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Rationalizing the Design of Hyaluronic Acid-Decorated Liposomes for Targeting Epidermal Layers: A Combination of Molecular Dynamics and Experimental Evidence.
Franzé, S, Rama, F, Rocco, P, Debernardi, M, Bincoletto, V, Arpicco, S, Cilurzo, F
Molecular pharmaceutics. 2021;(11):3979-3989
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Abstract
This work provides information on the features of low molecular weight hyaluronic acid (HA)-decorated liposomes to target resveratrol (RSV) in the skin. Deformable liposomes were made of soy-phosphatidylcholine with Tween 80 as the fluidizing agent. For HA conjugation, three different phosphoethanolamines were tested: 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). The different phosphoethanolamine-HA conjugates were inserted into the liposome bilayer by hydration (HA on both faces of the bilayer) or by the postinsertion method (HA only on the external face of the bilayer). The effect of these variables on deformability was experimentally assessed by an in-house method (K value, the lower the value, the higher the deformability) and molecular dynamics (MD) simulations. The results showed that the K values of HA-liposomes obtained by hydration were higher than the K values of HA-liposomes prepared by postinsertion, and both were at least 10-fold higher than the K values of the corresponding plain liposomes. The nature of the lipid anchor played a key role in deformability (DMPE > DOPE > DPPE) with high variability in the case of DOPE formulations. These data were justified by the trends found in silico for the bilayer bending modulus and the HA end-to-end distance. In addition to liposome flexibility, the HA extent seems to be the key factor governing the skin penetration of RSV. When the extent is higher, the amount of the drug retained in the skin is larger. Regarding skin permeation, a parabolic trend was recorded, and the optimal amount to favor skin permeation was an approximately 30 HA/phospholipid (μg/mmol) ratio. This study reports the first piece of evidence that it is possible to control drug delivery in the skin by tuning the amount of HA on the vesicle surface.
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Hyaluronan Hydrogels for Injection in Superficial Dermal Layers: An In Vitro Characterization to Compare Performance and Unravel the Scientific Basis of Their Indication.
La Gatta, A, Aschettino, M, Stellavato, A, D'Agostino, A, Vassallo, V, Bedini, E, Bellia, G, Schiraldi, C
International journal of molecular sciences. 2021;(11)
Abstract
BACKGROUND Skinboosters represent the latest category of hyaluronan (HA) hydrogels released for aesthetic purposes. Different from originally developed gels, they are intended for more superficial injections, claiming a skin rejuvenation effect through hydration and possibly prompting biochemical effects in place of the conventional volumetric action. Here, three commercial skinboosters were characterized to unravel the scientific basis for such indication and to compare their performances. METHODS Gels were evaluated for water-soluble/insoluble-HA composition, rheology, hydration, cohesivity, stability and effect, in vitro, on human dermal fibroblasts towards the production of extracellular matrix components. RESULTS Marked differences in the insoluble-hydrogel amount and in the hydrodynamic parameters for water-soluble-HA chains were evidenced among the gels. Hydration, rigidity and cohesivity also varied over a wide range. Sensitivity to hyaluronidases and Reactive Oxygen Species was demonstrated allowing a stability ranking. Slight differences were found in gels' ability to prompt elastin expression and in ColIV/ColI ratio. CONCLUSIONS A wide panel of biophysical and biochemical parameters for skinboosters was provided, supporting clinicians in the conscious tuning of their use. Data revealed great variability in gels' behavior notwithstanding the same clinical indication and unexpected similarities to the volumetric formulations. Data may be useful to improve customization of gel design toward specific uses.
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Efficacy of Long-term Use of 0.3% Sodium Hyaluronate Eye Drops for Traumatic Corneal Abrasion: A Randomized Controlled, Pilot Trial.
Wei, M, Zou, Y, Duan, F, Ding, X, Zhuang, J, Deng, J, Yuan, Z
Cornea. 2021;(10):1248-1252
Abstract
PURPOSE Traumatic corneal abrasion (TCA) causes damage to both corneal epithelium and the underlying hemidesmosomal junctions. Delayed recovery of hemidesmosomal junctions causes symptomatic episodes. However, there is no recommended treatment for recovery of hemidesmosomal junctions, indicating that a blank period exists in TCA treatment. In this study, the efficacy of long-term use of sodium hyaluronate on recovery of hemidesmosomal junctions during the blank period in TCA healing was investigated. METHODS In this prospective, randomized control pilot study, 60 patients with TCA were enrolled. The patients were randomized 1:1 to receive 0.3% sodium hyaluronate eye drops for 3 months (HA group) or observation alone (control group) after complete corneal epithelium recovery. The primary and secondary outcomes were the cumulative incidence of major and minor symptomatic episodes during a 12-month follow-up, respectively. RESULTS Fifty-six subjects (29 in the HA group and 27 in the control group) completed the 12-month follow-up. The 12-month cumulative incidence rate of major symptomatic episodes was 20.7% in the HA group and 18.5% in the control group. No significant difference was found between the 2 groups (P = 0.838). The 12-month cumulative incidence rate of minor symptomatic episodes was 48.3% and 37.0% in the HA and control groups, respectively, with no significant difference (P = 0.397). CONCLUSIONS Approximately one-fifth of patients with TCA experience major symptomatic episodes again within their 1-year follow-up. Long-term use of sodium hyaluronate in the period of recovery of hemidesmosomal junctions has no benefit to it.
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Inhaled high molecular weight hyaluronan ameliorates respiratory failure in acute COPD exacerbation: a pilot study.
Galdi, F, Pedone, C, McGee, CA, George, M, Rice, AB, Hussain, SS, Vijaykumar, K, Boitet, ER, Tearney, GJ, McGrath, JA, et al
Respiratory research. 2021;(1):30
Abstract
BACKGROUND Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) carry significant morbidity and mortality. AECOPD treatment remains limited. High molecular weight hyaluronan (HMW-HA) is a glycosaminoglycan sugar, which is a physiological constituent of the lung extracellular matrix and has notable anti-inflammatory and hydrating properties. RESEARCH QUESTION We hypothesized that inhaled HMW-HA will improve outcomes in AECOPD. METHODS We conducted a single center, randomized, placebo-controlled, double-blind study to investigate the effect of inhaled HMW-HA in patients with severe AECOPD necessitating non-invasive positive-pressure ventilation (NIPPV). Primary endpoint was time until liberation from NIPPV. RESULTS Out of 44 screened patients, 41 were included in the study (21 for placebo and 20 for HMW-HA). Patients treated with HMW-HA had significantly shorter duration of NIPPV. HMW-HA treated patients also had lower measured peak airway pressures on the ventilator and lower systemic inflammation markers after liberation from NIPPV. In vitro testing showed that HMW-HA significantly improved mucociliary transport in air-liquid interface cultures of primary bronchial cells from COPD patients and healthy primary cells exposed to cigarette smoke extract. INTERPRETATION Inhaled HMW-HA shortens the duration of respiratory failure and need for non-invasive ventilation in patients with AECOPD. Beneficial effects of HMW-HA on mucociliary clearance and inflammation may account for some of the effects (NCT02674880, www.clinicaltrials.gov ).
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The effect of oral low molecular weight liquid hyaluronic acid combination with glucosamine and chondroitin on knee osteoarthritis patients with mild knee pain: An 8-week randomized double-blind placebo-controlled trial.
Wang, SJ, Wang, YH, Huang, LC
Medicine. 2021;(5):e24252
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Abstract
BACKGROUND The popularity of dietary supplements for knee osteoarthritis (OA) management is on the rise; however, their effects are still debated. METHODS This study aimed to investigate the effect of an oral low molecular weight liquid hyaluronic acid supplement in the treatment of knee OA patients with mild knee pain (visual analogue scale [VAS] ≤ 3) in Taiwan population. This was a randomized, double-blind, placebo-controlled study. Forty-seven subjects were enrolled and randomly allocated to either the A+HA or the placebo groups. The subjects were required to drink a bottle contained 20 mL of A+HA or placebo daily throughout an 8-week study period. The efficacy was assessed by using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the 36-item Short Form Survey (SF-36). RESULTS At Week 8, significant reductions from baseline in the WOMAC pain (-2.6 ± 1.68, P < .0001), stiffness (-1.2 ± 1.50, P = .007), physical function (-5.8 ± 4.39, P < .0001), and total (-9.4 ± 5.82, P < .0001) scores were observed in the A+HA group but not in the placebo group. Significant differences in the mean change of WOMAC scores from baseline at Week 8 between groups were detected (P < .01). At Week 8, the A+HA group also showed significant improvements in SF-36 physical functioning (2.7 ± 3.10, P = .001) and bodily pain (0.7 ± 1.50, P < .05) domains. Although the A+HA group had a higher increase in the SF-36 total score than the placebo group but the difference was not statistically significant (2.1 ± 12.75 vs 0.3 ± 19.66, P = .12). CONCLUSIONS Oral administration of low molecular weight liquid HA appeared to be effective for knee OA patients with mild knee pain (VAS ≤ 3) in the relief of knee OA symptoms, particularly in pain and physical function.Clinical Trial Registration: NCT04352322.
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Wound Healing in Diabetic Foot Ulcer Patients Using Combined Use of Platelet Rich Fibrin and Hyaluronic Acid, Platelet Rich Fibrin and Placebo: An Open Label, Randomized Controlled Trial.
Kartika, RW, Alwi, I, Suyatna, FD, Yunir, E, Waspadji, S, Immanuel, S, Bardosono, S, Sungkar, S, Rachmat, J, Hediyati, M, et al
Acta medica Indonesiana. 2021;(3):268-275
Abstract
BACKGROUND Autologous platelet-rich fibrin (A-PRF) is an adjunctive method for diabetic foot ulcer (DFU) in addition to glycaemic control and debridement. This study aimed to evaluate the role of A-PRF + hyaluronic acid (HA), A-PRF and sodium chloride 0.9% (control) in DFU wound healing. Nowaday, the use of PRF autologous consider as adjuvant therapy in DFU treatment. METHODS This open-label randomized controlled trial was conducted at Koja District Hospital and Gatot Soebroto Hospital from July 2019 to April 2020. DFU patients with wound duration of three months, Wagner-2, and ulcer size < 40 cm2 were recruited and randomly assigned into A-PRF + AH, A-PRF and control group. On day-0, day-3 and day -7, samples and photographs were taken. Samples were analysed with ELISA and photographs were analysed with ImageJ to calculate granulation index (GI). Statistical analysis was performed using SPSS version 20. RESULTS Topical therapy with A-PRF + AH was associated with a significant increase in VEGF from day 0 (232.8 pg/mg) vs day 7 (544.5 pg/mg) compared to A-PRF on day 0 (185.7 pg/mg) vs day 7 (272.8 pg/mg), and the controls on day 0 (183.7 pg/mg) vs day 7 (167.4 pg/mg). On evaluation of VEGF swab, there is increasing significantly in A-PRF+HA group compare others group in day -3 ( p=0.022) and day -7 (p= 0.001).In the A-PRF + AH group, there was a significant decrease in IL-6 from day 0 (106.4 pg/mg) vs day 7 (88.7 pg/mg) compared with PRF on day 0 (91.9 pg/mg) vs day 7 (48,8 pg/mg). IL-6 was increased in the control group from day 0 (125.3 pg/mg) vs day 7 (167.9 pg/mg). On evaluation of IL-6 swab, there is decreasing significantly in A-PRF+HA group compare others group in day -7 (p= 0.041). CONCLUSION The PRF + HA combination increased angiogenesis and reduced inflammation in DFUs and may represent a new DFU therapy.
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Effect of sodium hyaluronate-arboxycellulose membrane (Seprafilm®) on postoperative small bowel obstruction: A meta-analysis.
Guo, Y, Zhu, Q, Chen, S, Li, Y, Fu, D, Qiao, D, Wang, Y, Yang, Y
Surgery. 2021;(6):1333-1339
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Abstract
BACKGROUND This meta-analysis was performed to evaluate the effect of Seprafilm® on postoperative small bowel obstruction. METHODS A literature search was conducted in the PubMed and EMBASE databases through August 2020. The pooled risk ratios as well as the corresponding 95% confidence intervals were calculated using RevMan 5.3 software. RESULTS A total of 9 clinical control trials involving 4,351 patients (2,123 in the Seprafilm® group and 2,228 in the control group) were included. The overall analysis showed that the pooled risk ratio was 0.45 (95% confidence interval = 0.34-0.60; P < .00001), indicating that the risk of postoperative small bowel obstruction can be significantly decreased by the application of Seprafilm®. Similarly, an obvious effect of Seprafilm® on reducing the rate of postoperative small bowel obstruction was also shown in the subgroup analyses by population (adult participants), study design (randomized control study or nonrandomized control study), region (Japan or Korea), follow-up duration (2 years or 5 years), and sheet number of Seprafilm® (1 sheet or >1 sheet). CONCLUSION In conclusion, the use of Seprafilm® is beneficial for decreasing the rate of postoperative small bowel obstruction.
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Ortho Isomeric Mn(III) N-Alkyl- and Alkoxyalkylpyridylporphyrins-Enhancers of Hyaluronan Degradation Induced by Ascorbate and Cupric Ions.
Valachová, K, Rapta, P, Moura, NMM, Batinic-Haberle, I, Šoltés, L
International journal of molecular sciences. 2021;(16)
Abstract
High levels of hyaluronic acid (HA) in tumors correlate with poor outcomes with several types of cancers due to HA-driven support of adhesion, migration and proliferation of cells. In this study we explored how to enhance the degradation of HA into low-molecular fragments, which cannot prevent the immune system to fight tumor proliferation and metastases. The physiological solution of HA was exposed to oxidative degradation by ascorbate and cupric ions in the presence of either one of three ortho isomeric Mn(III) substituted N-alkyl- and alkoxyalkylpyridylporphyrins or para isomeric Mn(III) N-methylpyridyl analog, commonly known as mimics of superoxide dismutase. The changes in hyaluronan degradation kinetics by four Mn(III) porphyrins were monitored by measuring the alteration in the dynamic viscosity of the HA solution. The ortho compounds MnTE-2-PyP5+ (BMX-010, AEOL10113), MnTnBuOE-2-PyP5+ (BMX-001) and MnTnHex-2-PyP5+ are able to redox cycle with ascorbate whereby producing H2O2 which is subsequently coupled with Cu(I) to produce the •OH radical essential for HA degradation. Conversely, with the para analog, MnTM-4-PyP5+, no catalysis of HA degradation was demonstrated, due to its inertness towards redox cycling with ascorbate. The impact of different Mn(III)-porphyrins on the HA decay was further clarified by electron paramagnetic resonance spectrometry. The ability to catalyze the degradation of HA in a biological milieu, in the presence of cupric ions and ascorbate under the conditions of high tumor oxidative stress provides further insight into the anticancer potential of redox-active ortho isomeric Mn(III) porphyrins.
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Liquid combination of hyaluronan, glucosamine, and chondroitin as a dietary supplement for knee osteoarthritis patients with moderate knee pain: A randomized controlled study.
Wang, SJ, Wang, YH, Huang, LC
Medicine. 2021;(40):e27405
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BACKGROUND Hyaluronan (HA), glucosamine, and chondroitin sulfate are widely consumed as dietary supplements for the treatment of knee osteoarthritis (OA). This study aimed to explore the efficacy and safety of a dietary liquid supplement mixture containing HA, glucosamine, and chondroitin in patients with knee OA who had moderate knee pain (visual analogue scale of 4-6 points). METHODS This was a short-term, randomized, double-blind, placebo-controlled study. Subjects were allocated to administer either a bottle of 20 mL supplement mixture (50 mg HA plus 750 mg glucosamine plus 250 mg chondroitin, namely A + HA) or placebo once daily for 8 weeks. Outcome measures included the Knee Injury and Osteoarthritis Outcome Score, Western Ontario and McMaster Universities Osteoarthritis Index, 36-item Short Form Survey (SF-36), Chinese version of Pittsburgh Sleep Quality Index, and incidence of adverse event were evaluated at the end of week 8. Efficacy analyses were conducted in the modified intent-to-treat population. RESULTS Of the 80 subjects in the modified intent-to-treat population, 39 received A + HA while 41 received placebo. After 8 weeks of treatment, the A + HA group failed to demonstrate a significant symptomatic efficacy and quality of life improvement in terms of Knee Injury and Osteoarthritis Outcome Score, Western Ontario and McMaster Universities Osteoarthritis Index, SF-36, and Chinese version of Pittsburgh Sleep Quality Index as compared to the placebo group. However, the mean changes in most of the SF-36 scale scores were numerically higher in the A + HA group than in the placebo group. No treatment-related adverse event was reported in both groups. CONCLUSIONS This present study found that the combination of liquid low molecular weight HA, glucosamine, and chondroitin oral supplement did not effectively improve knee OA pain and symptoms after short-term use in knee OA patients with moderate knee pain. However, these results should be interpreted with caution due to the intrinsic limitation of the study design.
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A novel platform for drug testing: Biomimetic three-dimensional hyaluronic acid-based scaffold seeded with human hepatocarcinoma cells.
Turtoi, M, Anghelache, M, Bucatariu, SM, Deleanu, M, Voicu, G, Safciuc, F, Manduteanu, I, Fundueanu, G, Simionescu, M, Calin, M
International journal of biological macromolecules. 2021;:604-619
Abstract
Hepatic cancer is one of the most widespread maladies worldwide that requires urgent therapies and thus reliable means for testing anti-cancer drugs. The switch from two-dimensional (2D) to three-dimensional (3D) cell cultures produced an improvement in the in vitro outcomes for testing anti-cancer drugs. We aimed to develop a novel hyaluronic acid (HA)-based 3D cell model of human hepatocellular carcinoma (HepG2 cells) for drug testing and to assess comparatively in 3D vs. 2D, the cytotoxicity and the apoptotic response to the anti-tumor agent, cisplatin. The 3D model was developed by seeding HepG2 cells in a HA/poly(methylvinylether-alt-maleic acid) (HA3P50)-based scaffold. Compared to 2D, the cells grown in the HA3P50 scaffold proliferate into larger-cellular aggregates that exhibit liver-like functions by controlling the release of hepatocyte-specific biomarkers (albumin, urea, bile acids, transaminases) and the synthesis of cytochrome-P450 (CYP)7A1 enzyme. Also, growing the cells in the scaffold sensitize the hepatocytes to the anti-tumor effect of cisplatin, by a mechanism involving the activation of ERK/p38α-MAPK and dysregulation of NF-kB/STAT3/Bcl-2 pathways. In conclusion, the newly developed HA-based 3D model is suitable for chemotherapeutic drug testing on hepatocellular carcinoma. Moreover, the system can be adapted and employed as experimental platform functioning as a proper tissue/tumor surrogate.