection. The most studied combination in this group is HA with calcium hydroxylapatite (CaHA). Scientific publications distinguish between two approaches: combination treatment, in which the two products are used separately within the same treatment plan, and hybrid treatment, in which the two products are mixed directly from syringe to syringe.

Hybrid use can take two forms. The first is a ready-made product: a single, pre-formulated product in which CaHA microspheres are embedded in a cross-linked HA gel. Products of this kind are also described as collagen stimulators in a new gel form. The second is a mixture prepared by the doctor: CaHA is combined with a separate HA filler before treatment. In a retrospective study (based on past patient records) of this approach in 41 women, the mixture was applied to the mid-face and lower face.

The expected effect comes from the different roles of the two components. According to research, the HA component provides fullness that is noticeable straight away, while the CaHA microspheres lead to new collagen formation (neocollagenesis). For this reason, the combination is seen as an approach that both adds volume immediately and aims for a longer-term effect through collagen production. You can read about collagen stimulators used on their own on the Collagen Stimulator Treatments page.

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What Does ‘Hybrid’ Mean?

‘Hybrid’ is not the name of a single product class; it is used for many approaches in which different substances are combined in the same injection. The combination with the most publications is HA with CaHA. However, the same name is also used for other combinations, and the fact that a product or procedure is called ‘hybrid’ does not, on its own, tell you what it contains.

Hybrids that combine HA with polylactic acid derivatives have also been described. A product combining cross-linked HA with poly-L-lactic acid (PLLA)-based microspheres was studied retrospectively in 13 participants for nasolabial folds (the lines running from the side of the nose to the corners of the mouth). In a prospective study of a product combining poly-D,L-lactic acid (PDLLA) with HA in the tear trough, 15 women received three treatments. Both studies are small and have no comparison group; for these hybrids, the evidence is even more limited than for the HA and CaHA combination.

The word ‘hybrid’ is also used in a third sense: hybrid cooperative complexes, which combine low- and high-molecular-weight HA. These products contain only HA and are made without adding any foreign substance; in other words, they are not a mixture of HA and a collagen-stimulating substance. So if you come across a product with ‘hybrid’ in its name, the first thing to ask is which substances it contains.

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How Do the Two Components Behave Together?

A hybrid mixture does not behave like the simple sum of two substances; it behaves like a new material whose properties change with the mixing ratio. In a laboratory study in which CaHA was mixed with different HA products at ratios from 1:1 to 1:4, the flow and firmness properties of the mixture (its rheology) changed according to the type of HA, the mixing ratio and the degree of cross-linking. Adding CaHA increased the firmness of the mixture in every case, depending on the volume added.

These properties also have a clinical counterpart. According to the authors of the same study, these material properties are closely linked to how the mixture behaves in different tissue layers. An expert panel of ten practitioners recommended choosing the HA product for the mixture according to skin quality, the degree of sagging, volume loss, the underlying anatomy and the person’s expectations; the panel’s most preferred ratio was 1:1.

The mixing method is another variable. A retrospective study introduced a technique in which the mixture is turned into a foam together with the local anaesthetic (numbing medicine) lidocaine, using repeated negative pressure; on electron microscopy, the foamed mixture was reported to be more homogeneous. An international consensus statement on the everyday use of hybrid fillers, prepared by experts through several rounds of exchanging views (a Delphi consensus), emphasises that standard guidelines for use in this field are limited and that more research is needed on long-term safety and rheological properties.

What this means for you: the name ‘hybrid’ does not describe a fixed recipe. In a ready-made product, the ratio is set during manufacture. In a mixture prepared by the doctor, however, the ratio, the type of HA and the mixing method can vary from one treatment to another, and each of these affects how the mixture behaves in the tissue. You can ask at your consultation which form and which ratio are being considered.

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What Does the Early Evidence Show?

The evidence on hybrid treatments is new and consists largely of retrospective case series. In a systematic review (a publication that collects and summarises the studies on a topic according to set rules) of the combination and hybrid use of HA and CaHA, the studies were so different from one another that their results could not be combined numerically; only a qualitative summary could be given. According to this summary, the treatments were associated with high aesthetic effectiveness and satisfaction in different areas of the face; however, after the sixth month there was a trend towards a slight decline in both aesthetic improvement and satisfaction. The researchers state that more rigorously designed studies are needed for strong, long-term evidence.

There is also a randomised trial (in which participants are randomly assigned to groups) that directly tested the expectation that the two substances would give better results together. In the temple area, the 40 sides of the face of 20 patients were divided into two groups: one group received HA alone, and the other received a hand-prepared mixture of 40% HA and 60% CaHA. Both groups showed significant improvement on the rating scale, but three-dimensional measurement at 90-day follow-up showed that the volume retained was greater in the group that received HA alone. The researchers state that the expected combined effect (synergy) was not seen and that mixing by hand may change how the filler behaves.

The other studies have no comparison group. In 41 women treated with the mixture in the mid-face and lower face, an improvement of at least one grade on the rating scale used by the doctor was reported in all participants at month 3 and in 85% at month 12. A retrospective multicentre study of 111 people treated in the forehead reported two temporary, minor adverse events. In a series of 12 women that looked at skin quality in the mid-face and lower face, improvement on ageing and wrinkle scales was seen at month 4. In an uncontrolled study of 106 people treated around the eyes with CaHA diluted with HA, the effect of the low-dilution mixture (1:1) was reported to last longer than that of the high-dilution mixture (1:4) in most patients.

These findings should be interpreted with caution: most of the studies were carried out by the treating doctors in their own patients, with specific products and without a control group. The fact that no adverse events were reported in the 1,559-patient series that introduced the foam technique or in the 126-patient series on the jawline should also be read in this light; when retrospective records report no adverse events, this does not mean the treatment is risk-free.

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Can It Be Dissolved with Hyaluronidase?

Partly. Hyaluronidase is an enzyme that breaks down (hydrolyses) HA molecules, and it is regarded as the preferred way to manage problems related to HA fillers. It can break down the HA component of the mixture, but it does not dissolve CaHA or other biostimulator components. For this reason, a hybrid treatment cannot be fully reversed with the enzyme in the way a pure HA filler can.

According to a review of how fillers break down in the body, CaHA and PDLLA are semi-permanent fillers. These substances are broken down by water (hydrolysis) and by enzymes from cells called osteoclasts; they can usually remain in the tissue for up to two years, and rarely, in some people, for more than five years. Sodium thiosulfate can speed up the breakdown of CaHA; however, it acts slowly and is not effective in an emergency.

Data on how this applies to hybrids in practice are limited. In a retrospective study of 2,112 patients treated with premixed CaHA and HA, four non-inflammatory nodules (small, firm lumps that can be felt under the skin) were reported; two of them resolved completely with hyaluronidase, and the course of the other two is not stated in the study’s abstract. In a case report of a patient who developed a vascular (blood vessel) problem in the nose after an HA and CaHA mixture, hyaluronidase was used to reduce the HA part of the mixture; mechanical drainage through small punctures in the skin surface was added to this. The authors stress that it is unclear how much benefit this additional method provides on its own.

Research also stresses that there is no antidote for non-HA fillers; a systematic review of filler selection likewise states that non-HA fillers require precise technique because they cannot be reversed. Hyaluronidase is kept at the clinic. If you have had filler elsewhere before, you are first asked about the type of filler, when it was injected and which area was treated; fillers of unknown type, or fillers that cannot be confirmed to be hyaluronic acid, are not dissolved straight away. This is why knowing the contents and ratio of a hybrid treatment is important for any assessment that may be needed in the future.

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Limits of This Treatment

Hybrid collagen stimulators address volume, contour and skin quality; they do not remove excess skin and are not a substitute for a surgical facelift. International expert recommendations prepared for a ready-made hybrid product describe its use to provide structural support and reposition soft tissue in people with skin laxity and sagging and with mild to moderate volume and contour loss. However, this is the view of an expert panel of eight people; the recommendations are limited to mild and moderate cases and do not cover the removal of excess skin.

The second limit concerns claims of lifting. According to a review that critically examined filler publications, including those on hybrid products, the commonly used term ‘lift’ has no agreed definition, no measurement standard and no threshold for what is clinically meaningful; all of the published numerical measurements reflect change at the skin surface. According to the researchers, this does not mean there is no effect; it only shows that the effect has not yet been defined as precisely as the claims require.

The third limit is the claim of synergy (two substances having a stronger effect together). A retrospective study of a premixed hybrid in 46 patients suggests that the mixture has a stronger collagen-stimulating effect than CaHA or HA alone. In the randomised trial in the temple area, however, the expected synergy was not seen with the hand-prepared mixture, and volume retention was better with HA alone. The two findings come from different study designs and do not directly disprove each other; but they show that the idea that the two substances give better results together has not yet been proven.

The last limit is time. The systematic review reported a trend towards a slight decline in improvement and satisfaction after the sixth month; the Delphi consensus also emphasises that more research is needed on long-term safety. For this reason, no reliable figure can be given for how long the effect will last.

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Area, Layer and Technique

As with any treatment containing CaHA, the key factors for safety in hybrid treatments are the area, the layer and the anatomy of the blood vessels. The Delphi consensus on the everyday use of hybrid fillers recommends injecting in the plane just under the skin (subdermal) and avoiding areas with a lot of muscle movement. International recommendations prepared for a ready-made hybrid product also include the following:

• Choosing entry points according to the line of the facial ligaments and the line of the cheekbone arch.
• Keeping injections to the sides of the face and the areas that move less.
• Using a cannula (a fine tube with a blunt tip) instead of a needle.
• Working with small volumes.
• Considering repeat treatment only when laxity returns.

The choice of area is also linked to the risk of nodules and granulomas. A systematic review of foreign body granulomas (inflammatory lumps the body forms in reaction to a foreign substance) related to collagen stimulators reported the area around the mouth as a high-risk area. The anatomy of the blood vessels is a separate issue: to reduce the risk of accidental injection into a blood vessel, an expert consensus statement prepared for CaHA highlights good knowledge of the facial blood vessel anatomy and the patient’s medical history, and recognition of high-risk areas and suitable injection techniques.

At the clinic, the doctor chooses a needle or a cannula individually, according to the treatment area and the anatomy. The recommendations in publications were written for specific products and specific groups of experts; which area, which layer and which instrument are suitable for you is decided at your consultation, based on your anatomy.

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Ready-Made Product, Mixture and Regulatory Status

A ready-made hybrid product and a mixture that the doctor prepares from two separate products are not the same thing. In a ready-made product, CaHA microspheres are incorporated into the HA gel, and the injection is marketed as a single product. In a mixture prepared by the doctor, two products that are marketed separately are combined before treatment by transferring them directly from syringe to syringe.

According to a review of the blurring boundary between cosmetic and medical treatments, the growing use of aesthetic technologies outside their intended purpose (off-label use) contributes to inconsistent oversight and possible risks to patient safety. The Delphi consensus on hybrid fillers also states that standard guidelines for their use are limited. A study comparing three products with CaHA microspheres under an electron microscope found substantial differences between the products in the shape of the microspheres; the researchers noted that this could have consequences for biocompatibility (compatibility with tissue) and clinical behaviour. In short, the microstructure of products containing CaHA can differ from one product to another.

When the clinic assesses a product, approval by the US Food and Drug Administration (FDA) is not a criterion on its own; the assessment is based on the product’s CE marking, its registration and conformity status in Türkiye and the manufacturer’s intended purpose. For a hybrid treatment, this leads to two questions: What is the registration and conformity status of each product used? Does the manufacturer’s intended purpose cover using the product in a mixture? You can ask your doctor these questions before treatment.

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Known Risks

A hybrid injection is a medical procedure and carries the risks of all the substances it contains. According to the systematic review, most of the adverse effects reported with combination and hybrid treatments are mild and go away on their own. In a case series of 25 patients treated with a ready-made HA and CaHA hybrid, the following were reported immediately after treatment: swelling (32%), firmness of the skin (16%), bruising (12%), tenderness (12%) and redness (4%).

Mixtures containing CaHA also carry a risk of nodules. The retrospective study of 2,112 patients reported five minor adverse events (0.24%): four were non-inflammatory nodules and one was temporary swelling (oedema). This study is a series of two experienced practitioners’ own patients. According to the systematic review of foreign body granulomas related to collagen stimulators, all the collagen stimulators studied can cause this reaction; it was noticed between one week and fifteen years after treatment, and the symptoms were most often resolved by surgical removal.

The most serious risk is accidental injection of the substance into a blood vessel. According to the expert consensus statement prepared for CaHA, this can lead to tissue death, permanent scarring, visual impairment and blindness; although it is rare, it needs immediate treatment. A review of vision loss related to biostimulators reported at least 11 cases of visual impairment with CaHA; most of these were related to treatment on the bridge of the nose. One case of vision loss has been reported with a hybrid combining PDLLA with HA; of the two cases reported with PLLA, one was also related to injection around the eyes and nose.

Mixtures add another dimension to this picture. According to the authors of the case report on a patient who developed a vascular (blood vessel) problem in the nose after an HA and CaHA mixture, mixtures that combine HA with a particulate biostimulator can form blockages (emboli) with two different flow behaviours; current management algorithms, however, are largely derived from events involving HA alone.

Before the procedure, you are asked about blood thinners, antiplatelet medicines and supplements that can affect bleeding. Do not stop any prescribed medicine on your own. If needed, the procedure is planned or postponed after consulting the relevant doctor.

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