Evidence-Based Aesthetics 2025: A Comprehensive Review of the Efficacy and Safety of Fillers (HA, PLLA, CaHA) and Peels

This analysis synthesizes the latest high-level evidence, primarily from systematic reviews and randomized controlled trials (RCTs) spanning 2015 to 2025 (US/Global), covering hyaluronic acid (HA), Poly-L-lactic acid (PLLA), Calcium Hydroxylapatite (CaHA), chemical peels, and emerging biostimulators. Clinicians must leverage this evidence to ensure optimal patient selection, robust safety protocols, and compliance in an environment marked by rapid innovation and evolving regulatory scrutiny.

Disclaimer: Not Medical Advice
The information contained in this article is for informational and educational purposes only for medical professionals, medspas, and distributors. It is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of a qualified healthcare provider with any questions you may have regarding a medical condition or treatment.

What’s New This Year — Big Picture

The aesthetic medicine field continues to solidify its evidence base, particularly concerning injectable dermal fillers and chemical peels, with Level 1a evidence supporting the efficacy and safety of HA and CaHA for major indications (US/Global, 2024–2025). A major trend observed is the strong evidence supporting biostimulatory effects, as seen with PLLA, which has demonstrated superior long-term results compared to HA fillers for volume correction, with sustained improvements extending beyond 25 months.

HA fillers remain foundational, characterized by predictable efficacy and a high safety profile, with systematic reviews confirming that most adverse events (AEs) are transient injection site reactions. Conversely, modalities like Polynucleotides (PN) and Exosomes highlight the need for caution; while PN shows promising early results, rigorous, high-quality studies are essential to validate optimal use and long-term safety. Furthermore, US clinicians must remain compliant with explicit FDA warnings regarding unapproved modalities, such as injectable exosome products (US, July 2020/April 2024).

Evidence Highlights by Modality

Hyaluronic Acid (HA) Fillers

HA fillers provide robust Level 1a evidence for nasolabial folds and lip augmentation (US/Global, 2024). A systematic review analyzing 48 high level of evidence studies confirmed that HA dermal fillers are generally safe and effective, with most adverse events being mild to moderate and transient.

Key Efficacy Outcomes & Durability

A recent multicenter, randomized, evaluator-blinded study on Resilient Hyaluronic Acid Redensity (RHAR) demonstrated its efficacy for correcting moderate-to-severe dynamic perioral rhytides. The treatment group achieved a statistically significant superiority over the no-treatment control group at Week 8 (80.7% vs 7.8% responder rate, $p < .0001$). The effect showed marked durability, with 66% of subjects in the pooled population maintaining a clinical response at the 52-week study completion (US/Canada, 2021). Subject satisfaction remained consistently high, peaking at 91.8% at Week 4 and staying at 88.3% at Week 52.

Notable Adverse Events (AEs)

Expected reactions, such as injection site pain, erythema, and swelling, occur in 85–99% of patients but are mild, resolve spontaneously, and typically last less than 15 days. Severe adverse events, most notably vascular occlusion, are extremely rare, occurring in less than 0.05% of procedures, necessitating immediate emergency protocols. HA filler complications are categorized into three groups: expected reactions, product or technique-related adverse events, and severe adverse events.

Technique Caveats

The RHAR product utilized in the study for dynamic perioral rhytides had a low degree of modification (MoD 2%) and a HA concentration of 15 mg/mL, designed to adapt to facial dynamics. For optimal results in this mobile area, intradermal injection using techniques like blanching serial puncture, linear threading, or cross-hatching was advised.

Poly-L-Lactic Acid (PLLA) Biostimulators

PLLA fillers (e.g., Sculptra) are supported by Level 1b evidence (Moderate-High Certainty) for facial volume correction, especially where long-term biostimulation is desired.

Key Efficacy Outcomes & Durability

PLLA operates by stimulating neocollagenesis, leading to a natural and semi-permanent correction of volume loss. A systematic review of 11 RCTs (2024) confirmed sustained aesthetic effects through at least 25 months, demonstrating superior long-term outcomes compared to other fillers in some comparative studies. For instance, PLLA demonstrated $90.57%$ efficacy for midfacial volume correction in a superiority trial (2024, Global). FDA indications (US) currently include correction of deep nasolabial folds, HIV-related lipoatrophy, and, recently, fine wrinkles in the cheek region (2023).

Notable Adverse Events (AEs)

Most adverse events are mild-to-moderate and self-limiting, including bruising, hematoma, tenderness, and edema, typically resolving within 1–3 days (15–30% incidence). Delayed events, such as subcutaneous papules and nodules, can occur weeks to months later and are often related to inadequate product reconstitution or insufficient post-injection massage. One study reported subcutaneous nodules in $41%$ of the studied population, highlighting the importance of proper technique.

Technique Caveats

Proper reconstitution is mandatory for optimal safety, requiring adequate mixing time (2 to 72 hours, though recent findings suggest immediate use may not alter efficacy, pending manufacturer protocol adherence) and appropriate diluent volume (e.g., 8 mL sterile water + 1 mL lidocaine, total 9 mL). Post-application massage is recommended to dissolve potential nodules.

Calcium Hydroxylapatite (CaHA)

CaHA (e.g., Radiesse) is a biocompatible, biodegradable, and biostimulatory filler supported by strong evidence (Level 1a-1b) for indications such as jawline contouring and nasolabial fold correction (Global, 2024).

Key Efficacy Outcomes & Durability

CaHA demonstrated superiority over human collagen and non-animal stabilized HA (NASHA) in terms of efficacy and durability for correcting nasolabial folds (Global, 2007–2008). It is effective for structural support, with long-term studies showing responder rates maintained through 60 weeks for jawline contouring. CaHA stimulates fibroblast activity, resulting in increased collagen I, angiogenesis, and elastin synthesis, supporting its biostimulatory properties.

Notable Adverse Events (AEs)

The overall AE rate is approximately 3% across large cohorts. Most are local and self-limiting injection site reactions. Nodules are the most common AE, especially when injected too superficially or in dynamic areas like the lips or periorbital region.

Technique Caveats (Off-Label Context)

Diluted or hyperdiluted CaHA is widely used (off-label context) to improve skin laxity and quality, employing dilution ratios of 1:1 or $\ge 1:2$ with a diluent. While this approach is supported by a global consensus of experts and retrospective experience showing good results, no randomized controlled trials (RCTs) have been published to definitively prove the efficacy and safety of diluted/hyperdiluted CaHA for biostimulation (Global, 2024). For on-label use, CaHA may be injected subdermally or supraperiosteally, with experts recommending the use of a cannula (22G or 25G preferred) in certain areas to mitigate vascular risk.

Polynucleotides (PN/PDRN)

Polynucleotides represent an emerging category of biostimulators used for biorevitalization and skin rejuvenation.

Efficacy and Clinical Status (Low Certainty)

Evidence for PN is currently limited (Level 2b-3, Low-Moderate Certainty). A systematic review (2025) synthesized findings from nine low-to-moderate quality studies involving 219 patients and reported promising outcomes for reducing wrinkles, improving skin texture, and enhancing elasticity. However, procedural characteristics (injection areas and techniques) showed significant variation, and limited consensus exists regarding optimal use.

Safety

PN injections are generally reported as well tolerated, with side effects being mild and transient, similar to other injectables, but long-term safety data is currently limited. The need for rigorous, high-quality RCTs is emphasized to validate the effectiveness and safety of PN.

Chemical Peels

Chemical peels are supported by Moderate Certainty evidence (Level 1b-2a) for acne vulgaris and other indications.

Key Efficacy Outcomes

A systematic review (2018, Global) of 12 RCTs involving 387 participants concluded that chemical peeling is an overall effective method for treating mild-to-moderate acne vulgaris. Glycolic acid (GA) peeling was superior to placebo for achieving excellent or good improvement in all lesions (RR 2.30; 95% CI 1.40 to 3.77). Generally, commonly used peels (Trichloroacetic Acid [TCA], Salicylic Acid [SA], GA, Jessner’s Solution [JS]) appear to be similarly effective for acne. However, SA peeling demonstrated superiority over JS peeling for reducing comedones (53.4% vs 26.3%, $p=0.001$). The combination of SA and mandelic acid (MA) peeling was superior to GA peeling in improving the total acne score (85.3% vs 68.5%, $p<0.001$).

Technique Caveats & AEs

Superficial peels are typically used for acne vulgaris, while deep peels are reserved for acne scars. All chemical peels evaluated were reported as well tolerated. Common AEs include transient burning or stinging sensations, erythema, scaling, topical edema, or dryness. Hyperpigmentation (PIH) was a rare AE reported by patients treated with TCA, SA, and JS peels, and the risk of PIH is higher in individuals with Fitzpatrick skin types IV–VI.

Radiofrequency Microneedling

Radiofrequency (RF) Microneedling provides consistent skin texture improvements, supported by Moderate Certainty evidence (Level 2b).

Key Efficacy and Safety

Clinical trials demonstrate 25–75% improvement in periorbital wrinkles sustained through 6 months. The procedure is generally well-tolerated, with an average pain score of 2.2/10 in one study. AEs are mostly transient, including universal erythema lasting 24–72 hours and mild swelling, with minimal reported serious adverse events.

Safety Signals & Risk Mitigation

Effective risk mitigation is based on adhering to standardized protocols informed by surgical and anatomical principles (US/Global, 2021).

Vascular Occlusion and Blindness

Vascular occlusion with dermal fillers (especially HA) is a rare but critical medical emergency, with HA fillers associated with less than 0.05% serious vascular events.

Prevention Strategies

The American Society for Dermatologic Surgery (ASDS) Task Force strongly recommends several strategies to reduce the risk of vascular occlusion and visual compromise (Strong recommendation, Moderate certainty evidence):

1. Anatomical Knowledge: Maintain a thorough knowledge of facial vascular anatomy, recognizing that variability exists.
2. High-Risk Areas: Be aware that the glabella, medial brow, nose, forehead, superior nasolabial fold, and medial tear trough carry a higher risk for blindness. Avoid deep, preperiosteal injection in locations where arteries lie on bone (e.g., medial brow/glabella, medial canthus).
3. Injection Technique: Inject slowly with low plunger pressure, using small volumes (e.g., 0.1 to 0.2 mL) with each pass, and keep the cannula or needle moving.
4. Device Choice: Strongly consider using a 25G blunt-tipped cannula or larger where possible, as they are less likely to perforate vessels than smaller needles in cadaver models.
5. Aspiration (Reflux Test): Retraction of the plunger before injection is recommended; however, a negative reflux test does not definitively exclude intravascular placement.

Management of Occlusion

Immediate recognition and intervention are paramount for vascular occlusion (Strong recommendation, Moderate certainty evidence).

1. Immediate Action: Stop injection immediately upon observing vascular compromise, such as tissue blanching or severe, disproportionate pain.
2. Hyaluronidase: Inject high-dose hyaluronidase promptly into the ischemic area (150–1500 IU suggested). Hyaluronidase is the most specific intervention for reversing HA vascular occlusion, although dosage consensus is lacking. Due to the enzyme’s short half-life, repeat injections should be considered.
3. Blindness Protocol: If signs of visual compromise are present, immediately conduct a visual status evaluation, inform the patient, and contact an eye expert. High-dose hyaluronidase should be injected quickly into the affected area and along the path of arteries leading to the eye.

Nodules and Delayed Inflammatory Reactions

Nodule formation is a rare but reported serious AE for all fillers, including PLLA, CaHA, and HA.

Prevention

Prevention involves meticulous technique and patient history (Strong recommendation, Low certainty evidence):

• Screening: Obtain a thorough history regarding autoimmune diseases, active facial infection, recent dental work, or immunizations. Patients should avoid dental procedures or immunizations for greater than 2 weeks both before or after filler procedures.
• Technique: Adopt aseptic technique and use the smallest possible bolus (0.1 to 0.2 mL).
• Post-Care: Provide patient education to avoid manipulation of the area post-procedure.
  Management of Nodules (Conditional recommendation, Low certainty evidence)
• Early Noninflammatory Nodules (HA): Often due to superficial placement or overcorrection; may be treated with reassurance or intralesional hyaluronidase if bothersome.
• Delayed Inflammatory Nodules (HA): Onset is typically 2 weeks to 6 months post-injection. If infection is suspected (warmth, drainage), incision, drainage, and broad-spectrum antibiotics are recommended. Oral corticosteroids may be used initially for non-infectious inflammatory nodules.
• PLLA Nodules: These often resolve spontaneously over months to years. Troublesome nodules may be treated with intralesional triamcinolone, potentially combined with 5-fluorouracil (5-FU).
• CaHA Nodules: These also usually resolve spontaneously. For persistent cases, intralesional injection of aqueous solutions combined with vigorous massage is recommended, with early evidence supporting the use of sodium thiosulfate (US, 2020). CaHA cannot be reversed with hyaluronidase.

Regulatory Snapshot (US/EU/UK/JP)

Regulatory oversight confirms that multiple formulations of HA, CaHA (Radiesse), and PLLA (Sculptra) are FDA-approved (US, 2025) for specified facial indications, including volume correction and wrinkles. PLLA is approved for HIV-related lipoatrophy and aesthetic volume correction. CaHA has specific FDA clearance for facial wrinkles and folds, and jawline treatment.

Exosome and Enzyme-Based Injectables Alert

Clinicians must be acutely aware of the regulatory status of emerging treatments:

• Exosomes: Exosomes remain investigational with no FDA-approved injectable products for any aesthetic indication in the US (July 2020, April 2024). The clinical use of exosomes is currently limited to topical applications, and injectable use outside of approved clinical trials is considered illegal and carries significant regulatory risk.
• Enzyme-Based Injectables (Non-HA reversing): These modalities lack sufficient clinical evidence and clear regulatory pathways for safety recommendations in most jurisdictions.

Practice Implications

Evidence supports tailoring treatment selection based on the desired outcome and durability.

• Immediate Volume Restoration: HA fillers are the first-line choice, offering immediate results and reversibility via hyaluronidase.
• Long-Term Biostimulation: PLLA is ideal when durability beyond 18 months is desired, achieving sustained dermal thickness and volume enhancement.
• Structural Support and Contouring: CaHA is indicated for creating structural support, such as jawline contouring, based on Level 1a evidence.
• Skin Quality Improvement: Chemical peels offer a strong evidence base for improving skin texture and treating acne. RF microneedling provides consistent results for skin tightening and wrinkles.

Counseling Points & Informed Consent

Comprehensive patient assessment and detailed informed consent are crucial risk mitigation strategies. Consent must cover realistic outcomes, expected transient reactions, and rare but serious complications, including vascular occlusion and the potential need for hyaluronidase (for HA). Clinicians should explicitly discuss that treatments involving off-label use (e.g., diluted CaHA) or investigational modalities (e.g., PN, Exosomes) have limited high-quality evidence supporting their claims.

Gaps & What to Watch Next (6–12 months)

While high-level evidence exists for core modalities, several gaps remain, requiring future high-quality RCTs to inform optimal practice.

• PLLA Quality of Evidence: Although PLLA shows high efficacy, the underlying evidence is often classified as low quality due to methodological flaws (e.g., inadequate randomization) in included RCTs. Future studies must adopt standardized methodologies and proper blinding to reduce bias.
• Polynucleotides: Robust RCTs are urgently needed to validate the efficacy, safety, and optimal treatment regimen for PN agents, moving beyond the current limited consensus derived from low-to-moderate quality studies.
• CaHA Dilution: While expert consensus supports the use of dilute/hyperdiluted CaHA for skin tightening (off-label context), methodologically rigorous RCTs are required to substantiate these claims and optimize regimen recommendations.
• Exosome Trials: The first FDA-approved investigational exosome trial launched recently (US, 2025), signaling potential regulatory pathways, but these products remain strictly investigational outside of approved protocols. Clinicians should monitor these Phase 1 results closely.
• Safety Surveillance: Priority areas include comparative effectiveness research, enhanced safety surveillance systems, and improved early recognition protocols for complications.

Conclusion

The aesthetic medicine market is defined by rapid technical advancements underpinned by increasing, albeit variable, levels of clinical evidence. HA and CaHA fillers demonstrate robust, high-certainty efficacy for volume and contouring, with PLLA securing its role as a superior long-term biostimulator. However, the reliance on low-quality evidence for emerging modalities like Polynucleotides necessitates cautious adoption and thorough patient counseling regarding expected outcomes. Safety remains paramount, requiring mandatory adherence to rigorous risk mitigation strategies for vascular occlusion, emphasizing anatomical knowledge, aspiration, and immediate access to hyaluronidase for HA complications (US/Global, 2021). What matters next quarter for clinics and doctors is prioritizing investment in continuous anatomical and complication management training, while demanding and monitoring high-quality, long-term RCTs for newer biostimulatory agents to solidify evidence-based protocols.

References

1. (Kyriazidis et al., 2023) Adverse Events Associated with Hyaluronic Acid Filler Injection for Non-surgical Facial Aesthetics: A Systematic Review of High Level of Evidence Studies. Aesthetic Plast Surg. 2024 Feb;48(4):719-741. doi: 10.1007/s00266-023-03465-1.
2. (Chen et al., 2018) Chemical peels for acne vulgaris: a systematic review of randomised controlled trials. BMJ Open. 2018 Apr 28;8(4):e019607. doi: 10.1136/bmjopen-2017-019607.
3. (Sundaram et al., 2021) Efficacy and Safety of a New Resilient Hyaluronic Acid Filler in the Correction of Moderate-to-Severe Dynamic Perioral Rhytides: A 52-Week Prospective, Multicenter, Controlled, Randomized, Evaluator-Blinded Study. Dermatol Surg. 2022 Jan;48(1):87–93. doi: 10.1097/DSS.0000000000003238.
4. (FDA, 2020/2024) Consumer Alert on Regenerative Medicine Products Including Stem Cells and Exosomes. FDA. Content current as of 04/09/2024.
5. (Signori et al., 2024) Efficacy and Safety of Poly-l-Lactic Acid in Facial Aesthetics: A Systematic Review. Polymers. 2024 Sep 11;16(18):2564. doi: 10.3390/polym16182564.
6. (Guida & Galadari, 2024) A systematic review of Radiesse/calcium hydroxylapatite and carboxymethylcellulose: evidence and recommendations for treatment of the face. Int J Dermatol. 2024 Feb;63(2):150-160. doi: 10.1111/ijd.16888.
7. (ASDS Task Force, 2021) Preventing and Treating Adverse Events of Injectable Fillers: Evidence-Based Recommendations From the American Society for Dermatologic Surgery Multidisciplinary Task Force. Dermatol Surg. 2021 Jan;47(1):1–20. doi: 10.1097/DSS.0000000000002921.
8. (Lampridou et al., 2025) The Effectiveness of Polynucleotides in Esthetic Medicine: A Systematic Review. J Cosmet Dermatol. 2025 Feb;24(2):e16721. doi: 10.1111/jocd.16721.

FAQ

Q: What is the highest level of evidence supporting the use of HA fillers?

A: HA fillers are supported by robust Level 1a evidence for indications like nasolabial folds and lip augmentation (Global, 2025). A systematic review analyzing 48 high level of evidence studies confirmed that HA fillers are generally effective and safe.

Q: Is the injection of exosomes currently FDA approved in the U.S.?

A: No. Exosomes remain an investigational modality, and there are currently no FDA-approved injectable exosome products for any aesthetic indication (US, July 2020/April 2024). Injectable use outside of approved clinical trials carries significant regulatory risk.

Q: How does PLLA compare to HA fillers in terms of durability?

A: PLLA demonstrates superior long-term biostimulatory effects compared to HA fillers, with effectiveness for midfacial volume correction maintained through at least 25 months post-treatment (Global, 2024). This difference is attributed to PLLA’s mechanism of action, which actively stimulates neocollagenesis.

Q: What is the primary risk mitigation technique recommended during high-risk filler injections?

A: The ASDS Task Force strongly recommends having a thorough knowledge of facial vascular anatomy, employing slow injection speeds with small volumes, and preferably using a 25G blunt-tipped cannula or larger, especially in high-risk areas like the glabella or nose. Immediate access to hyaluronidase is essential for managing vascular occlusion.

Q: Is diluted Calcium Hydroxylapatite (CaHA) supported by high-quality evidence?

A: The use of diluted or hyperdiluted CaHA for skin tightening is supported by global expert consensus and retrospective experience, but this remains an off-label context without published Randomized Controlled Trials (RCTs) (Global, 2024). While initial results are positive, more robust RCTs are needed to optimize regimens and confirm long-term safety.