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Background Mesenchymal stromal cells are a promising option to treat knee osteoarthritis. Their safety and usefulness must be confirmed and the optimal dose established. We tested increasing doses of bone marrow mesenchymal stromal cells (BM-MSCs) in combination with hyaluronic acid in a randomized clinical trial. Materials A phase I/II multicenter randomized clinical trial with active control was conducted. Thirty patients diagnosed with knee OA were randomly assigned to intraarticularly administered hyaluronic acid alone (control), or together with 10 × 10 6 or 100 × 10 6 cultured autologous BM-MSCs, and followed up for 12 months. Pain and function were assessed using VAS and WOMAC and by measuring the knee motion range. X-ray and magnetic resonance imaging analyses were performed to analyze joint damage. Results No adverse effects were reported after BM-MSC administration or during follow-up. BM-MSC-administered patients improved according to VAS during all follow-up evaluations and median value (IQR) for control, low-dose and high-dose groups change from 5 (3, 7), 7 (5, 8) and 6 (4, 8) to 4 (3, 5), 2 (1, 3) and 2 (0,4) respectively at 12 months (low-dose vs control group p = 0.005 and high-dose vs control group p < 0.009). BM-MSC-administered patients were also superior according to WOMAC, although improvement in control and low-dose patients could not be significantly sustained beyond 6 months. On the other hand, the BM-MSC high-dose group exhibited an improvement of 16.5 (12, 19) points at 12 months (p < 0.01). Consistent with WOMAC and VAS values, motion ranges remained unaltered in the control group but improved at 12 months with BM-MSCs. X-ray revealed a reduction of the knee joint space width in the control group that was not seen in BM-MSCs high-dose group. MRI (WORMS protocol) showed that joint damage decreased only in the BM-MSC high-dose group, albeit slightly. Conclusions The single intraarticular injection of in vitro expanded autologous BM-MSCs together with HA is a safe and feasible procedure that results in a clinical and functional improvement of knee OA, especially when 100 × 10 6 cells are administered. These results pave the way for a future phase III clinical trial. Clinical Trials.gov identifier NCT02123368. Nº EudraCT: 2009-017624-72

Background Psoriasis vulgaris is the most common form of psoriasis, yet current treatments often lead to significant side effects, resulting in a high rate of therapy desertion. Here, we explored a novel therapeutic approach using the secretome from Wharton Jelly-derived mesenchymal stem cells, biologically stabilized and enhanced with hyaluronic acid (HA), its presentation is an easy-to-apply topical sponge. This formulation had previously demonstrated efficacy in vitro and in experimental psoriasis mouse models. Methods In vitro characterization studies included dynamic light scattering, nanoparticle tracking analysis, optical/electronic microscopy, microbiological experiments, and angiogenic capacity (HUVEC cells). In vivo studies included angiogenic capacity in chicken embryo chorioallantoic membrane (CAM), safety (hypersensitive and healthy volunteers), and efficacy (double-blinded and randomized patients). Results We demonstrated the presence of spherical exosomes (164 ± 87 nm, PDI of 0.38, and 1.5 × 10⁷ particles/mL) within the selected secretomes, which exhibited significant proangiogenic activity in HUVEC cells and in a CAM assay. The secretome-containing sponges displayed distinct physicochemical properties, such as the absence of nitrogen and reduced carbon and oxygen content, resulting in a more cross-linked material with thinner fibers. These characteristics extended the dispersion time in aqueous media. Microbiological testing confirmed sterility in the packed, ready-to-use secretome-HA sponges after 3 months of storage. To assess safety, we selected doses (based on total protein content) that were applied to three patients with atopic dermatitis (42 µg of protein, patch test, 5 days) and four healthy volunteers (210 µg, 15 days) with no observed adverse topical or systemic effects. In a 30-day efficacy study, 12 patients with bilateral psoriasis exhibited up to a 33% reduction in mPASI scores and a 41% decrease in plaque size. Additionally, transepidermal water loss (TEWL) was reduced by up to 30%, while skin elasticity/flexibility improved by 43%. Conclusions These findings suggest that the topical application of the secretome-HA sponge is a safe and effective therapeutic option for alleviating symptoms of psoriasis vulgaris . Trial registration SSMN, SSMN047/2021. Registered 27 October 2021, https://www.ssmn.cl/comite_etica.php . Graphical abstract

Hyaluronic acid (HA) is a natural polymer, produced endogenously by the human body, which has unique physicochemical and biological properties, exhibiting desirable biocompatibility and biodegradability. Therefore, it has been widely studied for possible applications in the area of inflammatory diseases. Although exogenous HA has been described as unable to restore or replace the properties and activities of endogenous HA, it can still provide satisfactory pain relief. This review aims to discuss the advances that have been achieved in the treatment of inflammatory diseases using hyaluronic acid as a key ingredient, essentially focusing on studies carried out between the years 2017 and 2021.

Background Keratosis pilaris (KP) is a prevalent benign dermatological condition characterized by small bumps at the hair follicles alongside surrounding redness, significantly impacting both aesthetics and mental well‐being. Objective This study investigated the potential benefits of a non‐cross‐linked hyaluronic acid (HA) compound for treating KP. Methods A split‐body, investigator‐blinded, randomized, intraindividual comparative clinical trial was conducted. The non‐cross‐linked HA compound was injected into KP‐affected regions on both upper arms. The treatment was delivered across four sessions scheduled at 4‐week intervals. Blinded physicians and patients assessed differences in erythema, skin roughness, and overall scores between treated and control areas at the final follow‐up visit. At the 12th and 24th weeks post‐treatment, a four‐point scale was utilized to assess subjects' perceived treatment efficacy. Additionally, dermoscopic images, histological alterations, and adverse events were monitored. Results Physician assessments revealed a significant reduction in roughness and overall scores for treated areas compared to controls. Patient self‐assessments also reflected improvements in roughness, redness, and overall scores for treated sides at the final visit, with 35.71% of patients demonstrating sustained improvement in redness and 71.43% reporting persistent improvements in roughness at 24th weeks post‐treatment. The dermatoscopic examinations revealed a notable enhancement in both the quantity of follicular plugs and the extent of erythema among the subjects in the treatment group. Histopathological outcomes also demonstrated improvement. Conclusion This study suggests that the non‐cross‐linked HA compound effectively improves skin roughness and promotes hair shaft growth in KP treatment, demonstrating a favorable safety profile. These findings position it as a potentially viable alternative therapy in clinical practice.

The discovery of several unexpected complex biological roles of hyaluronic acid (HA) has promoted new research impetus for biologists and, the clinical interest in several fields of medicine, such as ophthalmology, articular pathologies, cutaneous repair, skin remodeling, vascular prosthesis, adipose tissue engineering, nerve reconstruction and cancer therapy. In addition, the great potential of HA in medicine has stimulated the interest of pharmaceutical companies which, by means of new technologies can produce HA and several new derivatives in order to increase both the residence time in a variety of human tissues and the anti-inflammatory properties. Minor chemical modifications of the molecule, such as the esterification with benzyl alcohol (Hyaff-11® biomaterials), have made possible the production of water-insoluble polymers that have been manufactured in various forms: membranes, gauzes, nonwoven meshes, gels, tubes. All these biomaterials are used as wound-covering, anti-adhesive devices and as scaffolds for tissue engineering, such as epidermis, dermis, micro-vascularized skin, cartilage and bone. In this review, the essential biological functions of HA and the applications of its derivatives for pharmaceutical and tissue regeneration purposes are reviewed.

Naked mole-rat (NMR), the longest-living rodent, produces very-high-molecular-mass hyaluronan (vHMM-HA), compared to other mammalian species. However, it is unclear if exceptional polymer length of vHMM-HA is important for longevity. Here, we show that vHMM-HA (>6.1 MDa) has superior cytoprotective properties compared to the shorter HMM-HA. It protects not only NMR cells, but also mouse and human cells from stress-induced cell-cycle arrest and cell death in a polymer length-dependent manner. The cytoprotective effect is dependent on the major HA-receptor, CD44. We find that vHMM-HA suppresses CD44 protein-protein interactions, whereas HMM-HA promotes them. As a result, vHMM-HA and HMM-HA induce opposing effects on the expression of CD44-dependent genes, which are associated with the p53 pathway. Concomitantly, vHMM-HA partially attenuates p53 and protects cells from stress in a p53-dependent manner. Our results implicate vHMM-HA in anti-aging mechanisms and suggest the potential applications of vHMM-HA for enhancing cellular stress resistance. Naked mole rats are the longest-lived rodents and produce very-high-molecular-mass hyaluronan (vHMM-HA). Here the authors show that naked mole rat vHMM-HA is better at protecting mouse and human cells from cell cycle arrest and cell death, compared to the high-molecular-mass hyaluronan produced by these species.

Objectives:The primary objective was to compare a single, 6 ml, intra-articular injection of hylan G-F 20 with placebo in patients with symptomatic knee osteoarthritis. The safety of a repeat injection of hylan G-F 20 was also assessed.Methods:Patients with primary osteoarthritis knee pain were randomly assigned to arthrocentesis plus a 6 ml intra-articular injection of either hylan G-F 20 or placebo in a prospective, double-blind (one injector/one blinded observer) study. Results were evaluated at 4, 8, 12, 18 and 26 weeks post-injection. The primary outcome criterion was change from baseline over 26 weeks in Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index A pain. Secondary outcome measures included WOMAC A1 and C, patient global assessment (PGA) and clinical observer global assessment (COGA) and Outcome Measures in Rheumatology, Osteoarthritis Research Society International responder rates. A 4-week, open, repeat treatment phase evaluated safety only.Results:A total of 253 patients (Kellgren–Lawrence grade II or III) was randomly assigned. Patients receiving hylan G-F 20 experienced statistically significantly greater improvements in WOMAC A pain scores (−0.15, SE 0.076, p = 0.047), and several of the secondary outcome measures (WOMAC A1, PGA and COGA), than patients receiving placebo. There was no difference between the safety results of the two groups. No increased risk of local adverse events was observed in the open, repeat treatment phase.Conclusions:This placebo-controlled study demonstrated that, in patients with knee osteoarthritis, a single 6 ml intra-articular injection of hylan G-F 20 is safe and effective in providing statistically significant, clinically relevant pain relief over 26 weeks, with a modest difference versus placebo.Trial registration number:NCT00131352.

Objective AMELIA (OsteoArthritis Modifying Effects of Long-term Intra-articular Adant) was designed to compare against placebo the efficacy and safety of repeated injections of hyaluronic acid (HA) and its effect on disease progression over 40 months. Methods A multicentre, randomised, patient and evaluator-blinded, controlled study in 306 patients fulfilling American College of Rheumatology criteria for knee osteoarthritis, radiological grades II–III (Kellgren–Lawrence) and joint space width ≥2 mm. Patients received four cycles of five intra-articular HA or placebo injections with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles. Osteoarthritis Research Society International (OARSI) 2004 responder criteria were used to assess efficacy. The consumption of rescue medication was a secondary outcome. Adverse events were recorded for safety purposes. Results At the 40-month visit significantly more patients responded to HA compared with placebo (OARSI 2004, p=0.004). The number of responders to HA increased through the study, whereas those to placebo did not change. Significant differences were also found in favour of HA for each individual component of the OARSI 2004. No safety problems were recorded. Conclusions The results of AMELIA offer pioneer evidence that repeated cycles of intra-articular injections of HA not only improve knee osteoarthritis symptoms during the in-between cycle period but also exert a marked carry-over effect for at least 1 year after the last cycle. In this respect, it is not possible to establish if this carry-over effect reflects true osteoarthritis remission or just a modification of the disease's natural course. ClinicalTrials.gov number, NCT00669032

Female sexual dysfunction is highly prevalent among postmenopausal females approaching 50%, with vulvovaginal atrophy (VVA) being a cardinal sign. For decades, hormone replacement therapy was the only solution to relieve symptoms associated with this atrophy. However, it was limited by its serious side effects, raising the need for new treatment strategies. This study aims to compare the efficacy and safety of injection of hyaluronic acid (HA) versus platelet rich plasma (PRP) in post-menopausal females presented with VVA to improve female sexual dysfunction. Twenty post-menopausal females presented with VVA were randomly divided into two groups, 10 patients in each group. Both groups received three sessions of injections into the vulva and vagina, one month apart. Group I was injected with non cross linked HA while Group II received PRP injection. Subjective assessment was carried out through female sexual function index questionnaire and global aesthetic improvement scale.While objective assessment was carried out by measuring the labia majora length and reviewing the histopathological changes occurring in the vulva through skin biopsies before and after treatment. The change in vaginal thickness was estimated by transvaginal ultrasound. Results showed that both HA as well as PRP were effective in the treatment of post-menopausal vulvovaginal atrophy. However, HA showed more significant improvement in female sexual dysfunction. There were also higher values in vaginal wall thickness as measured by transvaginal ultrasound in favor of HA injected group. Histopathological assessment showed more collagen deposition in papillary dermis in HA treated group. No complications were reported in both groups.

Background The selection of dermal fillers in aesthetic medicine often relies on factors such as cost, immediate outcomes, and practitioner experience. However, incorporating knowledge of fillers' rheological properties, such as viscoelasticity and cohesiveness, allows for more precise product selection tailored to patient needs and treatment goals while reducing the risk of complications. Aims This review aims to summarize essential considerations for filler selection, focusing on rheological properties, safety profiles, and clinical applications. Additionally, it seeks to highlight differences between hyaluronic acid (HA) fillers and non‐HA fillers to guide practitioners in aesthetic procedures. Patients/Methods A systematic review was conducted following PRISMA guidelines. Searches across PubMed, Scopus, Web of Science, and the Cochrane Library yielded 619 articles. After duplicate removal and rigorous screening, 50 peer‐reviewed studies were included. Data extraction focused on filler types, rheological properties (e.g., G′ and G″ values), safety, and efficacy. Results HA fillers, particularly monophasic types, exhibit smoother consistency and better cohesiveness, making them ideal for high‐mobility areas like the mouth. Biphasic fillers, with higher viscoelasticity, provide superior lifting capacity for deeper tissue support. Non‐HA fillers, such as poly‐L‐lactic acid and calcium hydroxylapatite, offer longer‐lasting results but require precise techniques due to irreversibility. Proper selection based on filler rheology, target area, and patient needs can mitigate risks such as overfilled syndrome, Tyndall effect, and delayed inflammatory responses. Conclusions Understanding the rheological and safety profiles of fillers is essential for achieving optimal aesthetic outcomes. HA fillers are recommended for novice practitioners due to their reversibility, while experienced clinicians may explore non‐HA options. Tailored filler selection based on rheological properties and clinical context ensures safer and more effective treatments.