Collagen Stimulator Treatments

What are collagen stimulator treatments?

In collagen stimulator treatments, the substance injected into the tissue triggers a controlled tissue response there, and this response stimulates the person’s own collagen production. These substances are also called biostimulators. The most commonly mentioned are calcium hydroxylapatite (CaHA), poly-L-lactic acid (PLLA) and polycaprolactone (PCL).

What sets them apart from hyaluronic acid fillers is their aim. According to research, hyaluronic acid gives instant volume, whereas polycaprolactone and poly-L-lactic acid have a longer-lasting effect by stimulating collagen production. With this group, the focus shifts from giving instant volume to the tissue renewing itself biologically: CaHA and PLLA activate cells called fibroblasts and start the formation of new collagen (neocollagenesis).

The three substances do not work in the same way. CaHA microspheres provide immediate structural support and also act as a scaffold for new collagen. PLLA particles are slowly broken down by water (hydrolysis) and stimulate fibroblasts over a long period. PCL is given as microspheres in a carrier gel; it gives both an immediate and a sustained volume effect. According to research, how strong the tissue response will be depends mainly on the physical and chemical properties of the substance and on the size and shape of its particles; injection technique can also affect the result.

Outside the face, these substances are used in treatments that target skin quality and skin laxity on the neck, décolletage, upper arms, abdomen, buttocks and thighs. For their use on the face to add volume and support, see the Liquid Facelift with Collagen Stimulators page; for their use on the backs of the hands, see the Hand Rejuvenation page.

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What is diluted CaHA?

Diluted CaHA is the same substance mixed with more liquid, so that it targets skin quality rather than adding volume. It is also known as highly diluted or hyperdiluted CaHA. Reviews of collagen stimulators note that hyperdiluted CaHA, like PLLA, can be used in many different areas.

A pilot study on the neck and décolletage shows this distinction clearly: highly diluting CaHA makes it possible to use its skin-tightening properties without creating a volume effect. In this study, the dilution ratio was set according to skin thickness, separately for normal, thin and thinned (atrophic) skin. A joint recommendation from a group of experts also links the choice of substance to skin structure: CaHA is recommended for thicker skin and when immediate volume is needed, and PLLA for thinner skin and when the aim is long-term collagen renewal.

What this means for you: the same substance serves a different purpose when it is prepared differently, and the same area does not need the same preparation in two different people. Which substance is used, at what dilution and in which area is decided at your consultation, taking into account your skin thickness and your expectations.

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Neck

Outside the face, the neck is one of the most studied areas for collagen stimulators, but the evidence still rests on small studies. A review of fillers and biostimulators for neck rejuvenation, covering 24 studies and 887 patients, reported that hyaluronic acid, PLLA and CaHA all improved neck wrinkles and skin laxity. However, the results were measured in different ways, participant numbers were small and long-term data are scarce, which makes it hard to reach a firm conclusion.

The data specific to CaHA are on a similar scale. In a study that tested highly diluted CaHA in 20 patients with skin laxity on the neck, an assessment of photographs 3 months after treatment showed significant improvement, and no major adverse events were reported. In a pilot study of 20 people on the neck and décolletage, tissue samples (biopsies) showed increases in type I collagen, elastin and blood vessel formation. According to an international consensus statement on PLLA body treatments, the available data also support a possible benefit in some areas, including the neck.

The front of the neck needs particular care. According to one publication on this subject, injecting PLLA into the front of the neck falls outside the product’s defined intended purpose (off-label use) and can cause nodules (small, firm lumps that can be felt under the skin) to form more often. In addition, the appearance of the neck is not always caused by skin quality; which factor plays the main role is identified at the consultation.

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Décolletage

On the décolletage, collagen stimulators target skin quality and fine wrinkles, not volume. At the clinic, treatment of the décolletage is assessed individually, with the aim of improving skin quality, fine wrinkles and tissue support rather than adding volume. In this area, collagen stimulator treatments such as CaHA or PLLA may also be considered, alongside hyaluronic acid.

Among areas outside the face, the décolletage is one where randomised trials (trials in which participants are randomly assigned to groups) have been carried out. A multicentre randomised trial studied diluted CaHA in women with moderate to severe décolletage wrinkles; the assessors did not know which group each participant was in (blinded assessment). Participants received up to 3 treatments 8 weeks apart or 2 treatments 16 weeks apart. At 16 weeks after the last treatment, an improvement of at least one point on a wrinkle scale was reported in 73.5% of participants. In an open-label randomised trial of PLLA in 30 people (the treatment given was not concealed), two different preparation volumes were compared. Treatments were given up to four times, one month apart. At month 9, most participants showed an improvement of at least one point, and no serious adverse events were reported.

In an open-label PLLA study of 25 women with sun-damaged skin on the décolletage, at the 6-month assessment the assessors reported improvement in 90% of participants, while 57% of participants reported improvement themselves. This difference is worth noting: the improvement a doctor sees on a scale may not be the same as what you see with your own eyes.

Some of these studies involved a few dozen people, and all of them used specific products. The numbers of sessions and the intervals reflect the study protocol, not an individual’s plan. Hyaluronic acid treatments on the décolletage are a separate topic, covered on the Body Fillers page.

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Arms and abdomen

On the upper arms and abdomen, collagen stimulators target skin laxity; the evidence for these areas comes from small case series (studies that follow a small number of patients). In two case series that tested diluted CaHA, each with 10 women, a single treatment was given. On the upper arms, skin elasticity measured with a device had increased significantly at month 3. On the abdomen, skin thickness measured by ultrasound increased by 0.7 mm around the navel and by 0.4 mm on the sides of the abdomen. In both series, 90% of participants and doctors rated the result as much improved or very much improved.

For PLLA, too, the international consensus statement on body treatments states that the available data support a possible benefit in some areas, including the abdomen and upper arms. However, published data on the use of PLLA on the body are still limited.

In these areas, the limit is clear. Marked excess skin, especially after major weight loss, is not something collagen stimulators are designed to treat. According to a review of non-surgical approaches to laxity outside the face, surgery may be considered for people who have had major weight loss. You can find more detail under Limits of this treatment below.

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Buttocks and thighs

Most studies of collagen stimulators on the buttocks and thighs look at cellulite and skin laxity; adding volume is not the subject of these studies. In a double-blind randomised trial (neither the participants nor the assessors knew which side was treated) of 20 women with mild to moderate skin laxity and cellulite on the buttocks and/or thighs, one half of the body was treated and the other half was used as a control. PLLA was injected 3 times, 4 weeks apart, and participants were followed for 330 days. On the treated buttock, a reduction in dimple depth and improvements in skin laxity and in the overall appearance of cellulite were reported; no significant treatment-related side effects were found.

In another study of 31 women that was controlled with a placebo (a dummy treatment), PLLA was used together with subcision. Subcision is a procedure in which bands of connective tissue under the skin are released with a needle. Because both groups had subcision, it is not possible to tell from this study’s abstract alone how much of the improvement came from PLLA.

The area above the knees has also been studied in this context. In a randomised trial of 20 women with skin laxity above the knees, one knee received PLLA and the other a placebo; doctors’ assessments showed a significant improvement. However, there was no significant difference between the two knees in the participants’ own assessments or on the satisfaction scale. The researchers state that larger studies with longer follow-up are needed.

This last finding is a reminder for every use of collagen stimulators: improvement on a rating scale does not always match how you see the result yourself. Adding volume to the buttocks is a separate topic, covered on the Buttock Filler page.

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When does the effect develop, and how many sessions are needed?

With collagen stimulators, you do not see the effect on the day of treatment; it develops over time as new collagen is produced. For this reason, explaining in detail beforehand that results will be delayed is considered a key part of setting realistic expectations. PLLA in particular requires staged sessions to build up a cumulative improvement.

A study that tracked the process with tissue samples (biopsies) shows this timing in the tissue itself: in people who had diluted CaHA on the neck and décolletage, the increase in type I collagen was significant at month 4 and was still present at month 7. With PCL, new collagen formation has been reported to continue for up to 24 months.

Research does not give a single number of sessions. In the studies mentioned above, protocols range from a single treatment (diluted CaHA on the upper arms and abdomen) to up to four treatments one month apart (PLLA on the décolletage), and intervals range from a few weeks to a few months. These are study protocols: they describe what was done in that study, not how many sessions any one person will have. There is a similar caveat about how long the effect lasts; research on neck treatments stresses that long-term evidence is limited. The plan being considered for you and how long the effect is expected to last are discussed at your consultation.

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Limits of this treatment

Collagen stimulators target skin quality and skin laxity. They do not remove excess skin or reposition sagging tissue, and they are not a substitute for surgery. Research on non-surgical and minimally invasive skin-tightening methods, most of them device-based, also states that these treatments will not replace surgery. According to research on non-surgical methods for laxity outside the face, surgery may be considered for people who have had major weight loss.

The second limit concerns measurement. According to a review that took a critical look at facial filler research, the term ‘lift’, which is also widely used in publications on CaHA, PLLA and PCL, has no agreed definition, no accepted measurement standard and no validated threshold for what is clinically meaningful. In addition, all the published numerical measurements reflect changes at the skin surface. This does not mean there is no effect; it shows that the effect has not yet been defined with the precision that the claims made about it would require.

The third limit is the evidence itself. According to the international consensus statement on PLLA body treatments, most of the evidence comes from prospective observational analyses and case series, and injection protocols for different areas need to be standardised. Published data on the use of PLLA on the body are also limited. In a systematic review of biostimulators used in combination with other methods, 29 studies out of 1,237 records met the criteria; because of differences in methods, small samples and inconsistent protocols, the reliability of the findings remained limited.

Finally, longevity: CaHA and PCL are biodegradable substances, and PLLA is also broken down by water over time. So these are not permanent fillers; whether they can be reversed with hyaluronidase depends on the contents of the product (see the section below). Long-term evidence to show how long the effect lasts in areas outside the face is still limited.

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Can it be dissolved with hyaluronidase?

Whether a collagen stimulator can be reversed depends on the contents of the product. Hyaluronidase is an enzyme that breaks down hyaluronic acid molecules, and it is regarded as the preferred option for managing problems (complications) caused by hyaluronic acid fillers. CaHA, PLLA and PCL, however, are not hyaluronic acid, and this enzyme does not dissolve them. In hybrid products that combine hyaluronic acid with collagen-stimulating components, the enzyme can dissolve only the hyaluronic acid component; the collagen-stimulating component stays in the tissue. You can find more detail on the Hybrid Collagen Stimulators page.

A multicentre case series on blood vessel problems caused by non-hyaluronic acid fillers stressed that the lack of an ‘antidote’ for these fillers makes the situation particularly difficult. In this series, hyaluronidase was added to the treatment in two CaHA cases and one PLLA case, and the condition resolved without necrosis (tissue death) or scarring. However, the researchers hypothesise that this effect came from the relaxation of a tightened blood vessel (spasm), not from dissolving the filler. This hypothesis is based on three cases; it is not an established method of reversal.

In practice, this means that if you do not like the result of a CaHA, PLLA or PCL treatment, or the result is different from what was expected, there is no way to reverse it with an enzyme as there is with hyaluronic acid filler. With hybrid products, this option is limited to the hyaluronic acid component. Problems such as nodules are managed in other ways, described in the Known risks section. You can find details of what hyaluronidase does and does not dissolve on the Filler Dissolving page.

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Choosing the layer, area and product

With collagen stimulators, one of the factors that determines both the result and safety is the layer in which the substance is placed. According to research, CaHA and PLLA act mainly in the dermis (the middle layer of the skin) and the connective tissue beneath the skin; a good result requires a precise injection technique in the plane just beneath the skin (subdermal plane). Patient selection and appropriate dilution are also among the factors that determine the result.

Blood vessels are a separate issue. According to an expert consensus statement on CaHA, accidental injection of the substance into a blood vessel can have serious consequences and needs immediate treatment. To reduce this risk, the key points are a good knowledge of the blood vessel anatomy of the face and of the patient’s medical history, and recognising high-risk areas and suitable injection techniques. An area-specific example, PLLA injection into the front of the neck, is described under Neck.

At the clinic, the doctor chooses a needle or a cannula individually, based on the treatment area and the anatomy; no fixed template is used. When a product is assessed, approval by the US Food and Drug Administration (FDA) is not, on its own, the deciding criterion; the assessment is based on the product’s CE marking, its registration and conformity status in Türkiye and the manufacturer’s intended purpose. Before treatment, you can ask which area and which purpose a product is approved for.

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Known risks

A collagen stimulator injection is a medical procedure and has risks. The most common injection-related effects are discomfort, bruising, swelling (oedema) and redness; according to research, these are usually temporary and go away on their own. The main issue specific to these substances, however, is nodules.

With PLLA, papules (small raised bumps) and nodules usually appear a few weeks after the injection. They can usually be felt but not seen, and most go away on their own. They are largely caused by faults in how the substance is prepared or placed. True inflammatory granulomas (clusters of inflamed tissue that the body forms in reaction to a foreign substance) are very rare (0.01%–0.1%); they can appear months or years later and can grow over time. According to a review comparing four biostimulators, nodule formation is most marked with PLLA, and its rate ranges from 4.7% to 28.6% depending on the study.

With CaHA, too, the main issue is nodules. A review of 5,081 treatments in 2,779 patients across 21 publications reported 173 adverse events (3%), and 96% of these were nodules. About half of the nodules occurred in mobile areas known to be prone to nodules; most were not visible and went away without treatment. A systematic review of foreign body granulomas linked to collagen stimulators found that all the collagen stimulators studied could cause this reaction. This reaction was noticed between one week and 15 years after treatment; in most cases, symptoms resolved after surgical removal.

The most serious risk is accidental injection of the substance into a blood vessel. According to the expert consensus statement on CaHA, this can cause tissue death, permanent scarring, visual impairment and blindness. A review of vision loss linked to collagen stimulators reported at least 11 cases of vascular occlusion (a blocked blood vessel) causing visual impairment with CaHA, and 2 confirmed cases of vision loss with PLLA; no blindness was reported with PCL, but one case of a blocked facial artery (embolism) was described. These cases involved treatments on the face. Being rare does not mean that these complications can be reversed when they happen.

Before the procedure, you will be 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. What the risks mean for you is discussed at your consultation, together with your medical history.

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