1. What is Biostimulator (CaHA・PLLA)
The field of aesthetic medicine continues to shift toward 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."
Biostimulators are agents that, when injected into the body, induce neocollagenesis (the generation of new collagen), improve skin texture, restore elasticity, and provide long-term facial volume replenishment. They have now become an essential tool in aesthetic medicine 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 an inorganic material similar to the components that make up bone and teeth, and is typically suspended in a carrier gel such as glycerin or carboxymethylcellulose before being injected into tissue (Christensen 2009). It provides both a structural filler effect and biostimulator characteristics within the 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, carboxymethylcellulose, and other carriers at the time of injection (Christensen 2009). PLLA breaks down into lactic acid within tissue, which attracts macrophages. Subsequently, the macrophages release growth factors that activate fibroblasts to promote collagen synthesis, exerting its effects through an inflammatory response cascade (Tam 2024).
These injectable agents differ from conventional homogeneous polymer gels (such as common hyaluronic acid) that simply fill space physically and retain moisture; they are also called "stimulators" because part or all of their filler effects depend on the host's foreign body response to microparticles (such as macrophage and foreign body giant cell reactions). Biodegradable microparticles (such as PLLA and CaHA) slowly degrade within the extracellular matrix, providing sustained effects over an extended 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 pairs biostimulators with other established treatments such as hyaluronic acid (HA). This is based on the concept that by simultaneously addressing multiple aspects of the aging process, more comprehensive and sustained aesthetic 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 volumizing effect, but also play an important role in fibroblast signaling and extracellular matrix (ECM) remodeling. HA supports fibroblast activation through binding to CD44 receptors on the cell surface, 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: HA provides immediate hydration and plumping (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 treatment is thought to provide tissues with the dual benefit of immediate physical filling and sustained tissue rejuvenation (Tam 2024).
Synergistic effects of PLLA and HA combination
The combination of PLLA and HA has also been suggested to aid tissue remodeling. As PLLA breaks down into lactic acid and macrophages are mobilized in the collagen generation process, HA can retain moisture and create an environment conducive to fibroblast activity. In this way, combining biostimulator-driven structural improvement and tissue regeneration with direct hydration and volume supplementation provided by HA exerts powerful effects in facial and body contouring (Tam 2024).
3. Evidence for combination treatment
Multiple research results have been reported as specific clinical evidence for combination treatments pairing biostimulators such as CaHA and PLLA with HA fillers (Tam 2024).
Evidence regarding the combination of CaHA and HA fillers
- Godin et al. (2006) study: A study of 72 subjects compared CaHA-based filler monotherapy with combination use of CaHA and HA-based fillers. As a result, patients who received combination treatment reported higher overall satisfaction and were more likely to recommend the treatment to others. This study emphasizes the added value of combining HA filler and CaHA for more comprehensive facial rejuvenation (Tam 2024).
- Chang et al. (2020) study: A study of 25 subjects used CaHA and HA fillers in combination for rejuvenation of nasolabial folds, jawline contour, and the area behind the ears. Consistent improvement in wrinkle severity was observed at both short-term and long-term follow-ups. Furthermore, skin biopsies showed increased dermal collagen bundles without excessive inflammation, suggesting a safe and effective combination for enhancing facial features (Tam 2024).
- Fakih-Gomez et al. (2022) study: A study of 41 subjects used a pre-blended mixture of HA with cohesive polydensified matrix (CPM) technology combined with CaHA. The results showed significant improvement in jawline aesthetics, 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: A study of 8 subjects compared staged injection (time-interval injection) and simultaneous injection of CaHA and CPM-HA fillers. The results suggested that staged injection provided superior skin remodeling effects, as evidenced by robust formation of elastic fibers and angiogenesis (Tam 2024).
- Felix Bravo et al. (2022) study: A study of 15 subjects confirmed by ultrasound that combination of CaHA and HA fillers significantly increased dermal thickness and homogeneity. Additionally, all participants reported high satisfaction (Tam 2024).
Evidence regarding combination use of PLLA and HA fillers
- Faria et al. (2023) study: Evaluated treatment combining collagen biostimulation with PLLA and volume enhancement with HA as a modeling protocol in the buttocks (Glutes). This study also reported no complications and demonstrated contribution to improved buttock appearance and volume enhancement (Tam 2024).
4. Differentiated use by treatment area
Combination use of biostimulators and HA fillers, or their monotherapy use, are differentiated across various areas depending on the anatomical characteristics of the target tissue and the degree of aging.
Facial and perioral areas (contouring and rejuvenation)
Combination treatment for various facial areas is performed to simultaneously improve volume loss accompanying aging and skin Sagging (skin laxity) (Tam 2024).
- Midface, lower face: CaHA and HA are used in combination for hollow cheeks and jawline Sagging (skin laxity). In the Fakih-Gomez et al. study, injection into these areas confirmed improvement in lower facial Sagging (skin laxity) and refined facial contours (Tam 2024).
- Nasolabial fold: For deep nasolabial folds, immediate volume enhancement with HA combined with tissue tightening and long-term collagen generation from 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 (fanning) technique, and HA is injected into the subcutaneous layer, improving facial Sagging (skin laxity) overall and increasing dermal thickness (Tam 2024).
- Post-auricular: In the research by Chang et al., this combination has been shown to be effective for Sagging (skin laxity) and rejuvenation of the skin behind the ears due to aging (Tam 2024).
Trunk and extremities (body contouring)
- Buttocks / Glutes: Faria et al. implement a buttock modeling protocol combining volume restoration with HA and biostimulation with PLLA. This aims to improve tissue quality and contour over a wide area (Tam 2024).
- Neck, décolleté: For wrinkles and reduced skin elasticity around the neck and chest, diluted CaHA or PLLA is often used, and when combined with HA or energy-based devices, it demonstrates high efficacy (Tam 2024).
Nose (non-surgical rhinoplasty)
For nose contour sculpting (non-surgical rhinoplasty), HA or CaHA is frequently used, primarily due to its excellent volume-forming capability and safety profile. According to a meta-analysis by DeVictor et al. (2021), the most commonly used substance for nasal filler injections was HA (75.67% of patients studied), followed by CaHA (18.92%) (DeVictor 2021). A systematic review by Williams et al. (2020) similarly demonstrated 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 (dissolution agent)" called hyaluronidase, which allows for decomposition and correction in case of vascular occlusion or over-injection, making it a safer option (DeVictor 2021). Conversely, CaHA has the advantage of longer duration, but since there is no specific dissolution agent, management of complications is difficult, and some physicians do not recommend the use of CaHA for the nose (Williams 2020). Although there are few large-scale studies on the "combined use" of HA and CaHA for the nasal region, established techniques exist for injecting HA deeply on the periosteum and perichondrium of the nasal anatomy (nasal dorsum, nasal tip, columella, etc.) to create structure (Trevidic 2022).
5. Risks and precautions
Treatments using biostimulators or HA fillers, as well as their combination therapy, offer many benefits but also carry risk of various 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 of treatment and resolving within several days. Management of these symptoms includes ice therapy (icing), use of mild analgesics, and avoidance of strenuous exercise (Tam 2024).
- Edema and delayed erythema: Following treatment, mild to moderate swelling may occur in approximately 20% of patients, typically 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 approaches (Tam 2024).
Severe complications
- Nodules and lumps: In 10–15% of patients, nodules or palpable "lumps" may develop several weeks to months after treatment. This is likely attributable to the biostimulator properties of the filler (foreign body reaction promoting collagen generation). Management strategies include intralesional corticosteroid injection to reduce inflammation, and surgical excision is considered for persistent nodules. For PLLA, massage to assist 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 to address this, and surgical removal is considered for resistant cases (Tam 2024).
- Vascular complications:Although rare, serious vascular complications occur in fewer than 1% of all cases. This results from filler being inadvertently injected into blood vessels (intravascular injection) or compression of vessels due to excessive injection volume. Symptoms include immediate pallor and severe pain (Tam 2024).
- Skin necrosis and vision loss:If vascular occlusion goes untreated, it can lead to catastrophic outcomes including skin necrosis (less than 0.5%) or blindness due to retinal artery occlusion. The nose, glabella, and nasolabial folds are considered high-risk sites for vascular complications (DeVictor 2021)(Trevidic 2022).
Complication management and addressing legal risks:
In cases of HA-related vascular occlusion, management includes immediate high-dose hyaluronidase injection, warm compresses, and vasodilators to improve blood flow. Conversely, for necrosis caused by 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 combination treatments, obtaining complete informed consent from patients regarding potential risks of adverse events is paramount. By clearly documenting and communicating expected results, limitations, and complications including rare but serious outcomes such as granulomas and vascular disorders, realistic expectations can be set and the possibility of patient dissatisfaction and associated medico-legal disputes (medicolegal risk) can be reduced (Tam 2024).
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6. Summary
Treatment combining biostimulators (CaHA or PLLA) with HA fillers is a highly promising approach in aesthetic medicine, as it enables sustained promotion of collagen and elastin production while allowing for immediate volume supplementation. These combinations may deliver more comprehensive and longer-lasting aesthetic improvements compared to single treatments, with high patient satisfaction 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 for long-term efficacy. Additionally, understanding of the mechanisms at the molecular level—how these combinations affect cellular signaling and specific collagen synthesis pathways—remains insufficient (Tam 2024).
To minimize the risk of complications, including applications to anatomically complex and high-risk sites such as the nose, profound anatomical knowledge, appropriate patient assessment, and careful product selection by physicians are essential (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 build evidence-based guidelines for clinical practice (Tam 2024).
About the author of this article
Hiromitsu NakamuraPhysician
Zetith Beauty Clinic Ginza, Osaka, Fukuoka
With a track record of research presentations at domestic and international conferences, he is involved in technical guidance and education across Zetith Beauty Clinic. He specializes in precision aesthetic medicine based on anatomical evidence, pursuing natural-looking results tailored to each individual's skeletal structure and tissues.