Cross-linked Hyaluronic Acid Research Articles

Single-cell RNA sequencing analysis of the retina under acute high intraocular pressure.

JOURNAL/nrgr/04.03/01300535-202419110-00032/figure1/v/2024-03-08T184507Z/r/image-tiff High intraocular pressure causes retinal ganglion cell injury in primary and secondary glaucoma diseases, yet the molecular landscape characteristics of retinal cells under high intraocular pressure remain unknown. Rat models of acute hypertension ocular pressure were established by injection of cross-linked hyaluronic acid hydrogel (Healaflow®). Single-cell RNA sequencing was then used to describe the cellular composition and molecular profile of the retina following high intraocular pressure. Our results identified a total of 12 cell types, namely retinal pigment epithelial cells, rod-photoreceptor cells, bipolar cells, Müller cells, microglia, cone-photoreceptor cells, retinal ganglion cells, endothelial cells, retinal progenitor cells, oligodendrocytes, pericytes, and fibroblasts. The single-cell RNA sequencing analysis of the retina under acute high intraocular pressure revealed obvious changes in the proportions of various retinal cells, with ganglion cells decreased by 23%. Hematoxylin and eosin staining and TUNEL staining confirmed the damage to retinal ganglion cells under high intraocular pressure. We extracted data from retinal ganglion cells and analyzed the retinal ganglion cell cluster with the most distinct expression. We found upregulation of the B3gat2 gene, which is associated with neuronal migration and adhesion, and downregulation of the Tsc22d gene, which participates in inhibition of inflammation. This study is the first to reveal molecular changes and intercellular interactions in the retina under high intraocular pressure. These data contribute to understanding of the molecular mechanism of retinal injury induced by high intraocular pressure and will benefit the development of novel therapies.

The "Tunneled Sandwich" Technique for Preserving the Buccal Tissue Volume After Immediate Implantation: A Retrospective Report of 10 Cases.

The tooth loss or extraction is associated with significant diminishing the volume of alveolar ridge extensively expressed in the anterior zone. The immediate implant placement itself is considered inappropriate to overcome this problem. The proposed approach combined the technique of immediate implant placement with the enhancement of the buccal tissue by applying a cross-linked collagen matrix hydrated with a cross-linked hyaluronic acid. In a series of ten cases, all presenting with a retained but narrow buccal socket wall, an immediate implant placement along with the "tunneled sandwich" technique was performed following tooth extraction. The tunneled sandwich technique helped to create a subperiosteal pouch for insertion of the collagen matrix buccal to the alveolar bone crest. The implants healed transmucosally by receiving either a gingiva former or an immediate temporary restoration. Ten sites in ten patients demonstrated stable non-inflamed peri-implant conditions and suitable ridge volume at the implant's neck and achieved high pink esthetic scores estimated 6 months after implant loading. The "tunneled sandwich" technique appears a suitable method to preserve the buccal volume, which contributes as biologically as esthetically to favorable long-term results. Int J Periodontics Restorative Dent. 10.11607/prd.6205.

Structural insights into the biological functions of the long pentraxin PTX3.

Soluble pattern recognition molecules (PRMs) are a heterogenous group of proteins that recognize pathogen- and danger-associated molecular patterns (PAMPs and DAMPs, respectively), and cooperate with cell-borne receptors in the orchestration of innate and adaptive immune responses to pathogenic insults and tissue damage. Amongst soluble PRMs, pentraxins are a family of highly conserved proteins with distinctive structural features. Originally identified in the early 1990s as an early inflammatory gene, PTX3 is the prototype of long pentraxins. Unlike the short pentraxin C reactive protein (CRP), whose expression is mostly confined to the liver, PTX3 is made by several immune and non-immune cells at sites of infection and inflammation, where it intercepts fundamental aspects of infection immunity, inflammation, and tissue remodeling. Of note, PTX3 cross talks to components of the complement system to control cancer-related inflammation and disposal of pathogens. Also, it is an essential component of inflammatory extracellular matrices (ECMs) through crosslinking of hyaluronic acid and turn-over of provisional fibrin networks that assemble at sites of tissue injury. This functional diversity is mediated by unique structural characteristics whose fine details have been unveiled only recently. Here, we revisit the structure/function relationships of this long pentraxin in light of the most recent advances in its structural biology, with a focus on the interplay with complement and the emerging roles as a component of the ECM. Differences to and similarities with the short pentraxins are highlighted and discussed.

Clinical evaluation of sodium hypochlorite/amino acids and cross-linked hyaluronic acid adjunctive to non-surgical periodontal treatment: a randomized controlled clinical trial

ObjectivesTo compare the clinical outcomes obtained with either mechanical subgingival debridement in conjunction with a sodium hypochlorite and amino acids containing gel followed by subsequent application of a cross-linked hyaluronic acid gel (xHyA) gel, or with mechanical debridement alone.Materials and MethodsFourty-eight patients diagnosed with stages II-III (Grades A/B) generalised periodontitis were randomly treated with either scaling and root planing (SRP) (control) or SRP plus adjunctive sodium hypochlorite/amino acid and xHyA gels (test). The primary outcome variable was reduction of probing depth (PD), while changes in clinical attachment level (CAL), bleeding on probing (BOP) and plaque index (PI) were secondary outcomes. The outcomes were assessed at baseline, at 3 and 6 months following therapy.ResultsAll patients completed the 6 months evaluation. At 6 months, the test group showed statistically significantly better results in terms of mean PD reduction (2.9 ± 0.4 vs 1.8 ± 0.6 mm, p < 0.001). Similarly, mean CAL gain was statistically higher in the test group compared to the control one (test: 2.6 ± 0.5 vs control: 1.6 ± 0.6 mm, p < 0.001). Mean BOP decreased from 81.8 ± 16.2% to 48.9 ± 14.5% in control (p < 0.001) and from 83.2 ± 15.5% to 17.6 ± 11.5% in test (p < 0.001) groups with a statistically significant difference favouring the test group (p < 0.001). Mean PI scores were reduced statistically significantly in both groups (from 38.8 ± 26% to 26.5 ± 20.5% in control (p = 0.039) and from 60.6 ± 10.9% to 12.7 ± 8.9% in test group (p < 0.001)), with a statistically significant difference between the groups (p < 0.001). The number of moderate pockets (4–6 mm) were reduced from 1518 (41.2%) to 803 (22.6%) in the control and from 1803 (48.6%) to 234 (7.7%) in the test group with a statistically significant difference between the groups (p < 0.001), while the number of deep pockets (≥ 7 mm) changed from 277 (7.6%) to 35 (1.0%) in the control and from 298 (8.7%) to 4 (0.1%) in test group (p = 0.003).ConclusionWithin their limits the present data indicate that: a) both treatments resulted in statistically significant improvements in all evaluated clinical parameters, and b) the adjunctive subgingival application of sodium hypochlorite/amino acid and xHyA to SRP yielded statistically significantly higher improvements compared to SRP alone.Clinical relevanceThe combination of sodium hypochlorite/amino acid and xHyA gels to subgingival mechanical debridement appears to represent a valuable approach to additionally improve the outcomes of non-surgical periodontal treatment.Clinical Trial Registration Number NCT04662216 (ClinicalTrials.gov).

Effects of Cross-linked Hyaluronic Acid in a Rat Model of Vestibular and Cochlear Toxicity.

To investigate the effects of cross-linked hyaluronic acid (CLHA) in an experimental model of vestibulotoxicity and cochleotoxicity. Twenty-eight female Wistar albino rats (200-250 g) were divided into four groups. Group A received 0.06 mL of 13.33 mg/mL gentamicin, Group B received 0.06 mL of CLHA, Group C received 0.03 mL of 26.66 mg/mL gentamicin and 0.03 mL CLHA, and Group D received 0.06 mL of 0.09% saline. All groups underwent auditory brainstem response testing at 4-32 kHz, signal-to-noise ratio of distortion product otoacoustic emission measurements at 1.5-8 kHz and vestibular tests on days 0,1,7,10. The rats were sacrificed, and their labyrinths were histologically assessed and scored. The hearing thresholds of Groups A and C were similar and significantly higher than those of the other groups at all frequencies, beginning from day 1. The vestibular and histological scores of Groups A and C were similar and significantly higher than those of the other groups from day 1. The audiological results, vestibular scores, and histological scores of Groups B and D were similar, except for a temporary middle ear effusion and hearing threshold shift in Group B. No significant deterioration was observed in the audiological, vestibular, and histological analyses of Groups B and D. That both Group A and Group C similarly showed worsening audiological, vestibular, and histological tests suggests that CLHA did not alter the pharmacokinetics and histologic results of gentamicin.

HArmonyCa: a first-in-class, hybrid, dual-functioning hyaluronic acid/calcium hydroxyapatite dermal filler

HArmonyCa is a first-in-class, dual-action, synthetic non-pyrogenic biodegradable hybrid dermal filler composed of calcium hydroxyapatite (CAHa) (55.5%) and cross-linked hyaluronic acid (44.5%) that is clinically indicated to enhance volume as well as lift and rejuvenate the mid and lower face and overlying skin. Its effects are illustrated in three case studies. Significant and immediate improvements in cheek projection, lifting of the midface, reduction of the pre-jowl sulcus and in the depth of the nasojugal groove were observed in these cases. The hybrid injectable is effective with a good tolerability profile, with the patients reporting a high level of satisfaction. The early clinical changes that were seen resulted mainly from the cross-linked hyaluronic acid filler and, secondly, from the CAHa. CAHa microspheres have been demonstrated to provide long-term efficacy through regional collagen synthesis. Effects will be monitored in the treated cases at 6, 12 and 18 months.

Clinical Evaluation of a Novel Combination of Sodium Hypochlorite/Amino Acid and Cross-linked Hyaluronic Acid Adjunctive to Non-surgical Periodontal Treatment: A Case Series.

The adjunctive subgingival application of sodium hypochlorite/amino acid and a mixture of natural and cross-linked hyaluronic acid gels (high molecular weight) has been recently proposed as a novel modality to enhance the outcomes of non-surgical periodontal therapy. The aim of this prospective case series was to evaluate the clinical outcomes obtained following the subgingival application of a combination of sodium hypochlorite/amino acid and a mixture of natural and cross-linked hyaluronic acid (high molecular) gels in conjunction with non-surgical periodontal therapy. Twenty-one systemically healthy, non-smoking patients diagnosed with stage II-III, grade A/B periodontitis underwent full-mouth subgingival debridement (SD) performed with ultrasonic and hand instruments. All sites with probing depths (PD) ≥ 4 mm were treated with additional repeated (i.e., 2-3 times) instillation of sodium hypochlorite/amino acid gel in the periodontal pockets prior to and during SRP. Following mechanical debridement, a mixture of natural and cross-linked hyaluronic acid (high molecular) gel was applied in the pockets. The primary outcome variable was PD reduction; changes in clinical attachment level (CAL) and bleeding on probing (BOP) were the secondary outcomes. The clinical parameters were assessed at baseline, 3 and 6 months after therapy. Compared to baseline, a statistically significant mean reduction of PD values was obtained after 3 and 6 months, amounting to 2.6 ± 0.4 mm, and 2.9 ± 0.4 mm, respectively (p < 0.001). Mean CAL gain measured 2.3 ± 0.5 mm at 3 months and 2.6 ± 0.5 mm at 6 months in comparison to baseline (p < 0.001). Mean reduction of BOP values was 54.9 ± 16.9 % at 3 months and 65.6 ± 16.4 % at 6 months (p < 0.001). The number of moderate pockets (4-5 mm) decreased from 1808 at baseline to 274 at the 6-month evaluation, and the number of deep (≥ 6 mm) pockets dropped from 319 to 3, respectively. The combination of sodium hypochlorite/amino acid and a mixture of natural and cross-linked hyaluronic acid (high molecular) adjunctive to subgingival debridement may represent a valuable approach to improve the outcomes of non-surgical periodontal treatment.

Skin Cell and Tissue Responses to Cross-Linked Hyaluronic Acid in Low-Grade Inflammatory Conditions.

Hyaluronic acid (HA), used in a variety of medical applications, is associated in rare instances to long-term adverse effects. Although the aetiology of these events is unknown, a number of hypotheses have been proposed, including low molecular weight of HA (LMW-HA) in the filler products. We hypothesized that cross-linked HA and its degradation products, in a low-grade inflammatory microenvironment, could impact immune responses that could affect cell behaviours in the dermis. Using two different cross-linking technologies VYC-15L and HYC-24L+, and their hyaluronidase-induced degradation products, we observed for nondegraded HA, VYC-15L and HYC-24L+, a moderate and transient increase in IL-1β, TNF-α in M1 macrophages under low-grade inflammatory conditions. Endothelial cells and fibroblasts were preconditioned using inflammatory medium produced by M1 macrophages. 24 h after LMW-HA fragments and HA stimulation, no cytokine was released in these preconditioned cells. To further characterize HA responses, we used a novel in vivo murine model exhibiting a systemic low-grade inflammatory phenotype. The intradermal injection of VYC-15L and its degradation products induced an inflammation and cell infiltration into the skin that was more pronounced than those by HYC-24L+. This acute cutaneous inflammation was likely due to mechanical effects due to filler injection and tissue integration rather than its biological effects on inflammation. VYC-15L and its degradation product potentiated microvascular response to acetylcholine in the presence of a low-grade inflammation. The different responses with 2D cell models and mouse model using the two tested cross-linking HA technologies showed the importance to use integrative complex model to better understand the effects of HA products according to inflammatory state.

Injection Treatments for Vulvovaginal Atrophy of Menopause: A Systematic Review.

Injection treatments have been proposed as novel treatment options for Vulvovaginal Atrophy of Menopause (VVA) also known as Genitourinary Syndrome of Menopause (GSM). However, to date data about these treatments are poor. To assess all available injection treatments for VVA. A systematic review was performed by searching five electronic databases for peer-reviewed studies that assessed injection treatments for VVA. Eight studies (7 observational and 1 randomized) with 236 women were included. Assessed injection materials were: autologous platelet-rich plasma (PRP) + hyaluronic acid (HA), not cross-linked HA plus calcium hydroxyapatite (NCLHA + CaHA), micro-fragmented adipose tissue (MFAT), hyaluronan hybrid cooperative complexes (HCC), crosslinked HA, microfat and nanofat grafting + PRP, and PRP alone. Improvement in GSM symptoms after treatment was assessed through Visual Analogic Scale (VAS) for GSM symptoms or patient satisfaction, several validated questionnaires (FSFI, VHI, FSD, SF12, ICIQ UI SF, PGI-I, FSDS-R, VSQ), symptoms severity, changes in vaginal mucosa thickness, flora, pH, and expression on vaginal mucosal biopsies of Procollagen I and III and ki67 immunofluorescence or COL1A1 and COL3A1 mRNA. Injection treatments showing significant improvement in GSM-related symptoms were: (i) HCC in terms of VAS for GSM symptoms and FSFI score; (ii) Crosslinked HA in terms of VAS for GSM symptoms, FSFI and VHI score, COL1A1 and COL3A1 mRNA expression on vaginal mucosal biopsies; (iii) NCLHA + CaHA in terms of FSFI score; (iv) PRP + HA in terms of VHI, FSD and SF12 score; (v) microfat and nanofat grafting + PRP in terms of VHI score and FSDS-R score; (vi) PRP alone in terms of VHI and VSQ scores. All assessed injection treatments except for MFAT seem to lead to significant improvement in VVA symptoms on validated questionnaires. Further studies are necessary in the field. 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 .

Self-Assembly of RGD-Functionalized Recombinant Spider Silk Protein into Microspheres in Physiological Buffer and in the Presence of Hyaluronic Acid.

Biomaterials made of self-assembling protein building blocks are widely explored for biomedical applications, for example, as drug carriers, tissue engineering scaffolds, and functionalized coatings. It has previously been shown that a recombinant spider silk protein functionalized with a cell binding motif from fibronectin, FN-4RepCT (FN-silk), self-assembles into fibrillar structures at interfaces, i.e., membranes, fibers, or foams at liquid/air interfaces, and fibrillar coatings at liquid/solid interfaces. Recently, we observed that FN-silk also assembles into microspheres in the bulk of a physiological buffer (PBS) solution. Herein, we investigate the self-assembly process of FN-silk into microspheres in the bulk and how its progression is affected by the presence of hyaluronic acid (HA), both in solution and in a cross-linked HA hydrogel. Moreover, we characterize the size, morphology, mesostructure, and protein secondary structure of the FN-silk microspheres prepared in PBS and HA. Finally, we examine how the FN-silk microspheres can be used to mediate cell adhesion and spreading of human mesenchymal stem cells (hMSCs) during cell culture. These investigations contribute to our fundamental understanding of the self-assembly of silk protein into materials and demonstrate the use of silk microspheres as additives for cell culture applications.

Progressive Facial Haemiatrophy (Parry–Romberg Syndrome) Treated with Hyaluronic Acid Fillers

Introduction: Parry–Romberg syndrome (PRS) is a rare neurocutaneous condition that can affect the skin, subcutaneous fat, muscle, and bone on one side of the face. PRS presents with progressive but self-limiting facial haemiatrophy, and its severity ranges from barely noticeable asymmetry to severe disfigurement. The authors describe a 35-year-old male with right facial haemiatrophy. The patient presented in a stable condition at the initial consultation. Objectives: Adipose tissue autografts were the most used tool to treat many congenital or acquired facial deformities. The authors proposed using cross-linked hyaluronic acid (HA) fillers over those traditionally used to correct facial deformities due to PRS. Discussion: PRS is usually self-limiting, with the maximal progression of the disease 2–5 years after onset. There is no specific cure for PRS at present. After 7 years of progression from the onset, this patient entered a stable phase. Reconstructive treatment was then indicated, since there were no further signs of atrophy. Since adipose tissue autografts require complicated surgical skills, which take a lot of time and cost, the authors report a case of PRS augmented by HA filler in a 35-year-old male patient to suggest that HA filler could be a safe and simple alternative to surgical treatment. The authors conclude that HA fillers are a safe tool for treating facial deformities in patients with PRS.

High molecular weight hyaluronic acid drastically reduces chemotherapy-induced mucositis and apoptotic cell death

Oral and intestinal mucositis (OIM) are debilitating inflammatory diseases initiated by oxidative stress, resulting in epithelial cell death and are frequently observed in cancer patients undergoing chemo-radiotherapy. There are currently few preventative strategies for this debilitating condition. Therefore, the development of a safe and effective mucositis mitigating strategy is an unmet medical need. Hyaluronic acid (HA) preparations have been tentatively used in oral mucositis. However, the protective effects of HA in chemotherapy-induced mucositis and their underlying mechanisms remain to be fully elucidated. This study aimed to assess these mechanisms using multiple formulations of enriched HA (Mucosamin®), cross-linked (xl-), and non-crosslinked high molecular weight HA (H-MW-HA) in an oxidative stress-induced model of human oral mucosal injury in vitro and an in vivo murine model of 5-flurouracil (5-FU)-induced oral/intestinal mucositis. All tested HA formulations protected against oxidative stress-induced damage in vitro without inducing cytotoxicity, with H-MW-HA also significantly reducing ROS production. Daily supplementation with H-MW-HA in vivo drastically reduced the severity of 5-FU-induced OIM, prevented apoptotic damage and reduced COX-2 enzyme activity in both the oral and intestinal epithelium. In 5-FU-injected mice, HA supplementation also significantly reduced serum levels of IL-6 and the chemokine CXCL1/KC, while the serum antioxidant activity of superoxide dismutase was elevated. Our data suggest that H-MW-HA attenuates 5-FU-induced OIM, at least partly, by impeding apoptosis, inhibiting of oxidative stress and suppressing inflammatory cytokines. This study supports the development of H-MW-HA preparations for preventing OIM in patients receiving chemotherapy.

Injection of Enriched Hyaluronic Acid for Vaginal Dryness in a Tamoxifen User

Studies indicate that &gt; 90% of breast cancer survivors taking adjuvant endocrine therapy as tamoxifen experience menopausal symptoms, including vaginal dryness and dyspareunia. Unfortunately, these sexual problems are closely related to depression and early discontinuation of treatment. The injectable use of cross-linked Hyaluronic Acid (HA) gel in the vaginal walls has demonstrated encouraging results in improving the symptoms of vaginal dryness but it was associated with non-thrombotic pulmonar embolism. We report the case of a young female patient, 39 years old, using tamoxifen for 4 years for preventing breast cancer recurrence, with vaginal dryness and dyspareunia, whose injection of a liquid formulation, containing non-cross linked hyaluronic acid, antioxidants and amino acids brought significant clinical improvement of sexual concerns.

Evaluation of Non-Cross Linked Xeno-Free Hyaluronic Acid Solutions as Visco Elastic Biomaterials.

Hyaluronic acid (HA) is a naturally occurring biodegradable, high molecular weight, non-sulfated glycosaminoglycan (GAG) polymer known for its excellent biocompatibility. HA-based products are widely used as viscosupplements, dermal fillers, and ophthalmic lubricants in clinical settings. Although animal and bacterial-derived HA are commonly reported, plant-sourced HA is not frequently reported. In this study, we have evaluated various viscoelastic properties of one such plant-based HA solution and propose them as an alternative to existing animal/bacteria-sourced HA. The viscoelastic properties of plant-sourced HA solution of various concentrations (0.1%, 0.5%, 1%, and 2% in PBS) were studied using a rheometer at 37°C. Flow curves, amplitude sweep studies, and frequency sweep studies were performed and compared for all HA solutions. The HA solutions displayed shear-thinning behavior, which is an important characteristic of an injectable biomaterial. The 0.1 and 0.5% HA were found to have viscoelastic properties appropriate for eye lubricants, while 1 and 2% HA solutions showed properties suitable for soft tissue fillers. Frequency sweep studies indicated that all the samples are typically viscoelastic liquids with a loss modulus (G″) higher than the storage modulus (G'). This indicated that the samples needed further processing like crosslinking of HA or using higher molecular weight HA to be suitable as viscosupplements. However, the frequency sweep studies also indicated that these solutions can be used as soft tissue fillers of any type based on the G' and tan δ values. The plant-sourced HA solutions are found to exhibit good shear-thinning properties with viscoelastic properties suitable for eye lubricants and soft tissue fillers. However, to be used as viscosupplements, the viscoelastic properties of HA solutions have to be further modified through non-toxic crosslinking strategies, and hydrophobic derivatives as well as by using high molecular weight HAs.

In vitro activity of hyaluronic acid and human serum on periodontal biofilm and periodontal ligament fibroblasts

ObjectivesA beneficial effect of cross-linked hyaluronic acid (cHA) on periodontal wound healing and regeneration has recently been demonstrated. The present in vitro study was designed to obtain deeper knowledge on the effect of cHA when applied in the gingival sulcus (serum-rich environment) during non-surgical periodontal therapy.Materials and methodsThe influence of cHA, human serum (HS), and cHA/HS on (i) a 12-species biofilm formation, (ii) the adhesion of periodontal ligament fibroblasts (PDLF) to dentine surface, (iii) the expression and secretion of interleukin-8, and (iv) the expression of receptors of HA in PDLF and gingival fibroblasts (GF) were evaluated.ResultsAt 4 h of biofilm formation, cHA and HS in combination (cHA/HS) slightly decreased the colony-forming unit counts in biofilm whereas the metabolic activity of biofilm was reduced in all test groups (cHA, HS, cHA/HS) vs. control. At 24 h, the quantity of biofilm was reduced in all test groups vs. untreated control. The test substances did not affect adhesion of PDLF to dentin. HS increased the expression of IL-8 by PDLF and GF which was partially downregulated by cHA. HS and/or cHA promoted the expression of the HA receptor RHAMM in GF but not in PDLF.ConclusionsIn summary, the present data indicate that serum neither negatively affect the activity of cHA against periodontal biofilm nor had any unwanted influence on the activity of PDLF.Clinical relevanceThese findings lend additional support for the positive effects of cHA on cells involved in periodontal wound healing, thus pointing to its potential use in non-surgical periodontal therapy.

Safety and effectiveness of intra-articular injection of a highly cross-linked hyaluronic acid, LBSA0103 (Synovian): Results from a post-marketing surveillance study in South Korea.

This study aimed to assess the safety and effectiveness of the highly cross-linked hyaluronic acid-LBSA0103-in patients with knee osteoarthritis (OA) as per the prescribing information (PI) in South Korea. A total of 3,140 subjects aged ≥19 years were enrolled in this post-marketing surveillance (PMS) study from 2013 to 2019. The subjects received one or two injections of LBSA0103. The median duration of follow-up was 308 days. Adverse events (AEs), adverse drug reactions (ADRs), and serious AEs (SAEs) were monitored. Effectiveness was evaluated based on an index of effectiveness in accordance with the guidelines established by the Ministry of Food and Drug Safety and using a 100-mm visual analog scale (VAS) for weight-bearing pain. Overall, 250 subjects (7.96%) experienced 292 AEs and of these, unexpected AEs occurred in 114 subjects (3.63% [95% CI: 3.00-4.35]). Injection site pain was the most frequent AE reported by 81 subjects (2.58% [95% confidence intervals (CI): 2.05-3.20]). One hundred subjects experienced 108 ADRs (3.18% [95% CI: 2.60, 3.86]) and 15 unexpected ADRs were experienced by 13 subjects (0.41% [95% CI: 0.22-0.71]). Seventeen subjects experienced 22 SAEs (0.54% [95% CI: 0.32-0.87]) during the entire PMS period, and all were considered "unlikely" related to the study drug. Most AEs were mild in terms of severity and resolved during the study period. LBSA0103 was also effective in relieving symptomatic pain in knee OA patients. The condition in more than 80% of the subjects was considered to be improved when assessed by the investigators. LBSA0103 resulted in a significant reduction in the mean VAS score at 12 weeks after the first and second injections (24.79 (± 20.55) mm and 17.63 (±12.31) mm, respectively; p<0.0001). In conclusion, LBSA0103, used for the treatment of knee OA in a real-world setting, was well tolerated, with an acceptable safety profile and consistent therapeutic effect.

In Knee OA, Adding Hyaluronic Acid (HA) Vs. Cross-Linked HA to Intra-Articular Platelet-Rich Plasma Did Not Differ for Pain at 6 Months.

In Knee OA, Adding Hyaluronic Acid (HA) Vs. Cross-Linked HA to Intra-Articular Platelet-Rich Plasma Did Not Differ for Pain at 6 Months.

Deformation characteristics of hydrogel products based on cross-linked hyaluronic acid.

The cross-linked hyaluronic acid (HA) fillers are the viscoelastic hydrogel with a dominant elasticity rather than a viscosity as a useful medical device in the soft tissue augmentation. These HA fillers undergo deformation to begin the biodegradation by the biochemical and physical environment of the body, and result of deformations are closely related to clinical performance. The specific equation of molding index is newly generated and proved with Collin's equation, which is used for strong elastomers, for selecting optimal product in facial treatment. In this study, the results of amplitude sweep test from five marketed HA fillers were mathematically demonstrated for the proper clinical application. The increment of loss modulus by deformation was evaluated as a useful factor for the maintenance of optimal shape molding performance and resistance to external deformation of the cross-linked HA gel. From this study, the equation of molding index for weak viscoelastic hydrogels like HA products can be applied for choosing which products even in aesthetic plastic field. This molding index equation is compared to Collins' equation that index of deformation as elastomer like rubber and then found the positive correlation between two equations. This study could provide a basic theory that achieve useful clinical performance according to characteristics among many types of medical devices based on the molding index.

Enzymatically cross-linked hyaluronic acid hydrogels as in situ forming carriers of platelet-rich plasma: Mechanical properties and bioactivity levels evaluation

New studies have shown the great potential of the combination of in situ enzymatically cross-linked hydrogels based on tyramine derivative of hyaluronic acid (HA-TA) with platelet-rich plasma (PRP) and platelet lysate in regenerative medicine. This study describes how the presence of PRP and platelet lysate affects the kinetics of gelation, viscoelastic properties, swelling ratio, and the network structure of HA-TA hydrogels and how the encapsulation of PRP in hydrogels affects the bioactivity of released PRP determined as the ability to induce cell proliferation. The properties of hydrogels were tuned by a degree of substitution and concentration of HA-TA derivatives. The addition of platelet derivatives to the reaction mixture slowed down the cross-linking reaction and reduced elastic modulus (G′) and thus cross-linking efficiency. However, low-swellable hydrogels (7–190%) suitable for soft tissue engineering with G’ 200–1800 Pa were prepared with a gelation time within 1 min. It was confirmed that tested cross-linking reaction conditions are suitable for PRP incorporation because the total bioactivity level of PRP released from HA-TA hydrogels was ≥87% and HA-TA content in the hydrogels and thus mesh size (285–482 nm) has no significant effect on the bioactivity level of released PRP.

The role of high molecular weight hyaluronic acid in mucoadhesion on an ocular surface model

Hyaluronic acid (HA) is frequently formulated in eye drops to improve the stability of the tear film by hydration and lubrication. Mucoadhesion is related to the ocular residence time and therefore to the effectiveness of the eye drops. The ocular residence time of the HA formulation is correlated with the ability of HA to create specific strong interactions in the ocular surface with the mucus layer, mainly composed of a mixture of secreted mucins (MUC; gel forming MUC5AC and MUC2) and shed membrane-bound soluble mucins (MUC1, MUC4, and MUC16). Dry eye disease (DED) is a multifactorial pathology of the preocular tear film with possible damage to the ocular surface classified in two types: (1) aqueous-deficient dry eye and (2) evaporative dry eye, caused by a decrease in goblet cell density that reduces MUC expression and/or by meibomian gland dysfunction, that results in a drop in the lipidic fraction of the tear film.In this work, the binding affinity between HA and MUC2 has been evaluated with three complementary approaches because the secreted MUCs play a pivotal role in the viscoelastic properties of the tear film: 1. Rheological analysis, measuring the mucoadhesive index and the complex viscosity in relation to MM (Molecular Mass) and concentration; 2. Fluorescence analysis, using a fluorescent hydrophobic probe, to investigate the conformational change of MUC2 during the interaction with the HA polymer; 3. Surface plasmon resonance analysis, used to measure the affinity between MUC2 (immobilized on the surface of a sensor chip) and the HA polymers that flowed on it at the molecular level.For all these tests, the mucoadhesive performance of the natural HA linearly increases with the MM, whereas cross-linked HA and other emollient and gelling agents (formulated in artificial tears) do not show the same mucoadhesive properties (with the exception of xanthan gum). The mucoadhesive performance of high MM HA has also been confirmed in conditions that simulate the pathological condition of the tear film during DED by decreasing the MUC2 or oleic acid concentration. Physico-chemical analysis of a series of marketed artificial tears confirms the linear correlation between the MM of the HA used in the products and the mucoadhesive index measured on the ocular surface model.