High Molecular Weight Hyaluronic Acid Research Articles

High-molecular-weight Hyaluronan Administration Inhibits Bone Resorption and Promotes Bone Formation in Young-age Osteoporosis Rats.

Osteoporosis poses a significant global health concern, affecting both the elderly and young individuals, including athletes. Despite the development of numerous antiosteoporotic drugs, addressing the unique needs of young osteoporosis patients remains challenging. This study focuses on young rats subjected to ovariectomy (OVX) to explore the impact of high-molecular-weight hyaluronan (HA) on preventing OVX-induced osteoporosis. Twenty-four rats underwent OVX, while 12 underwent sham procedures (sham control group). Among the OVX rats, half received subcutaneous injections of HA (MW: 2700 kDa) at 10 mg/kg/week into their backs (OVX-HA group), whereas the other half received saline injections (0.5 ml/week) at the same site (OVX-saline group). OVX-HA group exhibited significantly higher percentages of osteoclast surface (Oc. S/BS), osteoblast surface per bone surface (Ob. S/BS), and bone volume/tissue volume (BV/TV) compared with OVX-saline group at the same age. The proportions of Ob. S/BS and BV/TV in the OVX-HA group closely resembled those of the sham control group, whereas the proportion of Oc. S/BS in the OVX-HA group was notably higher than that in the sham control group. In summary, the administration of HA significantly mitigated bone resorption and enhanced bone formation, suggesting a crucial role for HA in the treatment of young adult osteoporosis.

Engineering a Hydrazone and Triazole Crosslinked Hydrogel for Extrusion-Based Printing and Cell Delivery.

Covalent adaptable crosslinks, such as the alkyl-hydrazone, endow hydrogels with unique viscoelastic properties applicable to cell delivery and bioink systems. However, the alkyl-hydrazone crosslink lacks stability in biologically relevant environments. Further, when formed with biopolymers such as hyaluronic acid (HA), low molecular weight polymers (<60kDa) or low polymer content (<2 wt%) hydrogels are typically employed as entanglements reduce injectability. Here, we modified a high molecular weight (>60kDa) HA alkyl-hydrazone crosslinked hydrogel with benzaldehyde-poly(ethylene glycol)3-azide to incorporate azide functional groups. By reacting azide-modified HA with a multi-arm poly(ethylene glycol) (PEG) functionalized with bicyclononyne, stabilizing triazole bonds are formed through strain-promoted azide-alkyne cycloaddition (SPAAC). Increasing the fraction of triazole bonds within the hydrogel network from 0% to 12% SPAAC substantially increased stability. The slow gelation kinetics of the SPAAC reaction in the 12% SPAAC hydrogel enabled transient self-healing properties and a similar extrusion force as the 0% SPAAC hydrogel. Methyl-PEG4-hydrazide was then introduced to further slowdown network evolution, which temporarily lowered the extrusion force, improved printability, and increased post-extrusion mesenchymal stem cell viability and function in the 12% SPAAC hydrogel. This work demonstrates improved stability and temporal injectability of high molecular weight HA-PEG hydrogels for extrusion-based printing and cell delivery. This article is protected by copyright. All rights reserved.

Different doses of hyaluronic acid injections in patients with knee osteoarthritis: A multicenter, randomized, prospective, single-blind, clinical study.

Many formulations and dosing regimens are available for hyaluronic acid (HA). To compare different doses of linear, high-molecular weight (HMW) HA injections among patients with knee osteoarthritis (OA). Hundred patients were included in this randomized, single-blinded trial and randomly divided into three HA injection groups. The first group received five weekly 20mg HA injections, the second group received three weekly 32mg HA injections, and the third group received a single 48mg HA injection. Patients were evaluated at baseline, 1, 3, and 6months after the last injection for pain, stiffness, and function using the visual analog scale (VAS) and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) questionnaire. Quality of life, patient's global assessment, and Timed Up and Go (TUG) test scores were also evaluated. There was significant improvement in the WOMAC, VAS-pain, quality of life, patient's global assessment, and TUG test mean scores at all follow-up time points (p< 0.001). However, the groups showed no significant differences in WOMAC, VAS-activity pain, and patient global scores at any follow-up point. Intra-articular injections of different doses of linear HMW HA can improve pain, stiffness, function, and quality of life in patients suffering from knee OA over a six-month period.

Research progress on the role of imbalanced high and low molecular weight hyaluronic acid in respiratory system inflammation caused by atmospheric particulate matter

Atmospheric particulate matter has an association with respiratory system inflammation, and low molecular weight hyaluronic acid (LMW-HA) is a key biomarker of inflammatory cascade reaction. This review summarized the possible pathways and biomarkers of atmospheric particulate matter causing respiratory system inflammation through high molecular weight hyaluronic acid (HMW-HA)/LMW-HA imbalance, including the synthesis and decomposition of HA, the reduction of particulate matter and HMW-HA, the increase of LMW-HA, and the relationship between LMW-HA and respiratory system inflammation. Furthermore, inhibitors and therapeutic drugs targeting certain biomarkers were further listed. This review could shed light on the mechanism of respiratory system inflammation caused by atmospheric particulate matter and the weak points that need attention in subsequent research.

High-Molecular-Weight Hyaluronic Acid Can Be Used as a Food Additive to Improve the Symptoms of Persistent Inflammation, Immunosuppression and Catabolism Syndrome (PICS).

Hyaluronic acid (HA) is a new functional food additive which has the potential to ameliorate persistent inflammation, immunosuppression and catabolism syndrome (PICS), but the biological effects of HA with various molecular weights differ dramatically. To systematically investigate the efficacy of HA in altering PICS symptoms, medium-molecular-weight (MMW) HA was specifically selected to test its intervention effect on a PICS mouse model induced by CLP through oral administration, with high-molecular-weight (HMW) and low-molecular-weight (LMW) HA also participating in the experimental validation process. The results of pathological observations and gut flora showed that MMW HA rapidly alleviated lung lesions and intestinal structural changes in PICS mice in the short term. However, although long-term MMW HA administration significantly reduced the proportions of harmful bacteria in gut flora, inflammatory responses in the intestines and lungs of PICS mice were significantly higher in the MMW HA group than in the HMW HA and LMW HA groups. The use of HMW HA not only rapidly reduced the mortality rate of PICS mice but also improved their grip strength and the recovery of spleen and thymus indices. Furthermore, it consistently promoted the recovery of lung and intestinal tissues in PICS mice, and it also assisted in the sustained restoration of their gut microbiota. These effects were superior to those of LMW HA and MMW HA. The experimental results indicate that HMW weight HA has the greatest potential to be an adjunct in alleviating PICS as a food additive, while the safety of other HAs requires further attention.

Immunohistochemical study of mixing mineral trioxide aggregate with hyaluronic acid as a pulp-capping agent in dog teeth

Objective: The purpose of this study was to evaluate the immunohistochemical effect of hyaluronic acid (HA) on the mineralization rate of the reparative dentin when it is used as a mixing medium with mineral trioxide aggregate (MTA). Materials and Methods: Direct pulp capping (DPC) was performed on 90 teeth from 10 dogs that had been experimentally exposed. The exposed pulps were divided into three groups according to the mixing medium with MTA: Group I: MTA + distilled water (control group), Group II: MTA + hybrid cooperative complex HA (HCC-HA), Group III: MTA + high molecular weight HA (HMW-HA). After pulp capping, all cavities were restored with final restoration. The dogs were divided randomly into five groups (two dogs each) according to the evaluation periods (7, 14, 21, 30, and 60) days. At the end of the study, the dogs were euthanized, and the sampled teeth were processed for immunohistochemical investigation. Results: Both types of HA (HCC-HA, HMW-HA) showed an increase in the expression of alkaline phosphatase (ALP) at a higher rate than using distilled water with MTA. Conclusions: Within the limitations of this study, HA proved to be an effective additive to MTA for DPC.

The Potential of the Fibronectin Inhibitor Arg-Gly-Asp-Ser in the Development of Therapies for Glioblastoma.

Glioblastoma (GBM) is the most lethal and common malignant primary brain tumor in adults. An important feature that supports GBM aggressiveness is the unique composition of its extracellular matrix (ECM). Particularly, fibronectin plays an important role in cancer cell adhesion, differentiation, proliferation, and chemoresistance. Thus, herein, a hydrogel with mechanical properties compatible with the brain and the ability to disrupt the dynamic and reciprocal interaction between fibronectin and tumor cells was produced. High-molecular-weight hyaluronic acid (HMW-HA) functionalized with the inhibitory fibronectin peptide Arg-Gly-Asp-Ser (RGDS) was used to produce the polymeric matrix. Liposomes encapsulating doxorubicin (DOX) were also included in the hydrogel to kill GBM cells. The resulting hydrogel containing liposomes with therapeutic DOX concentrations presented rheological properties like a healthy brain. In vitro assays demonstrated that unmodified HMW-HA hydrogels only caused GBM cell killing after DOX incorporation. Conversely, RGDS-functionalized hydrogels displayed per se cytotoxicity. As GBM cells produce several proteolytic enzymes capable of disrupting the peptide-HA bond, we selected MMP-2 to illustrate this phenomenon. Therefore, RGDS internalization can induce GBM cell apoptosis. Importantly, RGDS-functionalized hydrogel incorporating DOX efficiently damaged GBM cells without affecting astrocyte viability, proving its safety. Overall, the results demonstrate the potential of the RGDS-functionalized hydrogel to develop safe and effective GBM treatments.

New Regenerative and Anti-Aging Medicine Approach Based on Single-Stranded Alpha-1 Collagen for Neo-Collagenesis Induction: Clinical and Instrumental Experience of a New Injective Polycomponent Formulation for Dermal Regeneration.

This study explores the efficacy of a novel polycomponent formulation (KARISMA Rh Collagen® FACE, Taumedika Srl, Rome, Italy), containing 200 mg/mL of non-crosslinked high-molecular-weight hyaluronic acid (HMW-HA), 200 μg/mL of a human recombinant polypeptide of collagen-1 alpha chain, and 40 mg/mL of carboxymethyl cellulose (CMC) as a regenerative medicine for skin regeneration and rejuvenation. This formulation combines non-crosslinked high-molecular-weight hyaluronic acid, human recombinant polypeptide of collagen-1 alpha chain, and carboxymethyl cellulose to stimulate collagen type I production and enhance skin hydration. This study involved 100 subjects with varying skin conditions, divided into three groups based on skin aging, smoking history, and facial scarring, to evaluate the product's effectiveness in skin regeneration and aesthetic improvement. The methodology included two injections of Karisma (2 mL for each injection) one month apart, with evaluations conducted using FACE-Q questionnaires, the SGAIS Questionnaire, and Antera 3D skin scanner measurements at baseline, 30 days, and 60 days post-treatment. The results demonstrated a significant reduction in skin roughness and an improvement in skin quality across all the groups, with no correlation between the outcomes and the patient's age. The subjective assessments also indicated high satisfaction with the treatment's aesthetic results. The analyzed data allow us to conclude that the single-stranded collagen with hyaluronic acid and carboxymethyl-cellulose formulation is able to stimulate the skin's regenerative response, yielding significant results both in vitro and, through our study, also in vivo. This new polycomponent formulation effectively stimulates skin regeneration, improving skin quality and texture, with significant aesthetic benefits perceived by patients, and a low incidence of adverse events, marking a promising advancement in regenerative medicine.

Evaluation of Effectiveness of Combined Intra-Articular Injection of Ozone and High Molecular Weight Hyaluronic Acid in Patients With Knee Osteoarthritis

Osteoarthritis is one of the major causes of disability and a source of social cost in the elderly. Its prevalence is increasing due to ageing and increasing obese population. The knee is one of the most common joints to be affected by osteoarthritis and it can lead to serious effects on one’s mobility, quality of life and livelihood. One of non-surgical treatments is intra-articular injection. Injection of both ozone and hyaluronic acid into knee joint are common methods for treatment of knee osteoarthritis. The aim of this study was to evaluate reduction of pain and improvement of function in patients who received combination of intra-articular injection of high molecular weight hyaluronic acid and ozone. In this retrospective case series study data of patients with knee osteoarthritis who underwent intra-articular injection of high molecular weight hyaluronic acid with ozone were evaluated. Participants had fulfilled Western Ontario and McMaster Universities Arthritis Index (WOMAC) short form questionnaire before, three days, one month and six months after the intra-articular injection. Pain reduction and function improvement factors were assessed according to the WOMAC short form questionnaire. A total of 65 patients were evaluated in this study. There was significant decrease in the total score of WOMAC SF (stiffness and function) in all three follow-ups (P&lt;0.001). Also, patients who had more severe pain before the injection benefited more from the intra-articular injection. Our study showed that the effectiveness of intra-articular injection of high molecular weight hyaluronic acid with ozone does not depend on the age, sex and BMI of patients. Injection of high molecular weight hyaluronic acid and ozone into the joint cause to significant improvement in patient’s knee pain and function. It is recommended that the combination of high molecular weight hyaluronic acid and ozone be considered as an effective treatment in the process of these patients.

Study of the effectiveness and safety of a combination of a hypertonic solution and high molecular weight hyaluronic acid (Ingasalin® 3%) in the form of inhalation in the treatment of acute bronchitis against the background of acute respiratory infections in children 3-7 years old

Study of the effectiveness and safety of a combination of a hypertonic solution and high molecular weight hyaluronic acid (Ingasalin® 3%) in the form of inhalation in the treatment of acute bronchitis against the background of acute respiratory infections in children 3-7 years old

Abstract 2705: Hyaluronic acid impairs NK killing towards breast tumor spheroids despite elevated cytotoxicity

Abstract The tumor microenvironment (TME) is often regarded as a critical component in tumor progression and metastasis. Among the main structural components of the TME, such as collagen and glycosaminoglycans (GAGs), hyaluronic acid (HA) is highly elevated in the breast TME, and is associated with poor prognosis. In recent years, immunotherapy has gained tremendous success in the battle against hematological cancers. Yet, solid tumors have remained a significant clinical challenge for immunotherapy due to the physical constraints they impose on immune cells. Mechanically, our previous work has shown that the abundance of high molecular weight (HMW) HA significantly reduces matrix pore sizes and softens the collagen and HA cogel, and impairs breast tumor invasion. However, it is still unclear how modulating tumor invasion through the mechanics of the TME may correlate with the efficacy of immunotherapy. In this study, we aim to investigate the effect of HMW HA on natural killer (NK) cell-based immunotherapy using a tumor spheroid model (GFP-labeled MCF-7). We introduced NK-92 MI cells into tumor spheroid embedded collagen gels with or without HA, and followed spheroid-NK cell interactions through live cell imaging. Preliminary data shows that while tumor spheroids were still able to invade in the collagen only gel, they underwent apoptosis in the presence of NK cells. More importantly, the presence of HA within the ECM reduced NK cells’ ability to kill tumor spheroids. Specifically, when surrounded by NK cells, tumor spheroids remained intact and viable in the collagen-HA cogel, while they underwent apoptosis in collagen only gels. In a parallel experiment, multicolor flow cytometry data showed that HA increased NK activation and certain cytotoxic markers (interferon-gamma, perforin, and granzyme-B), despite the fact that spheroids appeared to be more resistant towards NK cells in the presence of HA. Taken together, we speculate that the presence of HMW HA in the TME may protect solid tumors from immune attacks by modulating the mechanical environment. Citation Format: Brian C. Cheung, Alan T. Li, Jeffrey E. Segall, Mingming Wu. Hyaluronic acid impairs NK killing towards breast tumor spheroids despite elevated cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2705.

Abstract 4133: Hyaluronidase inhibitor delphinidin inhibits cancer metastasis

Abstract Cancer remains a formidable global health challenge, with metastasis being a key contributor to its lethality. Abundant high molecular weight hyaluronic acid, a major non-protein component of extracellular matrix, protects naked mole rats from cancer and reduces cancer incidence in mice. Hyaluronidase plays a critical role in degrading hyaluronic acid and is frequently overexpressed in metastatic cancer. We investigated the potential of targeting hyaluronidases to reduce metastasis. High throughput screening identified delphinidin, a natural plant compound found in fruits and vegetables, as a potent hyaluronidase inhibitor. Delphinidin-mediated inhibition of hyaluronidase activity led to an increase in high molecular weight hyaluronic acid in cell culture and in mouse tissues, and significantly reduced proliferation, migration and invasion of breast (EO771), prostate (RM1), and melanoma (B16-F10) metastatic cell lines. Addition of exogenous hyaluronidase partially reversed all of these effects. Moreover, delphinidin treatment suppressed melanoma (B16-F10) metastasis in a spontaneous mouse model of metastasis. These results provide a proof of principle that inhibition of hyaluronidase activity suppresses cancer cell migration, invasion and metastasis. These results combined with the lack of adverse effect make delphinidin an attractive potential therapeutic option for inhibition of metastasis. We believe further investigation is warranted to fully elucidate the mechanisms and optimize the use of delphinidin in cancer therapy. Citation Format: Jeremy Jonathan McGuire, Taketo Taguchi, Greg Tombline, Victoria Paige, Michelle Janelsins, Nikesha Gilmore, Andrei Seluanov, Vera Gorbunova. Hyaluronidase inhibitor delphinidin inhibits cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4133.

Lactic Acid-Induced Colloidal Microrheology of Synovial Fluids.

The presence of colloidal scaffolds composed of proteins and hyaluronic acid engenders unique viscous and elastic properties to the synovial fluid (SF). While the elastic resistance of SF due to the presence of such nanoscale structures provides the load-bearing capacity, the viscous nature enables fluidity of the joints during the movements to minimize the wear and tear of the adjacent muscle, cartilage, or bone tissues. It is well-known that the hypoxic conditions at the bone joints often increase the lactic acid (LA) concentration due to the occurrence of excess anaerobic respiration during either hyperactivity or arthritic conditions. The present study uncovers that in such a scenario, beyond a critical loading of LA, the colloidal nanoscaffolds of SF break down to precipitate higher molecular weight (MW) proteins and hyaluronic acid (HA). Subsequently, the viscosity and elasticity of SF reduce drastically to manifest a fluid that has reduced load bearing and wear and tear resistance capacity. Interestingly, the study also suggests that a heathy SF is a viscoelastic fluid with a mild Hookean elasticity and non-Newtonian fluidity, which eventually transforms into a viscous watery liquid in the presence of a higher loading of LA. We employ this knowledge to biosynthesize an artificial SF that emulates the characteristics of the real one. Remarkably, the spatiotemporal microscopic images uncover that even for the artificial SF, a dynamic cross-linking of the high MW proteins and HA takes place before precipitating out of the same from the artificial SF matrix, emulating the real one. Control experiments suggest that this phenomenon is absent in the case when LA is mixed with either pure HA or proteins. The experiments unfold the specific role of LA in the destruction of colloidal nanoscaffolds of synovia, which is an extremely important requirement for the biosynthesis and translation of artificial synovial fluid.

The relationship of ALPK1, hyaluronic acid and M1 macrophage polarization in the temporomandibular joint synovitis.

M1 macrophage polarization and synovitis play an important role in the pathogenesis of temporomandibular joint osteoarthritis (TMJOA). Reduced molecular weight of hyaluronic acid (HA) in synovial fluid of patients with TMJOA. In addition, high molecular weight hyaluronic acid (HMW-HA) is often used clinically to treat TMJ inflammation. As a pattern recognition receptor of the cytoplasm, ALPK1 was found to be pro-inflammatory in a variety of diseases. However, the relationship of ALPK1, HA and M1 macrophage polarization in TMJ synovitis remains unclear. We aimed to investigate the role of ALPK1 and HA in macrophage polarization and TMJ synovitis and the underlying mechanisms. The results demonstrated that ALPK1 was highly upregulated in the synovial macrophages in the inflamed TMJ synovium of patients. Low molecular weight hyaluronic acid (LMW-HA) promoted the expression of ALPK1 and M1 macrophage-associated genes. Besides, rhALPK1 promoted the expression of M1 macrophage-associated factors and the nuclear translocation of PKM2. Furthermore, ALPK1 knockout mice exhibited limited infiltration of macrophages and decreased expression levels of M1 macrophage-associated genes in CFA-induced TMJ synovitis. While HMW-HA inhibited the expression of ALPK1 and M1 macrophage polarization. Our results elucidated that ALPK1 promoted TMJ synovitis by promoting nuclear PKM2-mediated M1 macrophage polarization, whereas HMW-HA inhibited the expression of ALPK1 as well as M1 macrophage polarization.

Intra-Articular Hyaluronic Acid for Osteoarthritis of the Hip, Shoulder, and Ankle

What Is the Issue?&#x0D; &#x0D; Osteoarthritis (OA) is a chronic disease of the joints, such as the hip, shoulder, and ankle. OA causes the joints to be painful, unstable, and less functional. In adults 55 years and younger, joint trauma is a common cause of OA.&#x0D; Hyaluronic acid (HA) is a naturally occurring molecule found in human cells that provides lubrication when injected into the joint. HA injections are a less invasive option than surgery, with potentially fewer complications.&#x0D; To support decision-making about treating hip, shoulder, or ankle OA in adults 55 years and younger, it is important to understand the potential benefits and harms of using HA in this population.&#x0D; &#x0D; What Did We Do?&#x0D; &#x0D; We reviewed the clinical effectiveness of high molecular weight (MW) injection of HA in adults between the ages of 18 and 55 years with OA of the hip, shoulder, or ankle joints to guide decisions on the use of high MW HA injection.&#x0D; An information specialist searched for peer-reviewed and grey literature sources published on January 1, 2013 to December 12, 2023. One reviewer screened citations and selected and critically appraised the included studies.&#x0D; &#x0D; What Did We Find?&#x0D; &#x0D; The evidence for this report was based on observational before-and-after studies. We found no relevant comparative studies examining the effect of high MW HA versus placebo or no treatment.&#x0D; While most studies reported post-treatment outcome improvements, it is uncertain whether high MW injection of HA improves pain, function, and disability in adults 55 years and under with hip, shoulder, or ankle OA. This is due to the low-quality evidence, small sample sizes, and methodological problems. Serious side effects of high MW HA were not reported.&#x0D; &#x0D; What Does This Mean?&#x0D; &#x0D; Due to the uncertainty of the clinical effectiveness evidence, health care providers and decision-makers may consider other factors when considering high MW IA-HA for patients with hip, shoulder, or ankle OA; these factors could include acceptability, feasibility, costs, health equity, and patient values and preferences.&#x0D; Future research from randomized studies in large populations is needed to understand the effectiveness and safety of high MW HA injections for hip, shoulder, and ankle OA.&#x0D;

The Role of Hyaluronan/Receptor for Hyaluronan-Mediated Motility Interactions in the Modulation of Macrophage Polarization and Cartilage Repair

Hyaluronan (HA), a negatively charged linear glycosaminoglycan, is a key macromolecular component of the articular cartilage extracellular matrix. The differential effects of HA are determined by a spatially/temporally regulated display of HA receptors, such as CD44 and Receptor for Hyaluronan Mediated Motility (RHAMM). HA signaling through CD44 with RHAMM has been shown to stimulate inflammation and fibrotic processes. This study shows an increased expression of RHAMM in pro-inflammatory macrophages. Interfering with HA/RHAMM interactions using a 15mer RHAMM-mimetic, HA binding peptide (P15-1) together with high molecular weight (HMW)HA reduced the expression and release of inflammatory markers and increased the expression of anti-inflammatory markers in pro-inflammatory macrophages. Interfering with HA/RHAMM interactions in vivo during the regeneration of a full thickness cartilage defect after microfracture surgery in rabbits using three intra-articular injections of P15-1 together with HMWHA reduced the number of pro-inflammatory macrophages and increased the number of anti-inflammatory macrophages in the injured knee joint and greatly improved the repair of the cartilage defect compared to intra-articular injections of HMWHA alone. These findings suggest that HA/RHAMM interactions play a key role in cartilage repair/regeneration via stimulating inflammatory and fibrotic events, including increasing the ratio of pro-inflammatory to anti-inflammatory macrophages. Interfering with these interactions reduced inflammation and greatly improved cartilage repair.

Evaluation of single and multiple hyaluronic acid injections at different concentrations with high molecular weight in the treatment of knee osteoarthritis

BackgroundKnee osteoarthritis is severe progressive and most commonly diagnosed articular disease and its incidence is increasing around the world depending on age. This pathologic condition which limits daily activity of patients can be characterized by degeneration of cartilage and inflammation. Although non-steroidal anti-inflammatory (NSAII) agents and other analgesics are routinely used treatment options, the potential effects of intraarticular injections including hyaluronic acid (HA) have also been demonstrated by various studies. However, few studies compare the efficacy of a single high molecular weight (HMW) high dose and a triple HMW low dose. This study aimed to compare the efficacy of single high molecular weight (HMW) high dose (2 mL / 60 mg) and triple HMW low dose (2 mL /30 mg) intra-articular injection of HA in knee osteoarthritis (OA) patients by evaluating function and pain parameters during 12 months.MethodsThis is a single-center, retrospective clinical study that included and involved 128 patients. Group I (n=64) patients received triple 30 mg HA injections (SEMICAL®) with one-week intervals, while Group II (n=64) patients received a single 60 mg HA injection (SEMICAL®). Lequesne Index, WOMAC and VAS scores were recorded to assess pain and function during a 12-month period.ResultsThere was no significant difference in characteristics of patient demographics. Our finding indicate that WOMAC, VAS score, and Lequesne Index values during follow-up visits exhibited a decrease, signifying improvement in the clinical condition. Notably, scores were significantly more favorable with the 30 mg of HA injection compared to the 60 mg of HA injection.ConclusionThis study suggests that the triple low-dose injection of HMW HA is more effective in improving WOMAC, VAS scores and Lequesne Index values than a single high-dose injection.

Highly Concentrated Stabilized Hybrid Complexes of Hyaluronic Acid: Rheological and Biological Assessment of Compatibility with Adipose Tissue and Derived Stromal Cells towards Regenerative Medicine.

Cells and extracts derived from adipose tissue are gaining increasing attention not only in plastic surgery and for aesthetic purposes but also in regenerative medicine. The ability of hyaluronan (HA) to support human adipose stromal cell (hASC) viability and differentiation has been investigated. However, the compatibility of adipose tissue with HA-based formulation in terms of biophysical and rheological properties has not been fully addressed, although it is a key feature for tissue integration and in vivo performance. In this study, the biophysical and biochemical properties of highly concentrated (45 mg/mL) high/low-molecular-weight HA hybrid cooperative complex were assessed with a further focus on the potential application in adipose tissue augmentation/regeneration. Specifically, HA hybrid complex rheological behavior was observed in combination with different adipose tissue ratios, and hyaluronidase-catalyzed degradation was compared to that of a high-molecular-weight HA (HHA). Moreover, the HA hybrid complex's ability to induce in vitro hASCs differentiation towards adipose phenotype was evaluated in comparison to HHA, performing Oil Red O staining and analyzing gene/protein expression of PPAR-γ, adiponectin, and leptin. Both treatments supported hASCs differentiation, with the HA hybrid complex showing better results. These outcomes may open new frontiers in regenerative medicine, supporting the injection of highly concentrated hybrid formulations in fat compartments, eventually enhancing residing staminal cell differentiation and improving cell/growth factor persistence towards tissue regeneration districts.

The Association of High-Molecular-Weight Hyaluronic Acid (HMWHA), Alpha Lipoic Acid (ALA), Magnesium, Vitamin B6, and Vitamin D Improves Subchorionic Hematoma Resorption in Women with Threatened Miscarriage: A Pilot Clinical Study

Background—We evaluated whether the oral intake of high-molecular-weight hyaluronic acid (HMWHA) in association with alpha lipoic acid (ALA), magnesium, vitamin B6, and vitamin D can improve the resorption of subchorionic hematoma in cases of threatened miscarriage. Methods—In this study, we enrolled 56 pregnant women with threatened miscarriage (i.e., subchorionic hematomas, pelvic pain/uterine contractions, and/or vaginal bleeding) between the 6th and the 13th week of gestation. They were treated with vaginal progesterone (200 mg/twice a day) (control group; n = 25) or vaginal progesterone plus oral 200 mg HMWHA, 100 mg ALA, 450 mg magnesium, 2.6 mg vitamin B6, and 50 mcg vitamin D (treatment group; n = 31; DAV®-HA, LoLi Pharma srl, Rome, Italy). An ultrasound scan was performed at the first visit (T0) and after 7 days (T1) and 14 days (T2) until hematoma resorption. Results—At the ultrasound scan, the treatment group showed faster resorption of the subchorionic hematoma compared with the control group, both at T1 (control group 140 (112–180), treated group 84 (40–112), p &lt; 0.0031), and T2 (control group: 72 (48–112), treated group: 0 (0–0), p &lt; 0.0001). Moreover, subjective symptoms, such as vaginal bleeding, abdominal pain, and uterine contractions, showed a faster decrease in the treatment group than in the control group. Conclusions—The association may more rapidly improve the resolution of threatened miscarriage and related symptoms compared to the standard local protocol.

High prevalence of CD44 and its ligand low molecular weight hyaluronan in plasma of HNSCC patients: clinical significance.

This study aims to evaluate the role of cancer stem cell marker, CD44, and its ligand HA as potential molecular biomarker for early detection of HNSCC. The expression profile (mRNA/Protein) of CD44 variants were analysed in primary HNSCC lesions and plasma of the patients. Then, prevalence of HA variants was analysed in plasma of the patients. The mRNA expression of CD44 variants, CD44S and CD44v3, were significantly high in both early (stage I/II) and late (stage III/IV) invasive lesions, with predominant expression of CD44v3 in the late-stage lesions. In plasma of HNSCC patients, increased levels of SolCD44, CD44-ICD and unique 62 KD CD44 variants with respect to standard CD44S were seen, in comparison to their prevalence in plasma of normal individuals. The abundance of CD44-ICD and 62 KD variants were significantly high in plasma of late stage HNSCC patients. Interestingly, significantly high level of low molecular weight HA(LMW HA) with respect to high molecular weight HA(HMW HA) was seen in plasma of HNSCC patients irrespective of clinical stages. On the contrary, high HMW HA level in plasma of normal individuals was seen. The high level of LMW HA in plasma of HNSCC patients might be due to combinatorial effect of increased mRNA expression of HA synthesizing enzyme HAS1/2/3 and HA degrading enzyme HYAL1/2, as seen in the primary HNSCC samples. Thus, our data revealed the importance of specific CD44 and HA variants in plasma of HNSCC patients during its development as potential non-invasive molecular biomarker of the disease.