A Systematic Review on the Effectiveness and Safety of Combining Biostimulators with Botulinum Toxin, Dermal Fillers, and Energy-Based Devices.

[INTRODUCTION] Aesthetic medicine has evolved towards minimally invasive procedures, with biostimulators like Poly-L-Lactic Acid (PLLA), Calcium Hydroxylapatite (CaHA), and Polycaprolactone (PCL) gaining attention for their role in collagen induction, improving skin texture, elasticity, and volume. Combining these agents with other treatments-such as botulinum toxin, dermal fillers, and energy-based devices (e.g. laser and radiofrequency therapies)-is hypothesised to provide enhanced aesthetic outcomes. However, studies on the efficacy and safety of these combinations remain sparse and methodologically varied, posing challenges in establishing definitive recommendations.

[METHODS] This systematic review adhered to PRISMA guidelines, involving a thorough literature search across PubMed, MEDLINE, Embase, and Cochrane databases. The search included terms related to biostimulators and combination treatments. Studies meeting inclusion criteria reported clinical outcomes of combined biostimulator treatments, including effectiveness, safety, patient satisfaction, and adverse effects. Key parameters extracted included treatment area, combination protocols, and outcomes. Data synthesis used a narrative approach due to variability in methodologies, treatment protocols, and outcome metrics.

[RESULTS] Out of 1,237 studies initially identified, 29 met the inclusion criteria. These studies included various combinations of biostimulators with botulinum toxin, dermal fillers, and energy-based devices, with sample sizes ranging from 10 to 350 subjects. Treatments combining CaHA or PLLA with energy-based modalities like high-intensity focused ultrasound (HIFU), fractional lasers, and microneedling demonstrated notable improvements in skin texture, elasticity, and contouring, particularly in areas with ageing signs. Adverse events included erythema, bruising, and nodules in 15-30% of cases, with rare but severe complications such as granulomas and vascular occlusions. Management protocols for these events involved corticosteroids, hyaluronidase, or surgical intervention. The review also found a lack of molecular understanding of the synergistic mechanisms.

[CONCLUSION] The review underscores the potential benefits of combined treatments in aesthetic outcomes, though limitations like heterogeneous methodologies, small sample sizes, and inconsistent protocols impact the reliability of findings. Current literature lacks a molecular understanding of the mechanisms underlying these combinations, limiting insights into the longevity and safety of results. Future studies with standardised protocols, objective outcome measures, and detailed molecular analyses are essential for developing evidence-based recommendations for combining biostimulators with other treatments in aesthetic practice.

[LEVEL OF EVIDENCE IV] This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors   www.springer.com/00266 .