1. What is biostimulator (CaHA · PLLA)
The field of aesthetic medicine continues to transition to minimally invasive treatment methods that not only temporarily improve facial appearance but also address the fundamental causes of aging (Tam 2024). At the center of these advances is the "biostimulator."
A biostimulator is an agent injected into the body that induces neocollagenesis (new collagen generation), improves skin texture, restores elasticity, and provides long-term facial volume supplementation. It has become an essential tool in aesthetic medical practice, offering long-lasting, natural-looking results and a high safety profile (Tam 2024).
Representative biostimulator formulations
- Calcium hydroxyapatite (CaHA):CaHA is a microparticle (microsphere) of inorganic material similar to the components that make up bone and teeth, and is typically suspended in a carrier gel such as glycerin or carboxymethyl cellulose for injection into tissue (Christensen 2009). It provides both a structural filler effect and biostimulator properties within tissue, primarily initiating fibroblast activation and collagen synthesis (Tam 2024).
- Poly-L-lactic acid (PLLA):PLLA is a biodegradable synthetic polymer particle that is suspended in mannitol, water, carboxymethyl cellulose, and other substances for injection (Christensen 2009). PLLA breaks down into lactic acid in tissue, which attracts macrophages. Subsequently, macrophages release growth factors, which activate fibroblasts and promote collagen synthesis through a cascade of inflammatory responses (Tam 2024).
These injectables differ from conventional homogeneous polymer gels (such as common hyaluronic acid) that simply fill space and retain moisture; they are also called "stimulators" because part or all of their filler effect depends on the host's foreign body response to microparticles (such as macrophage and foreign body giant cell responses). Biodegradable microparticles (such as PLLA and CaHA) break down slowly within the extracellular matrix, providing sustained effects over a long period (Christensen 2009).
2. Mechanism of combination with HA
As a new trend in aesthetic medicine, there is growing interest in a "combination approach" that combines biostimulators with other established treatments such as hyaluronic acid (HA). This is based on the idea that by simultaneously addressing multiple aspects of the aging process, more comprehensive and sustained cosmetic results can be achieved compared to a single treatment modality (Tam 2024).
Action and role of hyaluronic acid (HA)
HA fillers are primarily known for their immediate volume-enhancement effects, but also play an important role in fibroblast signaling and extracellular matrix (ECM) reconstruction. HA supports fibroblast activation through binding to CD44 receptors on cell surfaces, triggering downstream pathways such as mitogen-activated protein kinase (MAPK). This signaling is thought to promote fibroblast proliferation and collagen deposition (Tam 2024).
Synergistic effects of CaHA and HA combination
By combining CaHA and HA, synergistic effects can be expected in which HA provides immediate hydration and plumpness (volume), while CaHA promotes long-term collagen synthesis through the TGF-β pathway. The mild inflammation induced by CaHA mobilizes macrophages, which then signal fibroblasts to initiate collagen synthesis. Combination therapy is thought to provide tissue with the dual benefits of immediate physical filling and sustained tissue rejuvenation (Tam 2024).
Synergistic effects of PLLA and HA combination
Regarding PLLA and HA combination, effects that assist in tissue remodeling have also been suggested. In response to macrophage mobilization and collagen generation processes accompanying PLLA's breakdown into lactic acid, HA can retain moisture and create an environment suitable for fibroblast activity. Thus, combining structure improvement and tissue regeneration induced by biostimulators with direct hydration and volume supplementation by HA exerts powerful effects in facial and body contouring (Tam 2024).
3. Evidence for combination therapy
As specific clinical evidence regarding combination therapy combining biostimulators such as CaHA and PLLA with HA fillers, the following multiple research results have been reported (Tam 2024).
Evidence regarding combination use of CaHA and HA fillers
- Godin et al. (2006) study: The study compared CaHA-based filler alone versus combined use of CaHA and HA-based fillers in 72 subjects. As a result, patients who received combination treatment reported significantly higher overall satisfaction and were more likely to recommend the treatment to others. This study emphasizes the added value of combining HA fillers and CaHA for more comprehensive facial rejuvenation (Tam 2024).
- Chang et al. (2020) study: In 25 subjects, CaHA and HA fillers were combined for rejuvenation of nasolabial folds, jawline contour, and the area behind the ears. Consistent improvements in wrinkle severity were observed in both short-term and long-term follow-up. Additionally, skin biopsy demonstrated increased dermal collagen bundles without excessive inflammation, suggesting this combination is safe and effective for emphasizing facial features (Tam 2024).
- Fakih-Gomez et al. (2022) study: In 41 subjects, a pre-mixed combination of CaHA and HA using Coherent Pre-Mixed (CPM) technology was used. Significant improvements in jawline aesthetics were observed, with benefits lasting up to 12 months. This study highlights the long-term effects of combining these two fillers for facial contouring (Tam 2024).
- Yutskovskaya et al. (2024) study: In 8 subjects, staged injection (time-staggered injection) of CaHA and CPM-HA fillers was compared to simultaneous injection. The results suggested that staged injection provides superior skin remodeling effects, as evidenced by stronger elastic fiber formation and angiogenesis (Tam 2024).
- Felix Bravo et al. (2022) study: In this study of 15 subjects, ultrasound imaging confirmed that the combination of CaHA and HA fillers significantly increased dermal thickness and homogeneity. All participants also reported high satisfaction (Tam 2024).
Evidence on Combined Use of PLLA and HA Fillers
- Faria et al. (2023) study: This study evaluated treatment combining collagen biostimulation with PLLA and volume enhancement with HA as a modeling protocol for the buttocks (Glutes). This study also reported no complications and demonstrated improvements in buttock appearance and volume enhancement (Tam 2024).
4. Regional Application Guidelines
Combined use of biostimulators and HA fillers, or their individual use, are applied differently across various regions depending on the anatomical characteristics and aging status of the target tissue.
Facial and Perioral Region (Contouring and Rejuvenation)
Combination treatments for various facial areas are performed to simultaneously address volume loss and skin sagging associated with aging (Tam 2024).
- Midface, lower face: CaHA and HA are combined for sunken cheeks and jawline sagging. In the Fakih-Gomez et al. study, injection into these areas confirmed improvement in lower facial sagging and definition of the face line (Tam 2024).
- Nasolabial fold: For deep nasolabial folds, immediate volume enhancement by HA combined with tissue tightening and long-term collagen stimulation by CaHA is effective (Tam 2024).
- Temporal, malar, and jaw regions:In the protocol by Felix Bravo et al., CaHA is injected into these areas using a fan technique, and HA is injected into the subcutaneous layer, improving overall facial Sagging (skin laxity) and increasing dermal thickness (Tam 2024).
- Post-auricular:Chang et al.'s research demonstrates that this combination is effective for age-related skin laxity and rejuvenation behind the ears (Tam 2024).
Trunk and extremities (body contouring)
- Buttocks / Glutes:Faria et al. implement a gluteal modeling protocol combining HA volume replenishment with PLLA biostimulation. This aims to improve tissue texture and contours over a wide area (Tam 2024).
- Neck, décolleté:For wrinkles and loss of skin elasticity in the neck and décolleté regions, CaHA or PLLA are often used in diluted form, achieving high efficacy when combined with HA or energy-based devices (Tam 2024).
Nose (non-surgical rhinoplasty)
For nasal contour sculpting (non-surgical rhinoplasty), HA or CaHA are commonly used, primarily due to their strong volume-forming capability and safety profile. According to a meta-analysis by DeVictor et al. (2021), the most commonly used substance for nasal filler injection was HA (75.67% of patients), followed by CaHA (18.92%) (DeVictor 2021). A systematic review by Williams et al. (2020) similarly showed that HA (73.38%) and CaHA (12.44%) are the mainstream fillers for the nose (Williams 2020).
In nasal injections, HA has a 'reversal agent (dissolving agent)' called hyaluronidase, which allows decomposition and correction in the event of vascular occlusion or overfilling, making it a safer option (DeVictor 2021). In contrast, while CaHA has the advantage of longer duration, it lacks a specific dissolving agent, making complication management difficult, and some physicians do not recommend using CaHA on the nose (Williams 2020). Although there are few large-scale studies on the 'combined use' of HA and CaHA on the nose, techniques have been established for injecting HA deeply on the periosteum and perichondrium to create structure according to nasal anatomy (nasal dorsum, nasal tip, nasal columella, etc.) (Trevidic 2022).
5. Risks and precautions
Treatments using biostimulators or HA fillers, as well as their combination therapies, offer many benefits but carry various risks of complications. Appropriate patient selection and post-treatment monitoring are essential (Tam 2024).
Mild to moderate complications
- Erythema and bruising:When CaHA or PLLA is combined with HA or energy-based treatments, temporary erythema and mild bruising at the injection site are frequently reported. Erythema may be observed in approximately 30% of patients, typically appearing within hours after treatment and resolving within days. Management of these symptoms includes cold compress (icing), use of mild analgesics, and avoidance of strenuous exercise (Tam 2024).
- Swelling and delayed erythema:After treatment, mild to moderate swelling may occur in approximately 20% of patients, usually resolving within one week. However, in some cases (approximately 15%), delayed erythema persisting beyond two weeks may be observed. Such persistent inflammation requires management with topical corticosteroid application, among other measures (Tam 2024).
Severe complications
- Nodules and lumps:In 10–15% of patients, nodules or palpable 'lumps' may develop weeks to months after treatment. This likely results from the biostimulator properties of the filler (foreign body reaction promoting collagen production). Management strategies include intralesional corticosteroid injection to reduce inflammation, and surgical excision is considered for persistent nodules. For PLLA, massage to facilitate product distribution is recommended (Tam 2024).
- Granulomas: Several months after treatment, granulomas or firm inflammatory nodules may form in 3–5% of cases. High-dose steroid injections are administered for these as well, and surgical removal is considered in resistant cases (Tam 2024).
- Vascular complications: While rare, severe vascular complications occur in fewer than 1% of all cases. This results from filler being accidentally injected into blood vessels (intravascular injection) or compression of blood vessels due to excessive injection volume. Symptoms include immediate blanching and severe pain (Tam 2024).
- Skin necrosis and vision loss: If vascular occlusion is left untreated, it may lead to catastrophic outcomes such as skin necrosis (less than 0.5%) or blindness from retinal artery occlusion. The nose, glabella, and nasolabial folds are particularly high-risk sites for vascular complications (DeVictor 2021) (Trevidic 2022).
Management of complications and response to legal risks
In cases of vascular occlusion related to HA, management includes immediate administration of high-dose hyaluronidase, warm compresses, and use of vasodilators to improve blood flow. Conversely, in cases of necrosis from CaHA, hyaluronidase is ineffective, so supportive care including oral antibiotics, local wound care, and hyperbaric oxygen therapy as needed is necessary (Tam 2024).
Additionally, when performing these combined treatments, obtaining complete informed consent from patients regarding potential risks of adverse events is most important. By clearly documenting and communicating expected results, limitations, and complications including rare and serious outcomes such as granulomas and vascular disorders, and by establishing concrete procedures for managing them, realistic expectations can be set and the possibility of patient dissatisfaction and associated legal disputes (medicolegal risks) can be reduced (Tam 2024).
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6. Summary
Treatment combining biostimulators (CaHA or PLLA) with HA filler is a highly promising approach in aesthetic medicine, as it enables sustained promotion of collagen and elastin generation while allowing immediate volume supplementation. These combinations have the potential to deliver more comprehensive and long-lasting aesthetic improvements compared to single treatment modalities, and high patient satisfaction has been reported in numerous studies (Tam 2024).
However, current literature has several limitations, including heterogeneity in treatment protocols, small sample sizes, and lack of objective metrics regarding long-term efficacy. Additionally, understanding of the molecular-level mechanisms—specifically how these combinations affect cellular signaling and specific collagen-generation pathways—remains incomplete (Tam 2024).
Physician expertise in deep anatomical knowledge, appropriate patient evaluation, and careful product selection are essential to minimize the risk of complications, including applications to anatomically complex and high-risk sites such as the nose (Trevidic 2022). Going forward, further long-term research using standardized protocols and advanced histological and molecular analysis are needed to fully establish safety and efficacy, and to develop evidence-based guidelines for clinical practice (Tam 2024).
Author of this article
Hiromitsu NakamuraPhysician
Zetith Beauty Clinic Ginza, Osaka, Fukuoka
With a track record of research presentations at domestic and international academic conferences, and involved in technical guidance and education across Zetith Beauty Clinic. Specializing in precision aesthetic medicine based on anatomical evidence, pursuing natural results tailored to each individual's skeletal structure and tissues.