Weight Hyaluronic Acid Research Articles

In vitro study of the gel cohesivity and persistence to hyaluronidase degradation of a novel stabilized composition of 26 mg/mL of high molecular weight HA

Aim: Hyaluronic acid (HA) is extensively used in injectable skin quality products due to its documented role in skin rejuvenation. The rapid in vivo degradation of HA by the enzyme hyaluronidase necessitates the development of advanced formulations to ensure the efficacy and longevity of the treatments. In this context, a novel 2.6% high molecular weight HA (H-HA)/3.2% sorbitol composition has been introduced, featuring stabilization through hydrogen bonds rather than traditional crosslinking. Methods: The stabilized composition was evaluated through two in vitro enzymatic degradation tests. In the first test, the efficiency on the gel degradation was followed by rheology and compared with two crosslinked HA products available on the market. In the second test, the effect on the gel structure of a less diluted hyaluronidase dose was followed by rheological and cohesivity measurements. Results: In vitro study demonstrates that, before its complete degradation into a liquid-like state, the stabilized composition exhibits high elasticity and cohesivity during the enzymatic degradation process, surpassing traditional crosslinked HA products. Conclusion: The stabilization provided by the sorbitol in the stabilized composition effectively enhances product properties and protects them during gel degradation. These attributes indicate significant potential for improved clinical outcomes in skin quality treatments.

A retrospective claims data analysis of health care utilization and cost among patients receiving multi-injection intraarticular hyaluronic acid.

With the rising costs for knee arthroplasty, therapies that allow patients to avoid or delay surgery following knee osteoarthritis (KOA) may help in reducing overall health care costs. Multiple intraarticular hyaluronic acid (HA) products are available on the market, varying by formulation, molecular weight, and number of injections, but clinical and economic benefits may differ by product. OBJECTIVES: To evaluate the all-cause and KOA-related health care resource utilization (HCRU) and costs among newly diagnosed patients with KOA treated with multi-injection HA. A retrospective cohort study using a large commercial claims database (Merative MarketScan database) to identify patients with KOA treated with high molecular weight (HMW) (n = 11,200), medium molecular weight (MMW) (n = 10,225), or low molecular weight (LMW) HAs (n = 8,473) between 2016 and 2019. KOA-related and all-cause HCRU and costs were compared within 12 months after the index HA treatment date. The association between outcomes and HA treatments was evaluated using a doubly robust method to adjust for confounding factors. HCRU and costs among the propensity score-weighted HA groups were compared using generalized linear models. HMW HA patients were found to have lower adjusted KOA-related medical costs by $265.37 (P < 0.001) and pharmacy costs by $19.90 (P < 0.001) compared with LMW HA patients, as well as lower all-cause total medical costs by $130.42 (P = 0.013) and pharmacy costs by $63.33 (P < 0.001). HMW HA patients also had a lower adjusted KOA-related medical cost by $205.74 (P < 0.001) and pharmacy cost by $14.39 (P < 0.001) compared with MMW HA patients, as well as lower all-cause medical by $1,195.66 (P < 0.001) and pharmacy by $196.99 (P < 0.001). Three-injection treatment patients (HMW HA, 84%; MMW HA, 82%) had high completion rate, compared with the 5-injection treatment cohort (LMW HA, 48%). HMW HA patients had statistically significantly lower adjusted all-cause and KOA-related medical and pharmacy costs at 1 year follow-up compared with MMW HA and LMW HA patients. It is unclear if this is related to differences in molecular weight or specific mechanism of actions.

The Potential of Intra-Articular Therapies in Managing Knee Osteoarthritis: A Systematic Review.

Knee osteoarthritis (KOA) is a common degenerative and progressive joint disorder that negatively influences patients' quality of life. Intra-articular therapies, such as hyaluronic acid (HA) and platelet-rich plasma (PRP), have garnered attention for their potential to manage osteoarthritis OA symptoms effectively. This systematic review aims to identify the effectiveness and safety of HA and PRP treatment modalities in treating KOA. A literature search was conducted across MEDLINE (PubMed), Web of Science Core Collection, and Science Direct Collection Elsevier. Twenty-three randomized controlled trials, cohort studies, and observational studies were included in the review. The selection criteria focused on studies published in English within the last 10 years, involving subjects with KOA treated with intra-articular injections of HA or PRP and reporting on pain, function, or overall treatment efficacy outcomes. The analysis showed that both HA and PRP significantly improve functionality and reduce pain in KOA patients. High molecular weight HA consistently reduced pain and improved joint mobility in various studies. PRP had better long-term outcomes when combined with HA, leading to greater pain reduction and functional improvement. Both therapies had generally favorable safety profiles, with only minor adverse events reported. However, there were potential biases identified across the studies, such as selection, performance, detection, and reporting biases, which impacted the reliability of the results. Intra-articular treatments with HA and PRP show promise in managing knee osteoarthritis, with personalized treatment plans and further research needed to confirm these findings.

Identification and Characterization of a Highly Active Hyaluronan Lyase from Enterobacter asburiae.

Hyaluronic acid (HA) is a well-known functional marine polysaccharide. The utilization and derivative development of HA are of great interest. Hyaluronan lyase has wide application prospects in the production of HA oligosaccharides and lower molecular weight HA. In this study, a strain of Enterobacter asburiae CGJ001 with high hyaluronan lyase activity was screened from industrial wastewater. This strain exhibited an impressive enzyme activity of 40,576 U/mL after being incubated for 14 h. Whole genome sequencing analysis revealed that E. asburiae CGJ001 contained a cluster of genes involved in HA degradation, transport, and metabolism. A newly identified enzyme responsible for glycosaminoglycan degradation was designated as HylEP0006. A strain of E. coli BL21(DE3)/pET-22b(+)-hylEP0006 was successfully constructed. HylEP0006 exhibited optimal degradation at 40 °C and pH 7.0, showing a high activity of 950,168.3 U/mg. HylEP0006 showed specific activity against HA. The minimum degradation fragment of HylEP0006 was hyaluronan tetrasaccharides, and HylEP0006 could efficiently degrade HA into unsaturated disaccharides (HA2), with HA2 as the final product. These characteristics indicate that HylEP0006 has a potential application prospect for the extraction and utilization of hyaluronic acid.

Nitrilotriacetic Acid Functionalized Microgels for Efficient Immobilization of Hyaluronan Synthase.

Enzymes play a vital role in synthesizing complex biological molecules like hyaluronic acid (HA). Immobilizing enzymes on support materials is essential for their efficient use and reuse in multiple cycles. Microgels, composed of cross-linked, highly swollen polymer networks, are ideal for enzyme uptake owing to their high porosity. This study demonstrates the immobilization of His6-tagged hyaluronan synthase from Pasteurella multocida (PmHAS) onto nitrilotriacetic acid functionalized microgels using different bivalent ions (Ni2+, Co2+, Mn2+, Mg2+, and Fe2+) via metal affinity binding. The results indicate that using Ni2+ yields the microgels with the highest enzyme uptake and HA formation. The immobilized PmHAS enables repetitive enzymatic production, producing high molecular weight HAs with decreasing dispersities in each step. Furthermore, the highest reported yield of HA with high molecular weight for immobilized PmHAS is achieved. This system establishes a foundation for continuous HA formation, with future works potentially enhancing PmHAS stability through protein engineering.

Identification of hyaluronic acid in seized samples by Hypercarb chromatography-high resolution mass spectrometry.

Hyaluronic acid (HA) has been commonly used to treat osteoarthritis and joint injuries in horses and dogs since the 1970s. HA is a polysaccharide made up of alternating N-acetyl-d-glucosamine and d-glucuronic acid residues, with polymeric molecules achieving molecular weights as high as 20 MDa. High molecular weight HA forms a viscous hydrogel when dissolved in water, making HA solutions distinct from most other pharmaceutical preparations. Clear viscous solutions are often encountered during stable and kennel inspections, but in the absence of an analytical method, it is not possible to identify if these substances contain HA or other unknown compounds. This paper presents a simple method for the identification of HA in seized materials based on chemical hydrolysis followed by Hypercarb chromatography and MS/MS analysis.

Profhilo® Structura, Current Status and Future Perspectives: A Practical Review.

Hyaluronic acid (HA)-based injectables continue to grow in popularity and are used worldwide to improve facial changes associated with aging. Profhilo® Structura (IBSA Farmaceutici Italia, Lodi, Italy) is a novel HA-based product that uses nano hybrid complex of hyaluronic acid (NAHYCO)® technology to create hybrid cooperative complexes consisting of high and low molecular weight HA. Profhilo® Structura's high concentration (45 mg of total HA) and rheological properties (ie, viscosity [resistance to flow] and elasticity [stickiness]) have been specially formulated to restore facial adipose tissue. Because of their early involvement in the facial aging process, the superficial medial and lateral-temporal cheek fat compartments are good candidates for treatment. However, recommendations and guidelines are necessary to ensure that treatment is safe and effective. Three experts were invited to IBSA Farmaceutici Italia Srl to discuss clinical rationale, optimal injection techniques, and clinical outcomes for treating the superficial medial and lateral-temporal cheek fat compartments with Profhilo® Structura. These techniques were developed using patients presenting with either initial hypotrophy of fat compartments within the preauricular area (ie, sinkers) or jowl sagging due to hypotrophy within the preauricular and zygomatic areas (ie, saggers). Targeting these areas using the optimal injection site can maximize product diffusion and minimize the risk for vascular compromise. Targeting these areas also leads to lateral tightening and lipolifting effects due to adipose tissue restoration. The experts agreed that Profhilo® Structura is currently the first and only HA-based injectable treatment that can integrate and restore the adipose tissue in these affected fat compartments.

Late-Onset Reactions after Hyaluronic Acid Dermal Fillers: A Consensus Recommendation on Etiology, Prevention and Management.

Hyaluronic acid (HA) dermal fillers, generally considered low-risk, can lead to rare late-onset reactions (LORs) manifesting between 3 and 4 months postinjection, occasionally even as early as 24h postinjection. The Complication Assessment and Risk Evaluation (CARE) board was established to review these reactions. In this publication, the authors aims to explore the etiological hypotheses underlying LORs, associated risk factors, prevention, and management approaches suggested by the CARE board. The CARE board identified three etiological hypotheses contributing to LORs. Firstly, the physicochemical structure of the filler, particularly low molecular weight HA, which may trigger an immune response. Secondly, infection, potentially introduced during injection or by dormant biofilm activation. Lastly, an imbalance in the host immune system, caused by factors like autoimmune diseases or viral infections, may lead to extended foreign body reactions, delayed type IV hypersensitivity, or adjuvant-based reactions. Based on these hypotheses, the board categorized various risk factors as patient-related (e.g., recent dental treatment, current medical status, active autoimmune disease), product-related (e.g., molecular weight), and procedure-related (e.g., aseptic technique and trauma). To reduce the risk of LORs, the CARE board recommends diligent patient selection, including comprehensive medical history assessment and informed consent. Practitioners should maintain an effective aseptic technique, and choose an appropriate product and injection depth for the anatomical location. Post-procedure, patients should receive education on proper filler care. Management of LORs depends on the suspected etiology, and the CARE board has proposed an algorithm to determine the most appropriate treatment. Hyaluronidase is recommended for noninflammatory reactions in the absence of active infection, while watchful waiting and/or steroid treatment may be preferred for inflammatory reactions. Hyaluronidase is not recommended as a first-line treatment for infections, which require drainage, bacterial culture, and antibiotic treatment. However, the board emphasizes the need for individualized evaluation and treatment in all cases.

Comparison of Two Hyaluronic Acid Preparations for the Treatment of Rizoarthrosis

Osteoarthritis of the trapeziometacarpal joint (TOA) or rizoarthrosis is a pathology particularly prevalent in post-menopausal women. It can be symptomatic, with associated pain, or asymptomatic, and in this latter case it is diagnosed by radiographical examination. TOA, when symptomatic, strongly affects quality of life. The treatment of TOA involves both pharmacological and non-pharmacological treatment (including local application of heat, ultrasound and splints). The major treatments, recommended by the European League Against Rheumatism consists of corticosteroids for pain control and hyaluronic acid (HA) for amelioration of functional capacity. The present study aimed at comparing the efficacy and tolerance of intra articular injections of two HA preparations, high-low molecular weight HA (HL) (Sinovial® HL) and high molecular weight HA (HMW) (Sinovial® Mini), in patients with TOA. The observational and retrospective study involved overall 125 subjects, ageing from 45 to 85 years, who had clinical symptoms of TOA lasting at least 6 months. The patients received HL (66 subjects) or HMW (59 subjects) in two injections at baseline and after 15 days. The subjects were followed for 6 months, and the outcome measurements included pain control (through VAS scale) functional hand capacity, using the Duruoz Hand Index (DHI) and the change of the duration of morning stiffness, using the Italian version of the Health Assessment Questionnaire (HAQ). HL was found superior to HMW in all the three parameters examined, with a quicker and stronger pain relief, recovery of hand function as well as in self-assessment by the subjects. Both treatments were associated with very modest side effects. In conclusion, our data show the efficacy of HL and HMW for the treatment of TOA and the superiority of HL to HMW. Although these data are observational and retrospective, they pose the basis for future prospective studies focused on the use of HL and HMW in TOA.

Effectiveness of topical hyaluronic acid of different molecular weights in xerosis cutis treatment in elderly: a double-blind, randomized controlled trial.

Dry skin is a common dermatological condition that frequently affects the elderly. A contributing cause to dry skin is a reduced concentration of hyaluronic acid (HA) in both the epidermis and dermis. The effectiveness of moisturizer containing HA as a therapy for dry skin is impacted by its specific molecular weight. Low molecular weight HA (LMWHA) is believed to be more effective in replenishing skin hydration in aging skin compared to High Molecular Weight HA (HMWHA) due to its ability to penetrate the stratum corneum. However, there is a lack of clinical research supporting this claim. A double-blind, randomized controlled trial was conducted on 36 residents of a nursing home in Jakarta. The participants, aged between 60 and 80 years, had been diagnosed with dry skin. Each test subject was administered three distinct, randomized moisturizing lotions (LMWHA, HMWHA, or vehicle), to be topically applied to three separate sites on the leg. Skin capacitance (SCap), transepidermal water loss (TEWL), and specified symptom sum score (SRRC) were measured at weeks 0, 2, and 4. After four weeks of therapy, area that was treated with LMWHA showed greater SCap values compared to the area treated with HMWHA (56.37 AU vs. 52.37 AU, p = 0.004) and vehicle (56.37 AU vs. 49.01 AU, p < 0.001). All groups did not show any significant differences in TEWL and SRRC scores. No side effects were found in all groups. The application of a moisturizer containing LMWHA to the dry skin of elderly resulted in significant improvements in skin hydration compared to moisturizers containing HMWHA and vehicle. Furthermore, these moisturizers demonstrated similar safety in treating dry skin in the elderly. ClinicalTrials.gov Identifier NCT06178367, https://clinicaltrials.gov/study/NCT06178367 .

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. Furthermore, 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, a high molecular weight (>60kDa) HA alkyl-hydrazone crosslinked hydrogel is modified 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 increases stability. The slow gelation kinetics of the SPAAC reaction in the 12% SPAAC hydrogel enables transient self-healing properties and a similar extrusion force as the 0% SPAAC hydrogel. Methyl-PEG4-hydrazide is then introduced to further slowdown network evolution, which temporarily lowers the extrusion force, improves printability, and increases 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.

Hyaluronic acid hydrogel to modulate tumor cell clustering and programmed death ligand 1 signaling in cancer stem cells.

e14584 Background: The root of malignancy lies in the extracellular matrix (ECM) surrounding the stromal cells. Thus, current therapeutic targets manipulate abnormal tumor microenvironments (TME), which nourish cancer stem cells (CSC) and induce tumor cell clustering (TCC). Notably, despite the first line of clinical therapy with surgery and chemotherapy, uncontrolled self-renewal of CSCs, conversion of non-CSCs to CSCs, and TCC trigger cancer recurrence. The transmembrane glycoprotein CD44 is thought to be a potential master regulator in cancer recurrence as it interacts with hyaluronic acid (HA) in TME, expresses aberrantly on CSCs, induces TCC by homophilic interactions like Plakoglobin despite less understanding on their crosstalk, and promotes expression of pro-tumorigenic factor programmed death ligand 1 (PD-L1). Notably, CD44 is expressed in multiple isoforms, and splice isoform switching of CD44 dictates the properties of CSC, which still needs to be clarified. Hence, we aimed to characterize CSCs based on CD44 isoform expression, investigate the crosstalk between CD44 and Plakoglobin, and then design a novel injectable HA hydrogel that can disguise TME and suppress PD-L1 to combat cancer recurrence. Methods: To characterize CSCs, we prepared different scaffolds of HA of varied molecular weights and other ECM proteins, cultured cancer cells (MDA-MB-231, HeLa), and determined the expression of CD44 isoforms. We sorted CD44+/CD24- expressing CSC by flow cytometry. We implemented immunoprecipitation to detect the interaction between CD44 and Plakoglobin. We created a novel HA hydrogel composed of low and very high molecular weight HA, thiolated gelatin, and other components crosslinked with PEGDA. Using a torsional rheometer, we measured matrix stiffness. We assessed the cell proliferation efficiency of CSC by a colony-forming assay. Results: The study disclosed that CD44 isoforms expressed differently based on ECM properties. Matrix stiffness dictated CD44 isoform expression. We observed that CD44 interacted with Plakoglobin. CD44 ablation upregulated Plakoglobin significantly. Tumor suppressor p53 played a significant role in CD44-Plakoglobin crosstalk. We observed that the injectable hydrogel modulated CD44-Plakoglobin signaling and inhibited TCC, likely promoting anoikis. The hydrogel affected CD44 splicing and modified the activity of the CD44 intracellular domain, which interacts with PD-L1 and thus suppressed PD-L1 expression significantly in CSC. Conclusions: Currently, antibodies targeting PD-1/PD-L1 signaling have been clinically approved for various cancers. However, this regimen of treatment is expensive. We report a novel injectable hydrogel that can disguise TME, modulate CSCs and PD-L1, and may advance an alternative cost-effective avenue for cancer immunotherapy.

Collagen-Mesenchymal Stem Cell Microspheres Embedded in Hyaluronic Acid Solutions as Biphasic Stem Niche Delivery Systems for Pulmonary Differentiation.

Cell therapy has the potential to become a feasible solution for several diseases, such as those related to the lungs and airways, considering the more beneficial intratracheal administration route. However, in lung diseases, an impaired pulmonary extracellular matrix (ECM) precludes injury resolution with a faulty engraftment of mesenchymal stem cells (MSCs) at the lung level. Furthermore, a shielding strategy to avoid cell damage as well as cell loss due to backflow through the injection path is required. Here, an approach to deliver cells encapsulated in a biomimetic stem niche is used, in which the interplay between cells and physiological lung ECM constituents, such as collagen and hyaluronic acid (HA), can occur. To this aim, a biphasic delivery system based on MSCs encapsulated in collagen microspheres (mCOLLs) without chemical modification and embedded in an injectable HA solution has been developed. Such biphasic delivery systems can both increase the mucoadhesive properties at the site of interest and improve cell viability and pulmonary differentiation. Rheological results showed a similar viscosity at high shear rates compared to the MSC suspension used in intratracheal administration. The size of the mCOLLs can be controlled, resulting in a lower value of 200 μm, suitable for delivery in alveolar sacs. Biological results showed that mCOLLs maintained good cell viability, and when they were suspended in lung medium implemented with low molecular weight HA, the differentiation ability of the MSCs was further enhanced compared to their differentiation ability in only lung medium. Overall, the results showed that this strategy has the potential to improve the delivery and viability of MSCs, along with their differentiation ability, in the pulmonary lineage.

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.

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.

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.

Efficacy and tolerability of Profhilo® Structura intended to restore lateral cheek fat compartment: An observational pilot study.

Hyaluronic acid (HA)-based injections are used worldwide to improve skin defects associated with aging and ultraviolet light/environmental exposure. HA formulations developed according to molecular weight or with additional components, for example, cross-linking reagents, are limited by their low biological activity and concentration limit. NAHYCO™ technology has enabled the production of hybrid cooperative complexes (HCCs) of low and high molecular weight HA. Developed for injection into the fat compartments of the face and previously demonstrating potential benefits for adipose tissue restoration, Profhilo Structura® is a new 2 mL HCC formulation comprising low molecular weight HA (45 mg/mL) and high molecular weight HA (45 mg/mL). To evaluate the efficacy and tolerability of Profhilo Structura® to restore adipose tissue compartments in the lateral cheek fat compartment. Fifty healthy enrolled subjects received two injections, 1 month apart, and were evaluated 3 months posttreatment. Investigators performed clinical evaluations (Facial Volume Loss Scale [FVLS] and Wrinkle Severity Rating Scale [WSRS]) at different time points. Subjects also completed self-evaluation assessments following treatment. A significant improvement in FVLS and WSRS clinical scores after the first treatment was observed; treatment benefit was maintained 3 months after treatment completion and confirmed by subject self-assessment. Most participants reported an improvement, particularly a marked reduction of wrinkles and increased skin firmness. No serious adverse events were reported, confirming the excellent safety profile of HCC injectable devices. Overall, the study highlighted the efficacy and tolerability of the studied medical device proving its effect on adipose tissue.

Detection and analysis of hyaluronic acid raw materials from different sources by NIR and aquaphotomics.

Hyaluronic acid (HA), a polysaccharide, is widely used for its essential physiological functions. Although the structures of low molecular weight HA produced by both acid and enzyme degradation methods are extremely similar, there are still differences due to the different degradation principles. There is currently no clear way to distinguish between HA prepared by acidolysis and enzymatic hydrolysis. Based on near-infrared (NIR) spectroscopy and aquaphotomics technology, a method for distinguishing HA raw materials and their mixtures from different sources was proposed, and HA with different mixed ratios was accurately quantified. First, NIR spectra of the HA samples were collected. The spectra were then preprocessed to improve the spectral resolution. Spectral information was extracted based on wavelet transform and principal component analysis, resulting in a final selection of 12 characteristic wavelengths containing classification information. The discriminative and quantitative models were then constructed using the 12 wavelengths. The discriminative model achieved a 100% identification rate for HA from different sources. The correlation coefficient of calibration (Rc), validation (Rp), external test (Rt), root mean square error of cross validation (RMSECV), calibration (RMSEC), validation (RMSEP), and external test (RMSET) of the mixed proportion quantitative model were 0.9876, 0.9876, 0.9898, 0.0546, 0.0433, 0.0440, and 0.0347, respectively. In this study, the problem of structural similarity and non-identifiability of HA produced by acidolysis and enzymatic hydrolysis was addressed, and quality monitoring of HA feedstock in HA circulating links was achieved. This is the first time to achieve accurate quantification of solid mixtures using the aquaphotomics method.

The Effects of Ultrasound-Guided Intra-Articular Injections with Hyaluronic Acid and Corticosteroids in Patients with Hip Osteoarthritis: A Long-Term Real-World Analysis.

Intra-articular (IA) ultrasound-guided hip injections are currently considered a cornerstone of the conservative management of symptomatic hip osteoarthritis (HOA), although their effect on clinical outcomes has not been fully elucidated.The purpose of this study is to investigate the effectiveness of ultrasound-guided IA hip injections of hyaluronic acid (HA) with or without corticosteroids (CS) on pain relief and functional improvement in patients with HOA. In total, 167 patients with HOA were assessed at baseline (T0) and 12 months after injection (T1) using the VAS and GLFS scores. The sample consisted mainly of female subjects (58.1%), presenting an average age of 70.6 ± 12.2 years and grade 3 HOA (63.9%) according to the Kellgren-Lawrence classification. Most of the patients (76.2%) underwent unilateral hip injection with a combination of medium-high molecular weight HA (1500-2000 kDa) and CS. At T1, lower use of anti-inflammatory drugs, an increase in the consumption of chondroprotectors, and an overall reduction of instrumental physical therapies and therapeutic exercise were recorded. In addition, a statistically significant intragroup and between-group decrease observed at T1 for both the VAS and GLFS. Study results suggested that intra-articular hip injections with HA alone and with CS could represent a useful therapeutic tool for pain reduction and functional improvement for patients with hip osteoarthritis.