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Recent advancements in aesthetic medicine offer innovative cosmetic solutions to enhance patient skin quality and appearance. Advanced treatment options enable practitioners to effectively address skin aging signs, pigmentation imbalance, and loss of elasticity in ambulatory and home-based care regimens. Exosomes (nanoscale cell-derived vesicles) transport a variety of biomolecules and are pivotal in physiological intercellular communication. Importantly, exosomes have recently emerged as key endogenous players in tissular regeneration. More broadly (from an active ingredient purity standpoint), exosomes, stem cell secretomes, and cell culture-conditioned media have been clinically proven to exert multifaceted beneficial topical effects (anti-inflammatory, antioxidant, anti-aging, skin rejuvenation). Therefore, human, animal, and plant-derived exosomes or other refined sub-cellular biological fractions are gaining substantial interest within the aesthetic and cosmetic industries. Notably, such approaches are thought to be among the most promising novel contenders for advanced, biologically inspired skin prejuvenation and rejuvenation care. The present narrative review summarizes the latest clinically oriented research on exosomes and cell culture-conditioned media, highlighting their mechanisms of action in various topical applications. Furthermore, it explores the innovation landscape and currently commercially available products on the global cosmetic market and discusses the potential future applications of advanced, biologically inspired ingredients in the medical aesthetic industry.

Facial hyperpigmentation is a highly prevalent dermatological condition, characterized by dark spots on the skin resulting from excess melanin production. Hyperpigmentation significantly impacts patients’ quality of life and self-esteem. Current treatments often present disadvantages linked to poor product tolerability. A topical cosmetic approach combining three lightening active ingredients (tranexamic acid, niacinamide, vitamin C) offers a new option for treating dark spots on the skin. The present in-use test under dermatological control evaluated the clinical safety and efficacy of a cream and serum containing these three ingredients, formulated with hyaluronic acid for enhanced delivery, stability, and efficacy. A total of 22 Caucasian patients with facial hyperpigmentation, both male and female, aged between 45 and 67 years, applied the cream and serum for 8 weeks. Clinical assessments, colorimetric evaluations, standardized photography, and self-assessment questionnaires were used to measure outcomes. No serious adverse effects were recorded, and the incidence of local adverse effects was low, highlighting good tolerability of the investigated test items. In most participants, significant improvements in hyperpigmented areas were recorded. Clinical scoring by the dermatologist investigator indicated a statistically significant 13% reduction in color intensity and a 6% reduction in the size of dark spots after 8 weeks of treatment. Colorimetric evaluation showed a statistically significant 1% increase in luminosity (L* parameter) and an 8% improvement in the Individual Typological Angle (ITA°) in endpoint, indicating lighter skin spots. Subjective assessments reflected high user satisfaction, with 95% of participants noting improvements in skin hydration and luminosity, and 77% reporting a reduced appearance of dark spots. Overall, the present work supports the use of tranexamic acid, niacinamide, and vitamin C as an effective and well-tolerated combined topical management option for hyperpigmentation. This combination offers a viable alternative to classical whiteners for individuals seeking to reduce facial skin coloration imbalance and improve skin tone.

Hyaluronic acid (HA) hydrogels are commonly used for facial dermal filling and for alternative medical aesthetic purposes. High diversity exists in commercial formulations, notably for the optimization of finished product stability, functionality, and performance. Polyvalent ingredients such as calcium hydroxylapatite (CaHA) or vitamin B3 (niacinamide) are notably used as bio-stimulants to improve skin quality attributes at the administration site. The aim of the present study was to perform multi-parametric characterization of two novel cross-linked dermal filler formulas (HAR-1 “Instant Refine” and HAR-3 “Maxi Lift”) for elucidation of the various functional impacts of vitamin B3 incorporation. Therefore, the HAR products were firstly comparatively characterized in terms of in vitro rheology, cohesivity, injectability, and resistance to chemical or enzymatic degradation (exposition to H2O2, AAPH, hyaluronidases, or xanthine oxidase). Then, the HAR products were assessed for cytocompatibility and in vitro bio-stimulation attributes in a primary dermal fibroblast model. The results showed enhanced resilience of the cohesive HAR hydrogels as compared to JUVÉDERM® VOLBELLA® and VOLUMA® reference products in a controlled degradation assay panel. Furthermore, significant induction of total collagen synthesis in primary dermal fibroblast cultures was recorded for HAR-1 and HAR-3, denoting intrinsic bio-stimulatory effects comparable or superior to those of the Radiesse® and Sculptra™ reference products. Original results of high translational relevance were generated herein using robust and orthogonal experimental methodologies (hydrogel degradation, functional benchmarking) and study designs. Overall, the reported results confirmed the dual functionalization role of vitamin B3 in cross-linked HA dermal fillers, with a significant enhancement of hydrogel system stability attributes and the deployment of potent bio-stimulatory capacities.

Dermal filler injectability is a critical factor for commercial product adoption by medical aesthetic professionals and for successful clinical administration. We have previously reported (in vitro and ex vivo) cross-linked hyaluronic acid (HA)-based dermal filler benchmarking in terms of manual and automated injectability requirements. To further enhance the function-oriented product characterization workflows and the clinical relevance of dermal filler injectability assessments, the aim of this study was to perform in vivo evaluations. Therefore, several variants of the MaiLi® product range (OxiFree™ technology) were characterized in vitro and in vivo in terms of injectability attributes, with a focus on hydrogel system homogeneity and ease of injection. Firstly, standardized in vitro assays were performed in SimSkin® cutaneous equivalents, with variations of the clinical injector, injection site, and injection technique. Then, automated injections in SimSkin® cutaneous equivalents were comparatively performed in a texture analysis setup to obtain fine-granulometry injection force profile results. Finally, five female participants were recruited for the in vivo arm of the study (case reports), with variations of the clinical injector, injection site, and injection technique. Generally, the obtained quantitative force values and injection force profiles were critically appraised from a translational viewpoint, based on discussions around the OxiFree™ manufacturing technology and on in-use specialized clinician feedback. Overall, the present study outlined a notable level of homogeneity across the MaiLi® product range in terms of injectability attributes, as well as consistently high ease of administration by medical aesthetic clinicians.

Niacinamide (or nicotinamide) is a small-molecule hydrosoluble vitamin with essential metabolic functions in mammalian cells. Niacinamide has become a key functional ingredient in diverse skincare products and cosmetics. This vitamin plays a pivotal role in NAD+ synthesis, notably contributing to redox reactions and energy production in cutaneous cells. Via diversified biochemical mechanisms, niacinamide is also known to influence human DNA repair and cellular stress responses. Based on decades of safe use in cosmetics, niacinamide recently gained widespread popularity as an active ingredient which aligns with the “Kligman standards” in skincare. From a therapeutic standpoint, the intrinsic properties of niacinamide may be applied to managing acne vulgaris, melasma, and psoriasis. From a cosmeceutical standpoint, niacinamide has been widely leveraged as a multipurpose antiaging ingredient. Therein, it was shown to significantly reduce cutaneous oxidative stress, inflammation, and pigmentation. Overall, through multimodal mechanisms, niacinamide may be considered to partially prevent and/or reverse several biophysical changes associated with skin aging. The present narrative review provides multifactorial insights into the mechanisms of niacinamide’s therapeutic and cosmeceutical functions. The ingredient’s evolving role in skincare was critically appraised, with a strong focus on the biochemical mechanisms at play. Finally, novel indications and potential applications of niacinamide in dermal fillers and alternative injectable formulations were prospectively explored.

The injectability of cross-linked hyaluronic acid (HA) dermal fillers is influenced by polymer concentration, polymer cross-linking type and degree, the presence of lidocaine or other functional excipients, types of syringes, and injection techniques. Finished product injectability constitutes a critical quality attribute for clinical injectors, as it strongly influences product applicability and ease of use in aesthetic medicine. While injectable product extrusion force specifications are provided by the respective device manufacturers, the qualitative informative value of such datasets is low for injectors wishing to compare product brands and technologies from an injectability standpoint. Therefore, the present study comparatively assessed 28 cross-linked HA dermal fillers (JUVÉDERM®, Restylane®, BELOTERO®, TEOSYAL RHA®, and STYLAGE® brands) using various injectability benchmarking setups for enhanced clinical-oriented relevance. Manual product injections were performed by three specialized and experienced clinicians, whereas automatic product extrusion was performed using a Texture Analyzer instrument. The various hydrogel products were injected into ex vivo human skin and into SimSkin® cutaneous equivalents to appropriately account for injection-related counterpressure. The injectability results revealed important variability between and within product brands, with a strong influence of the local anesthetic lidocaine, HA contents, and needle gauge size. Critical appraisals of the investigated products were performed, notably from manufacturing process-based and clinical ease of application-based standpoints, centered on respective experimental injectability quality levels. Generally, it was confirmed that each HA-based dermal filler product requires specific expertise for optimal injection, mainly due to differing viscoelastic characteristics and injectability attributes. Overall, the present study set forth evidence-based and clinical-oriented rationale elements confirming the importance for injectors to work with injectable products with which they are experienced and comfortable to optimize clinical results.

While many injectable viscosupplementation products are available for osteoarthritis (OA) management, multiple hydrogel functional attributes may be further optimized for efficacy enhancement. The objective of this study was to functionally benchmark four commercially available hyaluronan-based viscosupplements (Ostenil, Ostenil Plus, Synvisc, and Innoryos), focusing on critical (rheological, lubricative, adhesive, and stability) attributes. Therefore, in vitro and ex vivo quantitative characterization panels (oscillatory rheology, rotational tribology, and texture analysis with bovine cartilage) were used for hydrogel product functional benchmarking, using equine synovial fluid as a biological control. Specifically, the retained experimental methodology enabled the authors to robustly assess and discuss various functional enhancement options for hyaluronan-based hydrogels (chemical cross-linking and addition of antioxidant stabilizing agents). The results showed that the Innoryos product, a niacinamide-augmented linear hyaluronan-based hydrogel, presented the best overall functional behavior in the retained experimental settings (high adhesivity and lubricity and substantial resistance to oxidative degradation). The Ostenil product was conversely shown to present less desirable functional properties for viscosupplementation compared to the other investigated products. Generally, this study confirmed the high importance of formulation development and control methodology optimization, aiming for the enhancement of novel OA-targeting product critical functional attributes and the probability of their clinical success. Overall, this work confirmed the tangible need for a comprehensive approach to hyaluronan-based viscosupplementation product functional benchmarking (product development and product selection by orthopedists) to maximize the chances of effective clinical OA management.

Most marketed HA-based dermal fillers use chemical cross-linking to improve mechanical properties and extend their lifetime in vivo; however, stiffer products with higher elasticity require an increased extrusion force for injection in clinical practice. To balance longevity and injectability, we propose a thermosensitive dermal filler, injectable as a low viscosity fluid that undergoes gelation in situ upon injection. To this end, HA was conjugated via a linker to poly(N-isopropylacrylamide) (pNIPAM), a thermosensitive polymer using “green chemistry”, with water as the solvent. HA-L-pNIPAM hydrogels showed a comparatively low viscosity (G′ was 105.1 and 233 for Candidate1 and Belotero Volume®, respectively) at room temperature and spontaneously formed a stiffer gel with submicron structure at body temperature. Hydrogel formulations exhibited superior resistance against enzymatic and oxidative degradation and could be administered using a comparatively lower injection force (49 N and >100 N for Candidate 1 and Belotero Volume®, respectively) with a 32G needle. Formulations were biocompatible (viability of L929 mouse fibroblasts was >100% and ~85% for HA-L-pNIPAM hydrogel aqueous extract and their degradation product, respectively), and offered an extended residence time (up to 72 h) at the injection site. This property could potentially be exploited to develop sustained release drug delivery systems for the management of dermatologic and systemic disorders.

Thermo-responsive hyaluronan-based hydrogels and FE002 human primary chondroprogenitor cell sources have both been previously proposed as modern therapeutic options for the management of osteoarthritis (OA). For the translational development of a potential orthopedic combination product based on both technologies, respective technical aspects required further optimization phases (e.g., hydrogel synthesis upscaling and sterilization, FE002 cytotherapeutic material stabilization). The first aim of the present study was to perform multi-step in vitro characterization of several combination product formulas throughout the established and the optimized manufacturing workflows, with a strong focus set on critical functional parameters. The second aim of the present study was to assess the applicability and the efficacy of the considered combination product prototypes in a rodent model of knee OA. Specific characterization results (i.e., spectral analysis, rheology, tribology, injectability, degradation assays, in vitro biocompatibility) of hyaluronan-based hydrogels modified with sulfo-dibenzocyclooctyne-PEG4-amine linkers and poly(N-isopropylacrylamide) (HA-L-PNIPAM) containing lyophilized FE002 human chondroprogenitors confirmed the suitability of the considered combination product components. Specifically, significantly enhanced resistance toward oxidative and enzymatic degradation was shown in vitro for the studied injectable combination product prototypes. Furthermore, extensive multi-parametric (i.e., tomography, histology, scoring) in vivo investigation of the effects of FE002 cell-laden HA-L-PNIPAM hydrogels in a rodent model revealed no general or local iatrogenic adverse effects, whereas it did reveal some beneficial trends against the development of knee OA. Overall, the present study addressed key aspects of the preclinical development process for novel biologically-based orthopedic combination products and shall serve as a robust methodological basis for further translational investigation and clinical work.

Cultured primary progenitor tenocytes in lyophilized form were previously shown to possess intrinsic antioxidant properties and hyaluronan-based hydrogel viscosity-modulating effects in vitro. The aim of this study was to prepare and functionally characterize several stabilized (lyophilized) cell-free progenitor tenocyte extracts for inclusion in cytotherapy-inspired complex injectable preparations. Fractionation and sterilization methods were included in specific biotechnological manufacturing workflows of such extracts. Comparative and functional-oriented characterizations of the various extracts were performed using several orthogonal descriptive, colorimetric, rheological, mechanical, and proteomic readouts. Specifically, an optimal sugar-based (saccharose/dextran) excipient formula was retained to produce sterilizable cytotherapeutic derivatives with appropriate functions. It was shown that extracts containing soluble cell-derived fractions possessed conserved and significant antioxidant properties (TEAC) compared to the freshly harvested cellular starting materials. Progenitor tenocyte extracts submitted to sub-micron filtration (0.22 µm) and 60Co gamma irradiation terminal sterilization (5–50 kGy) were shown to retain significant antioxidant properties and hyaluronan-based hydrogel viscosity modulating effects. Hydrogel combination products displayed important efficacy-related characteristics (friction modulation, tendon bioadhesivity) with significant (p < 0.05) protective effects of the cellular extracts in oxidative environments. Overall, the present study sets forth robust control methodologies (antioxidant assays, H2O2-challenged rheological setups) for stabilized cell-free progenitor tenocyte extracts. Importantly, it was shown that highly sensitive phases of cytotherapeutic derivative manufacturing process development (purification, terminal sterilization) allowed for the conservation of critical biological extract attributes.

Intimal hyperplasia (IH) is an undesirable pathology occurring after peripheral or coronary bypass surgery. It involves the proliferation and migration of vascular smooth muscle cells, leading to a reduction in the diameter of the vascular lumen, which can lead to stenosis and graft failure. Topically applied atorvastatin (ATV) has been shown to slow down this process. To be effective, the drug delivery system should remain at the perivascular site for 5–8 weeks, corresponding to the progression of IH, and be capable of releasing an initial dose of the drug followed by a sustained release. Ideally, bioadhesion would anchor the gel to the application site. To meet these needs, we encapsulated ATV in a 2-component system: a hyaluronic acid–dopamine bioadhesive gel for rapid release and biodegradable microparticles for sustained release. The system was characterized by scanning electron microscopy, rheology, bioadhesion on porcine arteries, and a release profile. The rheological properties were adequate for perivascular application, and we demonstrated superior bioadhesion and cohesion compared to the control HA formulations. The release profile showed a burst, generated by free ATV, followed by sustained release over 8 weeks. A preliminary evaluation of subcutaneous biocompatibility in rats showed good tolerance of the gel. These results offer new perspectives on the perivascular application towards an effective solution for the prevention of IH.

Anti-tumor responses can be achieved via the stimulation of the immune system, a therapeutic approach called cancer immunotherapy. Many solid tumor types are characterized by the presence of immune-suppressive tumor-associated macrophage (TAMs) cells within the tumor microenvironment (TME). Moreover, TAM infiltration is strongly associated with poor survival in solid cancer patients and hence a low responsiveness to cancer immunotherapy. Therefore, 2′3′ Cyclic GMP-AMP (2′3′ cGAMP) was employed for its ability to shift macrophages from pro-tumoral M2-like macrophages (TAM) to anti-tumoral M1. However, cGAMP transfection within macrophages is limited by the molecule’s negative charge, poor stability and lack of targeting. To circumvent these barriers, we designed nanocarriers based on poly(amidoamine) dendrimers (PAMAM) grafted with D-glucuronic acid (Glu) for M2 mannose-mediated endocytosis. Two carriers were synthesized based on different dendrimers and complexed with cGAMP at different ratios. Orthogonal techniques were employed for synthesis (NMR, ninhydrin, and gravimetry), size (DLS, NTA, and AF4-DLS), charge (DLS and NTA), complexation (HPLC-UV and AF4-UV) and biocompatibility and toxicity (primary cells and hen egg chorioallantoic membrane model) evaluations in order to evaluate the best cGAMP carrier. The best formulation was selected for its low toxicity, biocompatibility, monodispersed distribution, affinity towards CD206 and ability to increase M1 (STAT1 and NOS2) and decrease M2 marker (MRC1) expression in macrophages.

Hyaluronic acid (HA) constitutes a versatile chemical framework for the development of osteoarthritis pain treatment by means of injection in the joints, so-called viscosupplementation. Without appropriate physico-chemical tuning, such preparations are inherently hindered by prompt in vivo degradation, mediated by hyaluronidases and oxidative stress. To prolong hydrogel residence time and confer optimized product functionality, novel thermoresponsive nanoforming HA derivatives were proposed and characterized. Combined use of sulfo-dibenzocyclooctyne-PEG4-amine linkers and poly(N-isopropylacrylamide) in green chemistry process enabled the synthesis of HA-based polymers, with in situ obtention of appropriate viscoelastic properties. Spontaneous and reversible thermoformation of nanoparticles above 30 °C was experimentally confirmed. Lead formulations were compared to a commercially available HA-based product and shown significantly better in vitro resistance to enzymatic and oxidative degradation, required half the injection force with optimal viscoelastic hydrogel properties in equine synovial fluids. Results highlighted the vast potential of appropriately engineered HA-based systems as next-generation long-acting viscosupplementation products for osteoarthritic patients.

Cultured progenitor cells and derivatives have been used in various homologous applications of cutaneous and musculoskeletal regenerative medicine. Active pharmaceutical ingredients (API) in the form of progenitor cell derivatives such as lysates and lyophilizates were shown to retain function in controlled cellular models of wound repair. On the other hand, hyaluronan-based hydrogels are widely used as functional vehicles in therapeutic products for tendon tissue disorders. The aim of this study was the experimental characterization of formulations containing progenitor tenocyte-derived APIs and hyaluronan, for the assessment of ingredient compatibility and stability in view of eventual therapeutic applications in tendinopathies. Lyophilized APIs were determined to contain relatively low quantities of proteins and growth factors, while being physicochemically stable and possessing significant intrinsic antioxidant properties. Physical and rheological quantifications of the combination formulas were performed after hydrogen peroxide challenge, outlining significantly improved evolutive viscoelasticity values in accelerated degradation settings. Thus, potent effects of physicochemical protection or stability enhancement of hyaluronan by the incorporated APIs were observed. Finally, combination formulas were found to be easily injectable into ex vivo tendon tissues, confirming their compatibility with further translational clinical approaches. Overall, this study provides the technical bases for the development of progenitor tenocyte derivative-based injectable therapeutic products or devices, to potentially be applied in tendinous tissue disorders.