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.

Smooth, healthy-looking skin is a desired aesthetic goal for all age groups. This study evaluated a new protocol combining non-crosslinked hyaluronic acid (HA) with hydro-exfoliation and infrared technology for improving skin quality parameters. This retrospective, single-center medical data analysis included subjects aged 18 to 65 in good general health, with signs of skin atrophy or aging in the face or neck area. On Day 0, subjects underwent mesotherapy with injections of non-crosslinked HA (18 mg/mL) with 0.01% calcium hydroxyapatite, glycine, and l-proline to a depth of 0.5 to 4 mm. On Day 7, this was followed by treatment with a combined hydro-exfoliation and infrared device. Visual improvements in skin quality parameters (wrinkles, pores, brown spots, texture, and oiliness) were assessed by a blinded evaluator using photographs taken prior to treatment and 2 weeks after the final treatment with a facial analysis imaging system. The medical data analysis included 22 subjects with a mean age of 45 years (range 28 to 65 years). Comparison of post-treatment with baseline images showed improvements in wrinkles of 13%-23%, pores of 16%-30%, skin texture of 15%-28%, and oiliness of 10%-33%; brown spots improved by 0.1%-0.7%. All treatments were well tolerated. In conclusion, the combination of non-crosslinked HA mesotherapy, hydro-exfoliation, and infrared technology led to visible improvements in several skin quality parameters across a wide age range. While the study demonstrated cosmetic benefits, further research is needed to assess the safety profile of these treatments in more detail, as the current methodology was not designed to specifically evaluate device safety.

The use of fillers based on hyaluronic acid in correcting deficits in the upper part of the face, especially in the temporal area, can significantly improve the balance and appearance of the face. Such a procedure, apart from unquestionable aesthetic advantages, carries significant risks, including contour irregularities, vascular occlusion, skin necrosis, hair loss, blindness, stroke, and non-thrombotic pulmonary embolism. To increase the safety and precision of the volumization of the temple area, the technique of administration of the preparation, as well as the product itself, should be carefully selected.