Ting Song Lim

Background: Energy-based aesthetic devices alter tissue temperature across defined spatial and temporal distributions, producing biological effects commonly described as collagen contraction, neocollagenesis, elastogenesis, adipocyte injury, or tissue tightening. These clinical labels encompass distinct processes including protein damage, cellular stress adaptation, inflammation, cell death, extracellular matrix turnover, and long-term remodeling. Heat-shock proteins (HSPs) and mammalian cold-shock proteins provide a mechanistic framework for interpreting these responses. Objective: To evaluate the roles of heat- and cold-responsive proteins in energy-based aesthetic medicine and propose a temperature–time–depth framework linking device-specific tissue exposure to molecular, histological, and clinical responses. Materials and Methods: A structured narrative review was conducted using targeted PubMed searches and examination of reference lists from pivotal mechanistic and human-tissue studies. Literature through August 2026 was considered. Priority was given to studies reporting tissue-temperature measurements, human skin biopsies, spatial histology, protein or RNA measurements, controls, serial assessments, and late clinical or structural outcomes. Results: Heat activates heat-shock factor 1 and induces HSP70, HSP27, HSP90, and other chaperones. HSP47 (SERPINH1) is particularly relevant to dermal remodeling because it is an endoplasmic reticulum collagen chaperone required for procollagen folding, trafficking, and secretion. Human studies of fractional laser and radiofrequency, together with emerging microfocused ultrasound histology, support a sequence in which early stress and inflammatory responses precede HSP47-positive fibroblast recruitment and matrix remodeling. However, HSP induction alone does not establish durable clinical tightening, and excessive thermal exposure may cause necrosis, fibrosis, scarring, dyschromia, or injury to nerves and fat. Mammalian cold adaptation involves cold-inducible RNA-binding protein (CIRBP/CIRP) and RNA-binding motif protein 3 (RBM3), best characterized during sustained mild hypothermia near 32°C–34°C. These proteins regulate RNA stability, translation, metabolism, and cell survival. Their adaptive intracellular functions must be distinguished from profound cold injury and extracellular CIRP-mediated inflammation. Direct evidence linking aesthetic cooling to CIRBP- or RBM3-mediated dermal neocollagenesis remains insufficient. Conclusions: Mechanistic interpretation should be based on measured biological dose, tissue compartment, and response timing rather than console temperature, surface temperature, or device category alone. Heat-shock mechanisms are supported for several thermal modalities, whereas cold-shock-mediated aesthetic neocollagenesis remains a translational hypothesis requiring direct molecular, histological, and clinical validation.

Background: Dermal fillers composed of hyaluronic acid (HA) combined with glycerol have been clinically shown to enhance skin hydration and quality; the precise mechanisms underlying their efficacy have yet to be fully elucidated. Aims: Investigation of the dual hydration mechanisms, cell protection and tolerability, and tissue compatibility of the cohesive polydensified matrix (CPM) filler containing HA and glycerol (CPM‐HA20G), focusing on glycerol's unique role. Methods: Primary normal human epidermal keratinocytes, in vitro skin, ex vivo human skin models, and an in vivo study were used to evaluate CPM‐HA20G, with additional assessments of its humectant, glycerol. Comparisons were further made with a cross‐linked HA filler containing sorbitol (HA12.5S) indented for similar use, as well as with the humectants sorbitol and mannitol. Gene expression analysis, protein analysis, cell‐based assays, 3D micro‐computed tomography (μCT), TEWL, corneometry, and histology were performed to assess aquaporin‐3 (AQP3) modulation, cellular stress levels, protection from UVB—or H ₂ O ₂ ‐induced oxidative stress, hydration dynamics, tissue integration, and inflammation. Results: CPM‐HA20G immediately increased hydrated tissue volumes by 40% within 10 min and 63% after 120 min post‐injection, as measured via μCT indicating improved inner tissue hydration. Progressively, CPM‐HA20G increased surface hydration values from the inside out, whereas the glycerol component of CPM‐HA20G contributing a pronounced hydration effect. Glycerol uptake in keratinocytes occurred without upregulating AQP3 expression, in contrast to sorbitol and mannitol, which triggered AQP3 overexpression ( p < 0.001), along with the cellular stress marker, phosphorylation of P38 (pP38) ( p < 0.0001) and reduced keratinocyte viability ( p < 0.001, p < 0.01). Similarly, AQP inhibition by DFP00173 or phloretin elicited a comparable P38 stress response, which was attenuated by glycerol treatment. Compared to sorbitol and mannitol, glycerol demonstrated well cellular tolerability. Glycerol treatment reduced UVB—or H ₂ O ₂ ‐induced reactive oxygen species (ROS) in keratinocytes by 68% ( p < 0.0001), highlighting its antioxidative capacity. Furthermore, histological analysis verified improved tissue integration and reduced inflammatory response for CPM‐HA20G relative to the HA‐filler HA12.5S containing sorbitol. Conclusions: This preclinical study demonstrates that CPM‐HA20G achieves rapid tissue hydration via a dual hydration mechanism and is well tolerable with favorable tissue integration. Glycerol was found to play a unique role in enhancing hydration without inducing stress responses, providing antioxidative capacity and cell protection. These findings provide a mechanistic basis for the clinical efficacy of CPM‐HA20G.

Background: The concept of “natural outcomes” in filler treatments has been explored in clinical studies and literature, yet remains loosely defined, subjective, and lacks standardized assessment criteria. Aims: To propose a multidimensional Natural Outcomes Framework to systematically define, assess, and communicate natural outcomes following hyaluronic acid (HA) filler treatment, facilitating attainment of desired results. Methods: An international aesthetic multidisciplinary panel developed consensus statements and a practical framework for achieving safe and natural outcomes with HA fillers based on insights from a literature review, survey, and expert meeting. Results: This expert consensus emphasizes safety as a foundational aspect of natural outcomes. The framework extends beyond visual outcomes (“See”) to encompass tactile (“Touch”), experiential (“Feel”) and expressive (“Express”) dimensions of naturalness, which can be assessed by various methods. The panel identified three categories of factors affecting natural outcomes: product, patient, and injector factors. Treatment can be optimized by selecting HA fillers with biomimetic design, suitable rheological properties, and low inflammatory potential; ensuring knowledge and technical competency; individualizing treatment plans; and fostering effective communication. A practical clinical workflow was devised to guide the attainment and assessment of safe and natural outcomes from pre‐treatment to follow‐up. Conclusions: The Natural Outcomes Framework offers a structured approach to achieving safe and desired outcomes with HA fillers, aligned with this principle: “treat the patient, not the photograph.” It promotes patient‐practitioner alignment on treatment goals and use of appropriate products based on biomimetic design principles, contributing to the attainment of predictable and satisfying results with aesthetic HA filler treatments.

Background: Facial atrophic acne scars have a significant impact on patients’ psychosocial well-being and remain a therapeutic challenge. Existing treatments options are frequently limited by modest efficacy and adverse effects. The combination of Polynucleotide High-Purification Technology (PN HPT™) and hyaluronic acid (HA) represents a novel bioregenerative strategy aimed at improving dermal remodelling and overall skin quality. Methods: This six-month, prospective, real-world study evaluated the efficacy and safety of Newest^® (Mastelli S.r.l., Sanremo, Italy), a sterile intradermal gel containing highly purified polynucleotides (10 mg/mL) and HA (10 mg/mL). Eligible participants, aged 20–60 years with moderate-to-severe atrophic facial post-acne scars, underwent four treatment sessions in two-week intervals. Efficacy was assessed using the Acne Scar Assessment Scale (ASAS) and Global Aesthetic Improvement Scale (GAIS) at three and six months, while safety was monitored throughout the study. Results: A total of 62 patients (32 Caucasian, 30 Asian; 19 males, 43 females; mean age: 36.6 years) completed the study. At three and six months, 46.8% showed at least a one-grade reduction in ASAS score with respect to the baseline. Patient-reported GAIS indicated that 54.8% perceived an improvement in scar appearance, aligning with investigator assessments. Only one mild, transient adverse event (wheal formation) occurred, which resolved spontaneously without intervention. Conclusions: In this real-world study, treatment with Polynucleotide High-Purification Technology (10 mg/mL) combined with HA (10 mg/mL) was associated with observable improvementin atrophic facial acne scars, with an excellent safety and tolerability profile. These findings support the potential of polynucleotide-based therapies for use as well-tolerated options for managing moderate-to-severe atrophic acne scarring, while the need for further controlled studies to confirm efficacy is also acknowledged.

Introduction and Purpose: Marine collagens are environmentally friendly and biologically compatible collagens derived from aquatic organisms, including invertebrates like sponges and jellyfish. Starting from marine collagens as raw materials, sophisticated purification procedures lead to low-molecular-weight, bioactive fragments that are valuable functional ingredients for nutritional supplements, cosmeceuticals, and medical devices in regenerative medicine. From the mid-2010s to the late 2010s, several high-quality studies highlighted the skin bioregenerative properties of marine collagen-derived oligopeptides. The purpose of this review is to discuss these properties and their rationale. Methods: This review only analyzes studies focused on skin regeneration published in indexed journals with significant impact factors (the rule was rigid for human studies), supplemented by a few contributions from Google Scholar for methodologically sound in vitro and animal studies. Results: Activation of skin fibroblasts with high systemic bioavailability after oral intake supports the bioregenerative properties of hydrolyzed marine collagen. Marine collagen hydrolysates do not cause irritation or inflammation and have a negligible impact on pro-inflammatory mediators in animal studies. Preclinical research indicates that 50 μg/mL of hydrolyzed marine collagen peptides accelerates cell migration almost as effectively as 10 μg/mL of recombinant human epidermal growth factor, although the predictive value of in vitro studies for humans remains uncertain. Accelerated wound healing with collagen neosynthesis is associated with increased expression in immunohistochemistry of platelet-endothelial cell adhesion molecule-1, basic fibroblast growth factor, and transforming growth factor ß-1. Furthermore, enzyme-treated hydrolysates produced under acidic conditions exhibit antioxidant effects without affecting pro-inflammatory cytokines, while enzyme-treated hydrolysates under alkaline conditions have the opposite effect. Conclusion: An increasing number of preclinical and human studies highlight the skin and overall bioregenerative properties of hydrolyzed marine collagens. Their high systemic intestinal absorption after oral intake distinguishes them from hydrolysates from other sources. Long-term safety should be a primary concern of future research.

Introduction and Purpose: Biological differences between Asians and Caucasians contribute to variations in the prevalence of skin disorders such as melanocytoses and skin aging. The current regenerative medicine indications were primarily developed for Caucasians; adapting them to the specific needs of Asian individuals may be beneficial. Five distinguished Asian experts had this purpose in mind when they convened to develop evidence-based and experience-based recommendations on maximizing the benefits of natural-origin ingredient Polynucleotides High Purification Technology (PN HPT™) in individuals of Asian descent. They based their recommendations on available literature and the outcomes of a digital survey. PN HPT supports dermal fibroblasts in producing collagen, elastin, and matrix by replenishing the dermal pool of nucleotide precursors. Patients and Methods: One hundred and one East Asian specialists in aesthetic and regenerative medicine accepted an invitation from Mastelli S.r.l. Sanremo, Italy, and Ardence Aesthetic, Petaling Jaya, Selangor, Malaysia (corporate sponsors), to respond to a 50-item online survey questionnaire. A subsequent consensus-building board meeting elaborated on the survey outcomes with a simplified Delphi approach, providing recommendations for the safe and effective use of PN HPT in Asian individuals. Results: The paper highlights in specific chapters the perceptions of the surveyed East Asian specialists regarding the PN HPT indications and procedures (choice of PN HPT formulations, injection technique, scheduling, and layer) in facial areas and the neck. Furthermore, the paper discusses the experts’ views on combining PN HPT with other skin regenerative strategies, as well as the innovative concept of “PN HPT Priming”. Conclusion: Offering tailored PN HPT treatment algorithms that take into consideration the Asian biological and cultural specificities, although without stratification for age and skin quality determinants, the board’s suggestions are of immediate clinical applicability and may support clinicians who use PN HPT devices in their daily regenerative medicine practice.