Aesthetic medicine has progressed from the early 2000s fascination with bio-stimulation to the current dominance of hyaluronic acid (HA) fillers, prized for immediate, predictable, and reversible volumizing effects. Recently, demand for more natural results, stronger emphasis on skin quality, and increased post-pandemic self-scrutiny have renewed interest in regenerative strategies, sometimes called the “second wave of bio-stimulation.” This trend highlights the need for clearer terminology and a cautious, evidence-based reading of proposed biological mechanisms. This narrative review proposes a framework in which bio-regeneration denotes a hypothesized, controlled induction of physiological processes, fibroblast activation, collagen and elastin synthesis, extracellular matrix remodeling, and immune modulation, potentially producing sustained improvements in dermal structure and function beyond simple filling. Among emerging technologies, polyethylene glycol diglycidyl ether (PEGDE) cross-linking is reported to create a stable, flexible HA scaffold with homogeneous tissue integration, favorable rheology, thermal stability, and a reduced inflammatory profile, supporting safer multimodal use with energy-based devices. The framework is illustrated with PEGDE-crosslinked HA combined with low-concentration calcium hydroxyapatite (CaHA), exemplified by a PEGDE-HA filler containing CaHA microspheres plus glycine and L-proline. These formulations aim to deliver immediate correction via HA and delayed stimulatory effects possibly driven by gradual CaHA exposure and macrophage-associated signaling. Available clinical, imaging, and histological observations, including prospective ultrasound and biopsy assessments, suggest progressive dermal thickening and predominant type I collagen expression, without pathological inflammation or granuloma formation. Although evidence remains preliminary and largely non-comparative, findings are compatible with controlled remodeling and resolving inflammation; however, the underlying mechanism and any ‘regenerative’ versus ‘reparative’ classification require controlled comparative studies.

Background: Hyaluronic acid (HA) hydrogels are the most widely used injectable fillers for facial rejuvenation. A new generation of HA fillers crosslinked with poly(ethylene glycol) diglycidyl ether (PEGDE) has been developed to enhance cohesiveness, tissue integration, stability, and longevity while minimizing swelling and immunogenicity. Owing to their distinct viscoelastic properties, PEGDE-crosslinked HA fillers may require product-specific selection and adapted injection techniques. Objective: The objective of this study is to provide practical, expert-based recommendations for the safe and effective use of PEGDE-crosslinked HA hydrogels in facial aesthetic treatments. Methods: A multidisciplinary panel of nine Italian experts in aesthetic medicine, each with more than 15 years of experience using HA fillers, developed consensus recommendations based on clinical practice and available evidence. A pre-meeting questionnaire informed structured discussions during a face-to-face meeting held in Paris in January 2024. The nominal group technique was applied, with consensus defined as agreement by at least 80% of panel members. Results: Consensus was reached on product selection, injection planes, delivery devices, techniques, and typical treatment volumes for PEGDE-HA hydrogels across multiple facial regions, including the forehead, temples, midface, nasolabial folds, chin, jawline, and lips. Recommended injection techniques included microbolus, macrobolus, and retrograde linear threading, with placement ranging from superficial subcutaneous to supraperiosteal planes depending on the anatomical area and clinical indication. Typical injection volumes generally ranged from 0.1 to 0.5 mL per side. Optional ultrasound mapping was considered beneficial in selected high-risk or superficial procedures to improve anatomical safety. Conclusions: These expert consensus recommendations provide practical guidance for clinicians using PEGDE-crosslinked HA hydrogels in facial rejuvenation. Tailoring product characteristics to injection depth, technique, and regional anatomy may help optimize clinical outcomes and procedural safety. Future research priorities include prospective comparative studies with other crosslinking technologies, standardized reporting of adverse events, long-term outcome registries, and further evaluation of ultrasound-guided injection strategies.

Age-related deterioration of the dermal extracellular matrix is driven primarily by fibroblast dysfunction, leading to loss of collagen integrity, elasticity, and structural support. In aesthetic dermatology, injectable and biostimulatory interventions increasingly target qualitative dermal remodelling, with collagen reorganisation widely adopted as a histological endpoint. Picrosirius red (PSR) staining under polarised light remains the most frequently used method for visualising collagen architecture; however, its birefringence colour patterns are often misinterpreted as proxies for collagen subtype shifts, particularly between types I and III. This conceptual review examines the methodological basis of such interpretations. We summarise the biological roles of major dermal collagens and compare current histochemical, immunohistochemical, ultrastructural and molecular methods for collagen assessment. We propose an interpretative framework that separates architectural collagen remodelling from molecular collagen synthesis and addresses the temporal dissociation between early fibre reorganisation and later subtype-specific expression as a plausible explanation for between-study discrepancies. Practical guidance is provided to support responsible interpretation and reporting of PSR-based collagen analyses. PSR is best regarded as a complementary tool for assessing collagen architecture rather than a definitive method for collagen subtype identification.