Hyaluronic Acid Research Articles

Pain Management in Knee Osteoarthritis: Insights from an Exploratory Online Survey of Italian Patients and Physicians.

In Italy, knee osteoarthritis (KOA) accounts for over 5 million prevalent cases and requires long-term multidisciplinary management. The most frequent KOA symptom is pain. The aim of the survey is to provide a national overview of the current management of moderate-to-severe pain associated with KOA from both clinicians' and patients' perspectives. An exploratory qualitative survey was conducted in Italy between July and October 2023. The survey participants were members of four national scientific societies and two patient associations who were invited to participate via email and given an online questionnaire. Questions included a mix of single and multiple responses and scalar items. In total, 1473 clinicians and 150 patients with KOA completed the questionnaire. Patients rated knee pain as both the most burdensome symptom and the most frequent reason for treatment dissatisfaction and seeking consultation. One in two patients declared that they were unsatisfied/little satisfied with the current prescribed analgesic treatments. The clinicians surveyed preferentially prescribed intra-articular hyaluronic acid, oral non-steroidal anti-inflammatory drugs/paracetamol, non-pharmacological intervention, and intra-articular corticosteroids. The clinicians' selection of analgesic therapy often failed to adequately meet patients' expectations for pain relief. Our findings highlight the current unmet needs of patients with KOA in Italy and call for new approaches to effectively optimize the management of KOA-associated pain.

Fluconazole-loaded Hyaluronic Acid-modified Transfersomal Hydrogels Containing D-panthenol for Ocular Delivery in Fungal Keratitis Management.

Fungal keratitis (mycotic keratitis) is an eye infection in which the cornea is infected by fungi and such fungal keratitis management can be effectively possible by ocular administration of antifungal drugs. The main objectives of the present research were to develop and evaluate fluconazoleloaded transfersomal hydrogels for ocular delivery in the effective management of fungal keratitis. A 23 factorial design-based approach was used for statistical optimization, where (A) the ratio of lipid to edge activators, (B) the amount of hyaluronic acid (% HA), and (C) the ratio of edge activators (sodium deoxycholate to Span 80) were taken as three factors. The average vesicle diameter (Z, nm) of transfersomes was taken as a response. Further, fluconazole-loaded transfersomes (FTO) were incorporated into 1% Carbopol 940-based hydrogel (OF1) and 2% HMPC K4M-based hydrogel (OF2) containing D-panthenol (5% w/w). The optimal variable setting for the optimized formulations of FTO was (A) = 9.15, (B) = 0.30%, and (C) = 3.00. FTO exhibited 66.39 nm Z, 0.247 polydispersity index, - 33.10 mV zeta potential, and 65.38 ± 1.77 % DEE, and desirable elasticity. TEM image of FTO demonstrated a unilamellar vesicular structure. The ex vivo ocular permeation of fluconazole from transfersomal hydrogels was sustained over 24 h. All the transfersomal hydrogels showed good bioadhesion and excellent antifungal activity with respect to the zone of inhibition against Candida albicans than Aspergillus fumigates, in vitro. HET-CAM study results demonstrated that both the hydrogels were nonirritant and safe for ocular. Short-term physical stability study suggested the stability of the developed formulation. The current research demonstrated a new way to enhance the ocular penetration of fluconazole via transfersomal hydrogel formulations for ocular delivery in the effective management of fungal keratitis.

Smart Biopolymer Scaffolds Based on Hyaluronic Acid and Carbonyl Iron Microparticles: 3D Printing, Magneto-Responsive, and Cytotoxicity Study.

This study deals with utilization of the hyaluronic acid (HA) and carbonyl iron (CI) microparticles to fabricate the magneto-responsive hydrogel scaffolds that can provide triggered functionality upon application of an external magnetic field. The various combinations of the HA and CI were investigated from the rheological and viscoelastic point of view to clearly show promising behavior in connection to 3D printing. Furthermore, the swelling capabilities with water diffusion kinetics were also elucidated. Magneto-responsive performance of bulk hydrogels and their noncytotoxic nature were investigated,, and all hydrogels showed cell viability in the range 75-85%. The 3D printing of such developed systems was successful, and fundamental characterization of the scaffolds morphology (SEM and CT) has been presented. The magnetic activity of the final scaffolds was confirmed at a very low magnetic field strength of 140 kA/m, and such a scaffold also provides very good biocompatibility with NIH/3T3 fibroblasts.

Single-Dose Physically Cross-Linked Hyaluronic Acid and Lipid Hybrid Nanoparticles Containing Cyclic Guanosine Monophosphate-Adenosine Monophosphate Eliminate Established Tumors.

Activating the STING pathway in the cytosol of tumor-infiltrating antigen-presenting cells (APCs) represents a promising strategy to elicit potent antitumor immune responses for cancer therapy. However, STING agonists are mostly small hydrophilic molecules that suffer from rapid clearance and poor cytosolic delivery following systemic administration. While various nanoparticles have been developed to promote cytosolic delivery, they often exhibit premature drug release during circulation. Alternatively, stable nanoparticles with sustained release during circulation have poor cytosolic delivery. In this study, we have developed physically cross-linked hyaluronic acid (HA) and lipid hybrid nanoparticles containing cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), denoted as HLHC, to address these challenges. The HLH delivery system has sustained drug release due to multiple lipid layers physically cross-linked by HA. HLHC efficiently delivers cGAMP to the cytosol of APCs, inducing more IFNβ than cGAMP and liposomal cGAMP. HLH also improves the drug circulation time and biodistribution to the tumor compared with the liposomal formulation and free drug. Strikingly, a single dose of HLHC, but not liposomal cGAMP or free cGAMP, elicits potent antitumor immunity and regresses established MC38 tumors. A single dose of HLHC even regresses established B16F10 tumors upon combination with αPD-L1. Moreover, cured animals were protected from rechallenge with the same tumor cells. HLHC represents an efficient strategy to address delivery challenges associated with STING agonists and may have broad applications for the delivery of drugs acting in the cytosol.

Wharton's jelly of the umbilical cord serves as a natural biomaterial to promote osteogenesis.

Various factors can contribute to bone damage or loss, presenting challenges for bone regeneration. Our study explores the potential clinical applications of two processed forms of Wharton's jelly of the human umbilical cord for treating bone loss. Wharton's jelly from fresh umbilical cords underwent two distinct processes: (1) frozen Wharton's jelly (WJF), preserved with cryoprotective agents, and (2) decellularized Wharton's jelly matrix (WJD), prepared only via lyophilization without cryoprotectants. Both WJD and WJF are rich in collagen, hyaluronan, and polysaccharide proteins. Notably, WJD exhibited a porous structure lacking nuclei from human umbilical cord mesenchymal stem cells, unlike WJF. In direct contact experiments, WJD stimulated osteoblast migration, enhanced osteoblast maturation, and promoted calcium deposition for bone formation when administered to cultured rat osteoblasts. Furthermore, in transwell co-culture experiments, both WJD and WJF increased the rat osteoblast expression of RUNX2 and OPN genes, elevated alkaline phosphatase levels, and enhanced extracellular calcium precipitation, indicating their role in osteoblast maturation and new bone formation. Hyaluronic acid, one of the ingredients from WJD and WJF, was identified as a key component triggering osteogenesis. In vivo experiments involved creating circular bone defects in the calvarias of rats, where WJD and WJF were separately implanted and monitored over five months using micro-computerized tomography. Our results demonstrated that both WJD and WJF enhanced angiogenesis, collagen formation, osteoblast maturation, and bone growth within the bone defects. In summary, WJD and WJF, natural biomaterials with biocompatibility and nontoxicity, act not only as effective scaffolds but also promote osteoblast adhesion and differentiation, and accelerate osteogenesis.

Quercetin alleviates liver fibrosis via regulating glycolysis of liver sinusoidal endothelial cells and neutrophil infiltration.

Liver fibrosis, a common characteristic in various chronic liver diseases, is largely influenced by glycolysis. Quercetin (QE), a natural flavonoid known to regulate glycolysis, was studied for its effects on liver fibrosis and its underlying mechanism. In a model of liver fibrosis induced by carbon tetrachloride (CCl4), we aimed to assess pathological features, serum marker levels, and analyze the expression of glycolysis-related enzymes at both mRNA and protein levels, with a focus on changes in liver sinusoidal endothelial cells (LSECs). Our results showed that QE effectively improved liver injury and fibrosis evident by improved pathological features and lowered levels of serum markers, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyl transferase (GGT), total bile acid (TBA), total bilirubin (TBIL), direct bilirubin (DBIL), hyaluronic acid (HA), laminin (LN), and procollagen type III (PCIII). QE also decreased lactate production and downregulated the expression of glycolysis-related enzymes-pyruvate kinase M2 (PKM2), phosphofructokinase platelet (PFKP), and hexokinase II (HK2)-at both the mRNA and protein levels. QE reduced the expression and activity of these enzymes, resulting in reduced glucose consumption, adenosine triphosphate (ATP) production, and lactate generation. Further analysis revealed that QE inhibited the production of chemokine (C-X-C motif) ligand 1 (CXCL1) and suppressed neutrophil recruitment. Overall, QE showed promising therapeutic potential for liver fibrosis by targeting LSEC glycolysis and reducing neutrophil infiltration.

Ligand presentation controls collective MSC response to matrix stress relaxation in hybrid PEG-HA hydrogels

Cell interactions with the extracellular matrix (ECM) influence intracellular signaling pathways related to proliferation, differentiation, and secretion, amongst other functions. Herein, bone-marrow derived mesenchymal stromal cells (MSCs) are encapsulated in a hydrazone crosslinked hyaluronic acid (HA) hydrogel, and the extent of stress relaxation is controlled by systemic introduction of irreversible triazole crosslinks. MSCs form elongated multicellular structures within hydrogels containing RGD peptide and formulated with elastic composition slightly higher than the hydrogel percolation threshold (12 % triazole, 88 % hydrazone). A scaling analysis is presented (<RgStructure2>12 ∼Nα) to quantify cell-material interactions within these structures with the scaling exponent (α) describing either elongated (0.66) or globular (0.33) structures. Cellular interactions with the material were controlled through peptides to present integrin binding ECM cues (RGD) or cadherin binding cell-cell cues (HAVDI) and MSCs were observed to form highly elongated structures in RGD containing hydrogels (α=0.56±0.05), whereases collapsed structures were observed within HAVDI containing hydrogels (α=0.39±0.04). Finally, cytokine secretion was investigated, and a global increase in secreted cytokines was observed for collapsed structures compared to elongated. Taken together, this study presents a novel method to characterize cellular interactions within a stress relaxing hydrogel where altered cluster morphology imparts changes to cluster secretory profiles.

Polysaccharides and Peptides With Wound Healing Activity From Bacteria and Fungi.

Bacteria and fungi are natural sources of metabolites exhibiting diverse bioactive properties such as wound healing, antioxidative, antibacterial, antifungal, anti-inflammatory, antidiabetic, and anticancer activities. Two important groups of bacteria or fungi-derived metabolites with wound-healing potential are polysaccharides and peptides. In addition to bacteria-derived cellulose and hyaluronic acid and fungi-derived chitin and chitosan, these organisms also produce different polysaccharides (e.g., exopolysaccharides) with wound-healing potential. The most commonly used bacterial peptides in wound healing studies are bacteriocins and lipopeptides. Bacteria or fungi-derived polysaccharides and peptides exhibit both the in vitro and the in vivo wound healing potency. In the in vivo models, including animals and humans, these metabolites positively affect wound healing by inhibiting pathogens, exhibiting antioxidant activity, modulating inflammatory response, moisturizing the wound environment, promoting the proliferation and migration of fibroblasts and keratinocytes, increasing collagen synthesis, re-epithelialization, and angiogenesis. Therefore, peptides and polysaccharides derived from bacteria and fungi have medicinal importance. This study aims to overview current literature knowledge (especially within the past 5 years) on the in vitro and in vivo wound repair potentials of polysaccharides and peptides obtained from bacteria (Actinobacteria, Bacteroidetes, Cyanobacteria, Firmicutes, and Proteobacteria) and fungi (yeasts, filamentous microfungi, and mushrooms).

Dual-emission carbon dots-based biosensor for polarity/targeting bimodal recognition and mild photothermal therapy of tumor

It is essential to develop a multifunctional nanoplatform for biosensing, tumor diagnosis and treatment simultaneously. Herein, dual-emission fluorescent carbon dots (HA-CDs) were fabricated via a one-pot solvothermal method using spinach powder as carbon source and hyaluronic acid (HA) as targeting agent. The obtained HA-CDs exhibited outstanding optical properties, good targeted tumor and excellent photothermal conversion performance. Interestingly, HA-CDs can sensitively perceive the changes in polar environments attributed to the inherent ratiometric fluorescence characteristics, and combined with the intrinsic targeting tumor ability achieved tumor cell recognition. More importantly, the HA-CDs possess good photothermal conversion efficiency of 21.2 % to be beneficial for photothermal therapy of tumors. The survival rate of HeLa cells incubated with HA-CDs dramatically decreased to 14 % after 660 nm laser irradiation, revealing the significant tumor inhibition of HA-CDs in vitro. Notably, through individual intraperitoneal and intratumoral injection, it was found that HA-CDs demonstrated a similar tumor suppressed effect on 4T1 tumor-bearing mice exposed to laser irradiation, fully uncovering that HA-CDs can efficiently accumulate at tumor site by intraperitoneal injection. Besides, the histopathological analysis of major organs ex vivo revealed a good biosafety profile. Collectively, this strategy of designed HA-CDs provides a new multifunctional nanoplatform for potential clinical application.

Ex vivo imaging reveals the spatiotemporal control of ovulation.

During ovulation, an egg is released from an ovarian follicle, ready for fertilization. Ovulation occurs inside the body, impeding direct studies of its progression. Therefore, the exact mechanisms that control ovulation have remained unclear. Here we devised live imaging methods to study the entire process of ovulation in isolated mouse ovarian follicles. We show that ovulation proceeds through three distinct phases, follicle expansion (I), contraction (II) and rupture (III), culminating in the release of the egg. Follicle expansion is driven by hyaluronic acid secretion and an osmotic gradient-directed fluid influx into the follicle. Then, smooth muscle cells in the outer follicle drive follicle contraction. Follicle rupture begins with stigma formation, followed by the exit of follicular fluid and cumulus cells and the rapid release of the egg. These results establish a mechanistic framework for ovulation, a process of fundamental importance for reproduction.

Robust, self-lubricating and injectable dECM-loaded hydrogels based on rapid photo-crosslinking for articular cartilage regeneration

The restoration of articular cartilage poses a significant clinical challenge due to its avascular nature and the limited presence of chondrocytes. Recently, there has been a growing emphasis on developing materials that emulate the properties of cartilage to facilitate high-quality repair. Here, an injectable dECM-loaded hydrogel (HS-dECM) with potent compressive strength and self-lubricating ability was prepared by photo-crosslinking for cartilage regeneration. The HS-dECM hydrogel was formed by integrating cartilage decellularized extracellular matrix (dECM) with hyaluronic acid methacrylate (HAMA) and sulfobetaine methacrylate (SBMA). Once injected into irregular defects, a robust hydrogel was rapidly formed in situ by UV irradiation with negligible heat release. The HS-dECM hydrogel exhibited robust compressive strength (898 ± 86 kPa), excellent fatigue resistance and a low friction coefficient, and had the feasibility of minimally invasive implantation. Besides, HS-dECM hydrogel promoted chondrogenic differentiation of BMSCs in vitro and repaired articular cartilage defects in rats. Therefore, the high-performance injectable HS-dECM hydrogel represents a novel minimally invasive strategy that significantly promote the cartilage injuries repair and regeneration.

The Effect of Platelet-Rich Plasma and Hyaluronic Acid Nasal Injections in the Treatment of Traumatic Olfactory Dysfunction.

Objective: Platelet-rich plasma (PRP) has been injected into the olfactory cleft to treat olfactory dysfunction related to coronavirus disease 2019. In this study, we aimed to evaluate the effect of PRP combined with hyaluronic acid (HA) nasal injection in the treatment of traumatic olfactory dysfunction. Methods: Patients who had lost olfactory function after experiencing head trauma and were willing to receive PRP and HA nasal injections for treatment were enrolled. Before nasal injection, 10 cc of blood was drawn from the patients. The drawn blood was injected into a centrifuge tube for processing, and finally, 5 cc of the PRP mixed with HA was drawn out using an empty syringe. The PRP mixed with HA was injected into the upper part of the middle nasal septum and the medial side of the middle turbinate of the patient's nasal cavity under a nasal endoscope. The olfactory function of each patient was evaluated by the phenyl ethyl alcohol (PEA) odor detection threshold test before and at both 1 and 3 months after nasal injection and the traditional Chinese version of the University of Pennsylvania Smell Identification Test at 3 months after nasal injection. Results: A total of 28 patients received PRP and HA nasal injections between August and December of 2023 and came back for evaluation of the effect. In all, 20 (71.4%) patients felt their olfactory function improved 1 month after injection, and 24 of 28 (85.7%) patients reported their olfactory function improved at 3 months after injection. The bilateral or unilateral PEA threshold decreased in 22 (78.6%) patients 1 month after injection, and decreased in 15 (53.6%) patients 3 months after injection. Conclusions: Our results show that PRP and HA nasal injections were associated with favored patient-reported outcomes and improved the olfactory threshold in the treatment of traumatic olfactory dysfunction.

Safety and efficacy of female chin enhancement and facial contouring with a 3-point injection technique, an imaging follow up with ultrasound and magnetic resonance

This research aimed to assess the effectiveness of a 3-point injection technique using hyaluronic acid (25mg/ml HA reticulated Revanesse Shape G’ 203) to enhance the chin and mandibular border with hyaluronic acid 25mg/ml HA reticulated Revanesse Contour G’ 150. The technique involved injecting the filler into specific planes (supraperiostium for chin enhancement and subcutaneous for mandibular contouring) to achieve improved facial aesthetics. By combining needle and cannula, precise targeting was possible without severe complications. Thirty female participants with retrognathia and undefined mandibular border underwent the procedure and were evaluated at 21 days, and 9 months post-injection. Ultrasound technology facilitated accurate injections by visualizing facial structures and blood vessels. Additionally, one participant underwent magnetic resonance imaging with 3D reconstruction to confirm the precise placement of hyaluronic acid in the intended injection plane.

DEVELOPMENT OF A HUMAN-SPECIfiC 3D IN VITRO PAEDIATRIC CEREBELLAR TUMOUR MODEL USING DECELLULARISED BRAIN AUTOPSY TISSUE

Abstract AIMS Group-3 medulloblastoma (MB) is a paediatric cerebellar tumour with a dismal prognosis. Our objective was to establish a 3D in vitro model termed ‘tumoursphere matrix’ to recapitulate physiologically-relevant communication between tumour cells and reactive brain elements, aiming to discern differential gene expression in cancer cells upon co-culture with astrocytes and human brain extracellular matrix (ECM). METHOD Non-disease human autopsy brain was decellularised to generate ECM and extensively characterised to show DNA reduction, ECM ligand retention and compatibility with different cell lines. D283, D341 and D425 cells were co-cultured with primary human cerebellar astrocytes within a PEGDA hydrogel containing decellularised ECM. Following 7 days of culture, co-cultured cells were separated using fluorescence activated cell sorting to generate individual cell populations for transcriptomic analysis. RESULTS ECM characterisation showed a significant reduction in cellular material whilst retaining ECM ligands. Reduction of DNA content to 174 ng/mg was corroborated by an absence of nuclei in immunohistochemical staining. Colorimetric assays indicated collagen and glycosaminoglycan retention in decellularised ECM, and immunofluorescence confirmed retention of fibronectin, laminin and hyaluronic acid. Detection of all ECM ligands was cross-validated by Orbitrap-Secondary Ion Mass Spectrometry. Primary human cerebellar astrocytes, D283, D341 and D425 cells were cultured as spheroids within the ECM/PEGDA hydrogel for 7 days with no significant decrease in cellular viability. Cytokine and Human Matrix Metalloproteinase (MMP) Antibody Arrays showed retained cytokine and MMP expression in all three cell lines in the presence of ECM material. CONCLUSION We have developed a bespoke 3D model which can co-culture cells for over 7 days, whilst recapitulating the in vivo tumour environment. RNA sequencing on all 3 cell lines in mono and co-culture is currently in progress to identify differentially expressed genes in medulloblastoma cells upon astrocytic and brain ECM crosstalk. We hypothesise that biochemical signalling underlying this communication network will reveal putative therapeutic vulnerabilities.

Direct M2 macrophage co-culture overrides viscoelastic hydrogel mechanics to promote fibroblast activation.

Fibroblast activation drives fibrotic diseases such as pulmonary fibrosis. However, the complex interplay of how tissue mechanics and macrophage signals combine to influence fibroblast activation is not well understood. Here, we use hyaluronic acid hydrogels as a tunable cell culture system to mimic lung tissue stiffness and viscoelasticity. We applied this platform to investigate the influence of macrophage signaling on fibroblast activation. Fibroblasts cultured on stiff (50 kPa) hydrogels mimicking fibrotic tissue exhibit increased activation as measured by spreading as well as type I collagen and cadherin-11 expression compared to fibroblasts cultured on soft (1 kPa) viscoelastic hydrogels mimicking normal tissue. These trends were unchanged in fibroblasts cultured with macrophage-conditioned media. However, fibroblasts directly co-cultured with M2 macrophages show increased activation, even on soft viscoelastic hydrogels that normally suppress activation. Inhibition of interleukin 6 (IL6) signaling does not change activation in fibroblast-only cultures but ameliorates the pro-fibrotic effects of M2 macrophage co-culture. These results underscore the ability of direct M2 macrophage co-culture to override hydrogel viscoelasticity to promote fibroblast activation in an IL6-dependent manner. This work also highlights the utility of using hydrogels to deconstruct complex tissue microenvironments to better understand the interplay between microenvironmental mechanical and cellular cues.

GINGIVAL MARGIN, CORRECTION IN ORTHOPEDIC DENTISTRY

A big problem for obtaining aesthetic and functional results of dental treatment is the condition of the gingival papillae. The effectiveness of orthopedic interventions without high-quality correction of the marginal edge of the gums can lead to an unsatisfactory result and the occurrence of numerous complications Materials and methods. A literature search was conducted in the PubMed and Medline databases for the period 2000-2024, for which the following keywords were used: correction of soft gingival tissues, fixed dentures, effectiveness, front group of teeth. A general search revealed 112 sources regarding gingival margin correction in fixed dentures. The primary exclusion referred to literary sources in which the correction of the gingival margin applied to all types of prosthetics. Literary sources that contained only reference information were included in the secondary exclusion. As a result, only relevant full-text articles in professional journals remained (n=25). The purpose of the research is to analyze the methods of gingival margin correction in orthopedic dentistry at the current stage, to formulate relevant tasks for further research. Research results. Methods of restoration of the aesthetics of the marginal part of the gums during orthopedic treatment are divided into the following groups: plastic of soft and bone tissues; laboratory and technical procedures; use of materials for artificial gums. It has been established that the plastic-surgical method is used for the loss of the gingival papilla, defects of the ridge of the alveolar process, asymmetric contour of the gums, and their unaesthetic shape. Correction of the gums allows to achieve satisfactory aesthetic results both at the final stage of orthopedic treatment (prosthetics with fixed orthopedic prostheses) and at the intermediate stage of temporary prosthetics with plastic fixed prostheses. It was found that the most common methods of gingival margin correction are flap operations on the gums using the technique of lateral movement of the muco-osseous flap. These include the following types of interventions: endothelial modification from the tooth-alveolar ridge; oblique displaced flap; periosteally stimulated flap; partial or complete split flap. The positive effect of hyaluronic acid on the healing of the gingival margin and tissue regeneration has been proven. Several researches have shown the positive effects of hyaluronic acid on gingival margin healing and tissue regeneration due to its properties to stimulate cell adhesion, migration and proliferation, mediate cell signaling. The authors indicate a better effectiveness of hyaluronic acid in relation to periodontal parameters during the correction of the marginal gingival margin. The use of a laser scalpel is characterized by less pronounced traumatization of tissues, lower temporary costs for intervention, reduced blood loss, less pronounced signs of inflammation in the postoperative period, relative simplicity and cost-effectiveness of use. Conclusions. To date, only a combination of various orthopedic and surgical manipulations allows to achieve an optimal aesthetic result during prosthetics with fixed dentures of the front group of teeth.

Early Effects of Porcine Placental Extracts and Stem Cell-Derived Exosomes on Aging Stress in Skin Cells.

The initial efficacy of placental extracts (Pla-Exts) and human mesenchymal stem-cell-derived exosomes (hMSC-Exo) against aging-induced stress in human dermal fibroblasts (HDFs) was examined. The effect of Pla-Ext alone, hMSC-Exo alone, the combined effect of Pla-Ext and hMSC-Exo, and the effect of hMSC-Exo (Pla/MSC-Exo) recovered from cultures with Pla-Ext added to hMSC were verified using collagen, elastin, and hyaluronic acid synthase mRNA levels for each effect. Cells were subjected to photoaging (UV radiation), glycation (glycation end-product stimulation), and oxidation (H2O2 stimulation) as HDF stressors. Pla-Ext did not significantly affect normal skin fibroblasts with respect to intracellular parameters; however, a pro-proliferative effect was observed. Pla-Ext induced resistance to several stresses in skin fibroblasts (UV irradiation, glycation stimulation, H2O2 stimulation) and inhibited reactive oxygen species accumulation following H2O2 stimulation. Although the effects of hMSC-Exo alone or the combination of hMSC-Exo and Pla-Ext are unknown, pretreated hMSC-Exo stimulated with Pla-Ext showed changes that conferred resistance to aging stress. This suggests that Pla-Ext supplementation may cause some changes in the surface molecules or hMSC-Exo content (e.g., microRNA). In skin cells, the direct action of Pla-Ext and exosomes secreted from cultured hMSCs pretreated with Pla-Ext (Pla/MSC-Exo) also conferred resistance to early aging stress.

Evaluation of a New Technique of Gingival Smile Reduction after Hyaluronic Acid Infiltration: A Cohort Study Focusing on Gingival Exposure and Patient-Oriented Outcomes.

A gummy smile is the visualization of more than 3 mm of gingiva above the maxillary incisors. This study aimed to evaluate the long-term effects on aesthetics and patient satisfaction of a new hyaluronic acid infiltration technique in reducing the gummy smile. Fifty patients with gummy smiles were treated using hyaluronic acid infiltration points by applying 0.1 mL per injection at specific points. Post-treatment evaluations were performed one week, one month, three months, six months, and 12 months later. A questionnaire assessed patient satisfaction, willingness to recommend the treatment, and side effects (pain and bruising during and after treatment). An average reduction of 2.5 mm in gingival exposure during smiling was observed. After one week, the reduction was constant. At six months, 40% of the original gingival exposure was recovered, and recovery was complete at 12 months. Patient satisfaction was 82.1%, and 100% of patients would recommend the treatment. Bruising, swelling, and pain decreased to 0% from the first month. In conclusion, this technique is a safe and effective option to improve the smile's appearance with minimal complications.

Evaluating Synergistic Effects of Hyaluronic Acid, Human Umbilical Cord-Derived Mesenchymal Stem Cells, and Growth Hormones in Knee Osteoarthritis: A Multi-Arm Randomized Trial.

Knee osteoarthritis (OA) significantly affects quality of life and imposes economic burdens due to its prevalence and the disability it causes. The efficacy of current treatments is limited to alleviating the symptoms, and they cannot be used for regenerative purposes. This study aims to evaluate the efficacy and safety of combining hyaluronic acid (HA), human umbilical cord-derived mesenchymal stem cells (hUC-MSCs), and synthetic human growth hormone (somatotropin) in the treatment of knee OA, assessing pain relief, functional improvement, and cartilage regeneration. A four-arm, double-blind randomized trial was conducted with 51 knees from 28 subjects aged ≥50 with primary knee OA. The treatments involved were HA alone, HA with hUC-MSCs, HA with somatotropin, and a combination of all three. Efficacy was measured through the International Knee Documentation Committee (IKDC) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and visual analog score (VAS), and MRI T2 mapping of cartilage was conducted on pre-implantation at the 6th and 12th month. All treatment arms showed improvements in the VAS and WOMAC scores over 12 months, suggesting some pain relief and functional improvement. However, MRI T2 mapping showed no significant cartilage regeneration across the groups. While the combined use of HA, hUC-MSCs, and somatotropin improved symptoms of knee OA, it did not enhance cartilage regeneration significantly. This study highlights the potential of these combinations for symptom management but underscores the need for further research to optimize these therapies for regenerative outcomes.

Effectiveness and Safety of IPN-20-SENSE LIDOCAINE for Lip Volume Augmentation and/or Redefinition (SMILE Study): A Non-inferiority Randomized Double-Blinded Controlled Study.

Hyaluronic acid (HA) is a widely used dermal filler for lip augmentation. IPN-20-SENSE LIDOCAINE (Laboratoires VIVACY) is a monophasic gel consisting of cross-linked HA and includes lidocaine hydrochloride for the reduction of injection-associated pain. The SMILE study was designed to assess the non-inferiority of IPN-20-SENSE LIDOCAINE compared to HA-RK-Lido in improving aesthetic lip appearance. The secondary objectives were to evaluate the effectiveness and safety of IPN-20-SENSE LIDOCAINE against the chosen similar active control device. This was a prospective, multicenter, double-blinded, randomized active controlled parallel group study undertaken in two investigational sites between May 2021 and July 2022 (14 months). The primary endpoint of this study was the proportion of subjects reporting an improvement on the Global Aesthetic Improvement Scale (GAIS) 3 months after treatment initiation. Regarding the primary endpoint, the difference between the treatment arms in the proportion of improved subjects was +7.0[-2.2;17.7]. The lower limit of this 90%CI, being above the non-inferiority margin of -15 and below zero, demonstrated the non-inferiority of IPN-20-SENSE LIDOCAINE vs. HA-RK-Lido. The secondary outcomes reported by subjects and the blinded live evaluators supported this result. All injection site reactions and device-related adverse events reported in this study were expected, already described and were mostly mild and transient. The study demonstrated the non-inferiority of IPN-20-SENSE LIDOCAINE to HA-RK-Lido in the aesthetic improvement of the lips. The effect of both treatments decreased over time. Nonetheless, aesthetic improvement was sustained longer in the IPN-20-SENSE LIDOCAINE arm. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .