Raúl Pérez González

Synovial fluid (SF) rheological properties deteriorate progressively in knee osteoarthritis (OA) due to a reduction in hyaluronic acid (HA) concentration and molecular weight, compromising joint lubrication and load distribution. Restoring these properties through intra-articular viscosupplementation with HA is a widely used therapeutic strategy. However, commercially available linear HA formulations differ substantially in their mechanical behavior, and single-parameter assessments are insufficient for capturing their functional differences. In this study, eight commercially available intra-articular linear HA hydrogels—TrHLINE 1%^®, TrHLINE 2%^®, Hyalubrix^®, Hyalgan Bio^®, Pronolis^® HD 2.5%, Biolevox™ HA ONE 2.5%, Suplasyn^®, and Arthrum H 2%^®—were evaluated under standardized conditions using steady-state viscosity, mechanical stress response, first normal stress difference (N1), storage and loss moduli (G′, G″), loss factor (tan δ), and elasticity percentage. Results revealed three distinct functional profiles: lubricant-oriented with low to moderate structural organization (Hyalgan Bio^®, Suplasyn^®, TrHLINE 1%^®); balanced viscoelastic with sustained structural persistence (TrHLINE 2%^®, Hyalubrix^®, Arthrum H 2%^®); and high initial rigidity with reduced dynamic persistence (Biolevox™ HA ONE 2.5%, Pronolis^® HD 2.5%). These findings demonstrate that multi-parametric rheological benchmarking effectively discriminates functional differences among HA viscosupplements and supports indication-oriented product selection based on OA severity and patient mechanical demand.

Osteoarthritis is a progressive joint disorder characterized by cartilage degeneration and alterations in synovial fluid (SF) composition. One of the earliest pathogenic events is the loss of SF viscosity, which compromises joint lubrication, accelerates cartilage wear, promotes inflammation and contributes substantially to paint and patient disability. Despite its high prevalence and growing socioeconomic burden, no current therapeutic option effectively halts or reverses disease progression. Intraarticular hyaluronic acid (HA) viscosupplementation is widely used to restore lubrication and alleviate symptoms. However, clinical outcomes remain inconsistent, largely due to the absence of standardized physicochemical criteria across commercial formulations, particularly regarding molecular weight (MW), rheological behavior and crosslinking. Recent evidence underscores that HA products differ significantly in rheology, durability, intraarticular residence time and symptomatic relief, with linear high-molecular-weight (HMW) and crosslinked (CL) HA hydrogels consistently demonstrating the most robust and reproducible clinical benefits, in terms of pain reduction, functional improvement, and manteinance of therapeutic effects. This chapter examines the relationship between HA chemistry and clinical efficacy, aiming to define the essential physicochemical attributes that intraarticular HA should possess to achieve both symptomatic relief and regenerative potential. Furthermore, HA-based hydrogels extend their utility beyond viscosupplementation. Recent advances show that they serve as versatile scaffolds for cell delivery and as controlled-release platforms for bioactive agents such as platelet-rich plasma (PRP), extracellular vesicles (EVs), mesenchymal stromal cells (MSCs) and therapeutic nanoparticles. These advances highlight the potential of HA hydrogels as key components of next-generation regenerative strategies for novel osteoarthritis management.

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disorder. Revodiol Calming Cream^® (RCC) is a novel dermocosmetic product containing cannabidiol (CBD) and Annona cherimola fruit extract, designed for the management of atopic-prone and sensitive skin. Objective: Clinically assess the efficacy and safety of RCC in the management of atopic-prone and/or sensitive skin. Materials and methods: A prospective study included 20 adults and 22 children with mild-to-moderate atopic-prone skin. RCC was applied daily, for 56 days. Clinical evaluation included the SCORAD index, pruritus and dryness scales; and a Visual Analog Scale (VAS). Biometric assessments (Mexameter^®, Tewameter^®, Visioscan^®, Corneofix^®) were performed. Subjective satisfaction and quality of life (DLQI) were also recorded. Results: RCC was well tolerated, with no significant adverse events. After 56 days, SCORAD scores decreased by 55% in adults and 60% in children. Pruritus and dryness were significantly reduced, and VAS scores indicated a 65% decrease in discomfort. Biometric assessments demonstrated improvements in erythema, skin barrier function, topography, and desquamation. Subjective satisfaction reached 75% in both populations, and DLQI improved by 23%. Conclusions: The synergistic combination of CBD, Annona cherimola extract, and natural humectants offers a safe and effective daily dermocosmetic care for both adults and children.

Dry eye disease (DED) is a multifactorial ocular surface disorder that significantly affects vision and quality of life. While artificial tears are the standard first-line therapy, their effectiveness is limited by the complex pathophysiology of DED. This study evaluated DayDrop^® Triple Action, a novel formulation combining hyaluronic acid (HA), ectoine, and carboxymethylcellulose (CMC), designed to enhance tear film stability and ocular surface protection. Physicochemical and rheological properties were assessed, including viscosity, pseudoplasticity, and viscoelastic behaviour under dynamic conditions, along with ectoine release over 24 h. An in vitro allergic conjunctivitis model using conjunctival fibroblasts exposed to a pro-allergic cytokine cocktail was employed to examine immunomodulatory effects. DayDrop^® Triple Action demonstrated high viscosity with pronounced pseudoplasticity and stable viscoelasticity, supporting improved mucoadhesion. The formulation provided sustained ectoine release and exhibited a positive immunomodulatory effect, likely linked to ectoine’s preferential hydration mechanism, which stabilizes membranes and reduces inflammatory signalling. These findings suggest that DayDrop^® Triple Action integrates viscoelastic optimization, osmoprotection, and targeted anti-inflammatory action, offering a promising non-pharmacological strategy for managing DED and allergic ocular surface disorders.

Crosslinked hyaluronic acid dermal fillers are widely used for non-permanent aesthetic enhancement, offering safe and effective solutions for facial volume restoration. Specific formulations are designed for targeted facial regions, with highly crosslinked hydrogels often recommended for volumizing areas such as the jawline, chin, and cheeks due to their structural properties. While elasticity and viscosity are commonly evaluated, broader comparative analyses remain limited. In this study, we assess five commercially available HA-based fillers with similar HA concentrations, all optimised for volume enhancement. Alongside widely used reference products, we evaluate BtHCROSS 2%^®, a novel formulation not previously compared to established fillers. We examined the degree of chemical modification, mechanical viscoelastic behaviour, susceptibility to enzymatic degradation by hyaluronidase, and injection force. While all tested fillers are suitable for volume restoration, BtHCROSS 2%^® demonstrates a distinctive combination of mechanical adaptability, structural support, enzymatic resistance, and low injection force, making it a versatile option for practitioners.

Prolonged sun exposure disrupts the skin’s structural, mechanical, and functional properties, accelerating aging and contributing to skin disorders. To counteract these effects, we developed a formulation containing potent antioxidant, anti-inflammatory, moisturizing, and reparative ingredients to protect and repair sun-damaged skin. The efficacy of the formulation was evaluated through in vitro, ex vivo, and in vivo studies. Results demonstrated that the formulation reduced oxidative stress and suppressed the production of pro-inflammatory cytokines interleukin-6 (IL-6) and interleukin-8 (IL-8), as well as lactate dehydrogenase (LDH) secretion, in a photodamaged skin model, nearly reaching levels observed in undamaged skin. It also restored collagen levels, improving structural integrity. In vivo, no adverse reactions were observed when used for 28 or 56 days. The formulation improved skin hydration by up to 46%, reduced transepidermal water loss by 20%, increased luminosity by 70%, and reduced hyperpigmented spots by 14%. It also enhanced skin firmness and elasticity by 30% and reduced wrinkle volume and density by up to 53% and 19%, respectively. These findings demonstrate that the formulation’s active ingredients effectively target the pathways altered by UV exposure, offering considerable potential for preventing and reversing sun-induced skin damage while improving both the appearance and functionality of the skin.

Traditional wound dressings have not been able to satisfy the needs of the regenerative medicine biomedical area. With the aim of improving tissue regeneration, nanofiber-based wound dressings fabricated by electrospinning (ES) processes have emerged as a powerful approach. Nowadays, nanofiber-based bioactive dressings are mainly developed with a combination of natural and synthetic polymers, such as polycaprolactone (PCL) and chitosan (CHI). Accordingly, herein, PCL/CHI nanofibers have been developed with varying PCL:CHI weight ratios (9:1, 8:2 and 7:3) or CHI viscosities (20, 100 and 600 mPa·s) using a novel alternating current ES (ACES) process. Such nanofibers were thoroughly characterized by determining physicochemical and nanomechanical properties, along with wettability, absorption capacity and hydrolytic plus enzymatic stability. Furthermore, PCL/CHI nanofiber biological safety was validated in terms of cytocompatibility and hemocompatibility (hemolysis < 2%), in addition to a notable antibacterial performance (bacterial reductions of 99.90% for S. aureus and 99.91% for P. aeruginosa). Lastly, the enhanced wound healing activity of PCL/CHI nanofibers was confirmed thanks to their ability to remarkably promote cell proliferation, which make them ideal candidates for long-term applications such as wound dressings.

Granular polymer hydrogels based on dynamic covalent bonds are attracting a great deal of interest for the design of injectable biomaterials. Such materials generally exhibit shear-thinning behavior and properties of self-healing/recovery after the extrusion that can be modulated through the interactions between gel microparticles. Herein, bulk macro-hydrogels based on thiolated-hyaluronic acid were produced by disulphide bond formation using oxygen as oxidant at physiological conditions and gelation kinetics were monitored. Three different thiol substitution degrees (SD%: 65%, 30% and 10%) were selected for hydrogel formation and fully characterized as to their stability in physiological medium and morphology. Then, extrusion fragmentation technique was applied to obtain hyaluronic acid microgels with dynamic disulphide bonds that were subsequently sterilized by autoclaving. The resulting granular hyaluronic hydrogels were able to form stable filaments when extruded through a syringe. Rheological characterization and cytotoxicity tests allowed to assess the potential of these materials as injectable biomaterials. The application of extrusion fragmentation for the formation of granular hyaluronic hydrogels and the understanding of the relation between the autoclaving processes and the resulting particle size and rheological properties should expand the development of injectable materials for biomedical applications.

Hyaluronic acid (HA) injectable biomaterials are currently applied in numerous biomedical areas, beyond their use as dermal fillers. However, bacterial infections and painful inflammations are associated with healthcare complications that can appear after injection, restricting their applicability. Fortunately, HA injectable hydrogels can also serve as drug delivery platforms for the controlled release of bioactive agents with a critical role in the control of certain diseases. Accordingly, herein, HA hydrogels were crosslinked with 1 4-butanediol diglycidyl ether (BDDE) loaded with cefuroxime (CFX), tetracycline (TCN), and amoxicillin (AMX) antibiotics and acetylsalicylic acid (ASA) anti-inflammatory agent in order to promote antibacterial and anti-inflammatory responses. The hydrogels were thoroughly characterized and a clear correlation between the crosslinking grade and the hydrogels’ physicochemical properties was found after rheology, scanning electron microscopy (SEM), thermogravimetry (TGA), and differential scanning calorimetry (DSC) analyses. The biological safety of the hydrogels, expected due to the lack of BDDE residues observed in ¹H-NMR spectroscopy, was also corroborated by an exhaustive biocompatibility test. As expected, the in vitro antibacterial and anti-inflammatory activity of the drug-loaded HA-BDDE hydrogels was confirmed against Staphylococcus aureus by significantly decreasing the pro-inflammatory cytokine levels.

Additive manufacturing (AM), frequently cited as three-dimensional (3D) printing, is a relatively new manufacturing technique for biofabrication, also called 3D manufacture with biomaterials and cells. Recent advances in this field will facilitate further improvement of personalized healthcare solutions. In this regard, tailoring several healthcare products such as implants, prosthetics, and in vitro models, would have been extraordinarily arduous beyond these technologies. Three-dimensional-printed structures with a multiscale porosity are very interesting manufacturing processes in order to boost the capability of composite scaffolds to generate bone tissue. The use of biomimetic hydroxyapatite as the main active ingredient for bioinks is a helpful approach to obtain these advanced materials. Thus, 3D-printed biomimetic composite designs may produce supplementary biological and physical benefits. Three-dimensional bioprinting may turn to be a bright solution for regeneration of bone tissue as it enables a proper spatio-temporal organization of cells in scaffolds. Different types of bioprinting technologies and essential parameters which rule the applicability of bioinks are discussed in this review. Special focus is made on hydroxyapatite as an active ingredient for bioinks design. The goal of such bioinks is to reduce the constraints of commonly applied treatments by enhancing osteoinduction and osteoconduction, which seems to be exceptionally promising for bone regeneration.