Hyaluronic Acid Matrix Research Articles

The combination of hydrogels and rutin-loaded black phosphorus nanosheets treats rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by inflammation, joint pain, and cartilage degradation. The fluctuating nature of RA often necessitates long-term oral administration of treatment drugs, which can unfortunately lead to adverse effects such as gastrointestinal discomfort and hepatic and renal dysfunction. Therefore, a percutaneous local delivery method for the release of inflammatory modulators in arthritic joints represents a promising therapeutic approach for RA. In this study, we have developed a unique and innovative therapeutic platform (named BP-Rut@Gel). This hydrogel was formulated by incorporating the drug Rutin (Rut) into Black phosphorus nanosheets (BP) and subsequently integrating them within a Hyaluronic Acid (HA) and Polyvinyl Alcohol (PVA) matrix to create a composite hydrogel. Notably, Secondly, photothermal therapy (PTT) under Near-Infrared Irradiation (NIR) and anti-inflammatory drugs synergistically worked together to efficiently quell inflammation and enhance therapeutic effectiveness. Additionally, toxicity experiments have revealed that our synthesized black phosphorus nanosheet composite hydrogel possesses excellent biocompatibility and significantly reduces the inflammatory response in RA joints. Given these remarkable properties, our BP-Rut@Gel hydrogel held significant promise and demonstrated immense clinical potential for the treatment of RA.

A modified hyaluronic acid hydrogel with strong bacterial capture and killing capabilities for drug-resistant bacteria-infected diabetic wound healing

Management of diabetic wounds becomes increasingly challenging as bacterial infections intensify the inflammation. Employing polysaccharide hydrogels with inherent antibacterial qualities can significantly reduce the need for antibiotics to manage infections in diabetic wounds. The typical approach to achieving antibacterial outcomes with hydrogels relies on the penetration of bacteria into their porous architecture. Such penetration not only takes time but can also prolong inflammation, thus impeding the healing of wounds. Hence, the quick capture and eradication of bacteria are essential for optimizing the hydrogel's antibacterial performance. Herein, we introduce a multifunctional polysaccharide hydrogel dressing—designated as HAQ—created for managing bacterial infections in diabetic wounds. This dressing is based on hyaluronic acid, which is modified with methacrylic anhydride, and special functional groups are added to the modified hyaluronic acid matrix: phenylboronic acid for capturing bacteria and quaternary ammonium chitosan for bacterial destruction. As expected, the HAQ system exhibits robust antibacterial effectiveness against both methicillin-resistant Staphylococcus aureus and multidrug-resistant Pseudomonas aeruginosa in vitro and in vivo. Consequently, HAQ stands as a promising hydrogel dressing with intrinsic antibacterial capabilities and offers significant potential for managing diabetic wounds infected by drug-resistant bacteria.

Evaluation of morphology, physical and mechanical properties of hyaluronic acid matrices of various molecular weights by atomic force microscopy

Using atomic force microscopy the morphology of 1 and 2 % sodium hyaluronate solutions matrix with low molecular weight (LM) and high molecular weight (HM) hyaluronic acid (HA) fabricated by bioenzymatic synthesis was evaluated. The presence of a proteoglycan aggregate with processes of the core protein in the absence of sulfated glycosaminoglycans was established. The effect of irradiation with a light flux on the ordering of the HA matrix was observed. Intermolecular consolidation of high molecular HA was established. The elastic modulus of the matrix with LM and HM HA has also been determined.

Clinical and Radiographic Evaluation of Intrabony Periodontal Defects Treated with Hyaluronic Acid or Enamel Matrix Proteins: A 6-Month Prospective Study.

To compare the regenerative clinical and radiographic effects of cross-linked hyaluronic acid (xHyA) with enamel matrix proteins (EMD) at six months after regenerative treatment of periodontal intrabony defects. Sixty patients presenting one intrabony defect each were randomly assigned into control (EMD) and test (xHyA) groups. Clinical attachment level (CAL) gain was the primary outcome, while pocket probing depth (PPD), gingival recession (REC), bleeding on probing (BOP), full-mouth plaque score (FMPS), full-mouth bleeding score (FMBS), and radiographic parameters such as defect depth (BC-BD), and defect width (DW) were considered secondary outcome variables. Parameters were recorded at baseline and after 6 months. At the 6-month follow-up, 54 patients were available for statistical analysis. In the control and test groups, the mean CAL gain was statistically significant in the intragroup comparison (p < 0.001). 48.1% of test sites showed a CAL gain ≤ 2 mm compared with 33.3% of control sites. The mean PPD reduction was statistically significant in the intragroup comparison in both groups (p < 0.001). The mean REC increase was similar in the two groups: 1.04 ± 1.29 mm vs 1.11 ± 1.22 mm (test vs control). The mean BC-BD, DW, FMPS, FMBS, and BOP changed statistically significantly only in the intragroup comparison, not in the intergroup comparison. Both treatments, EMD and xHyA, produced similar statistically significant clinical and radiographical improvements after six months when compared with baseline.

Effectiveness of different advanced wound dressings versus standard of care for the management of diabetic foot ulcers: a meta-analysis of randomized controlled trials for the development of the Italian guidelines for the treatment of diabetic foot syndrome.

to assess the effects of advanced wound dressings (AWD) commonly used in the treatment of predominantly neuropathic diabetic foot ulcers (DFU) The present meta-analysis was designed to support the development of the Italian Guidelines for the Treatment of Diabetic Foot Syndrome (DFS). A Medline and Embase search were performed up to April 1st, 2024 collecting all RCTs including diabetic patients or reporting subgroup analyses on diabetic patients with DFU comparing AWD with placebo/standard of care (SoC), with a duration of at least 12 weeks. Prespecified endpoints were: ulcer healing (principal), time-to-healing, frequency of dressings change, major and minor amputation, pain, and all-cause mortality. AWD assessed were: alginates; foam, hydrocolloids, hydrogels, hyaluronic acid, hemoglobin spray, silver-impregnated, sucrose octasulfate-impregnated, honey-impregnated, micro-organism-binding, and protease-modulating matrix dressings. Mantel-Haenzel Odds ratios and 95% confidence intervals (MH-OR, 95% CIs) were either calculated or extracted directly from the publications. Weighted mean differences (WMD) and 95% CIs were calculated for continuous variables. Fifteen studies fulfilled all inclusion criteria. Participants treated with AWD had a significantly higher ulcer healing rate and shorter time-to-healing in comparison with SoC/placebo (MH-OR 1.50 [0.80, 2.79], p = 0.20 and WMD:: - 24.38 [- 42.90, - 5.86] days, p = 0.010). No other significant effect on the above reported prespecified endpoints were observed. For the primary endpoint, the quality of evidence was rated as "moderate". In conclusion, AWD, particularly sucrose-octasulfate, hydrogels, hyaluronic acid, and honey dressings, can actively promote wound healing and shortening time-to-healing in patients with DFU.

The gold protocol: A combined treatment approach for neck rejuvenation with calcium hydroxyapatite, botulinum toxin, and hyaluronic acid in the same session.

The signs of aging seem to be more visible on the neck compared to other locations, especially if a patient has already gone through facial rejuvenation procedures. Treatment of the aging neck imposes a challenge to the clinician, since one single approach is usually not enough to achieve the desired result, requiring multiple injections and sessions, which apart from being painful for the patients, is time-consuming for the clinician. To describe the use of calcium hydroxyapatite, incobotulinum toxin type A and Cohesive poly-densified matrix hyaluronic acid diluted in the same syringe and injected in the same session for neck rejuvenation. Fifteen women, older than 18 years, with cervical skin flaccidity grade 1-4 in a previously validated 5-point rating scale (Dermatologic Surg, 2016; 42, S94), who sought neck rejuvenation were injected in this pilot study with a single session with a combined hybrid mixture of calcium hydroxyapatite, incobotulinum toxin type A, and Cohesive poly-densified matrix hyaluronic acid and followed up for 90-180 days. At the 4-month post injection evaluation, 93.3% of the patients presented at least 1-grade improvement in the 5-point scale as evaluated by the investigator. No serious adverse events were reported, being most mild and transient in nature. CaHA, incoBonTA, and CPM-HA have complementary mechanisms of action and may be injected from the same syringe in the same session, boosting the final outcome, with high patient satisfaction, and ease of process for both patients and clinicians.

Development of a Cissus quadrangularis-Doped Extracellular Matrix and a Hyaluronic Acid-Incorporated Scaffold for Periodontal Regeneration: An In Vitro Study.

The study aimed to analyze whether adding Cissus quadrangularis (CQ) extract and the extracellular matrix of ovine tendon (TENDON) increases the regenerative potential of mesenchymal stem cells produced in hyaluronic acid (HA) scaffolds for tenogenesis. Fifty grams of powdered CQ was mixed with 250 mL of ethanol to prepare the extract. Two grams of hyaluronic acid powder was added to 100 mL of distilled water to make the HA solution. The ovine tendon was decellularized using a mixture of 10% phosphate-buffered saline (PBS), sodium dodecyl sulfate (SDS), and Triton-X. The hydrogel samples were prepared by mixing the extracellular matrix of tendon, HA, and CQ, after which they were divided into study groups such as HA, HA + CQ, HA + TENDON, and HA + CQ + TENDON. Scanning electron microscopy (SEM) analysis, swelling analysis, differentiation analysis, compression test, compatibility assay, and tenogenesis assay were later conducted. The morphology of the samples was analyzed using SEM. Low levels of swelling of the hydrogels were observed. Cells were found to be viable and showed good differentiation and tenogenesis. Optimal compression levels were observed, and the properties of the prepared hydrogels were satisfactory. The results suggest that the addition of CQ considerably increases the tenogenic potential of the extracellular matrix/HA scaffold. Hence, it can be used as a regenerative material for periodontal tissue regeneration.

Matrix hyaluronic acid and bilayer poly-hydroxyethyl methacrylate-hyaluronic acid films as potential ocular drug delivery platforms

This study aimed to design hydrogel based films comprising hyaluronic acid (HA) to overcome limitations of currently used eye drops. Timolol-loaded crosslinked (X2) HA-based and bilayer (B2) (pHEMA/PVP-HA-based layers) films were designed and characterized. The films were transparent (UV, visual observation) with crosslinked (<80 %) films showing lower light transmittance than bilayer (>80 %) films. X2 showed significantly higher swelling capacity, tensile strength and elastic modulus (5491.6 %, 1539.8 Nmm−2, 1777.2 mPa) than B2 (1905.0 %, 170.0N mm−2, 67.3 mPa) respectively. However, X2 showed lower cumulative drug released and adhesive force (27.3 %, 6.2 N) than B2 (57.5 %, 8.6 N). UV sterilization did not significantly alter physical properties, while SEM and IR microscopy showed smooth surface morphology and homogeneous drug distribution. Timolol permeation (EpiCorneal™/porcine cornea) depended on the film matrix with erodible films showing similar permeation to commercial eyedrops. Drug permeation for porcine cornea (X2 = 549.0.2, B2 = 312.1 μgcm−2 h−1) was significantly faster than EpiCorneal™ (X2 = 55.2, B2 = 37.6 μgcm−2 h−1), but with a linear correlation between them. All the selected optimized films showed acceptable compatibility (MTT assay) with both HeLa cells and EpiCorneal™. In conclusion, crosslinked and bilayer HA based films showed ideal characteristics suitable for potential ocular drug delivery, though further work is required to further optimize these properties and confirm their efficacy including in vivo tests.

Scale-Dependent Rheology of Synovial Fluid Lubricating Macromolecules.

Synovial fluid (SF) is the complex biofluid that facilitates the exceptional lubrication of articular cartilage in joints. Its primary lubricating macromolecules, the linear polysaccharide hyaluronic acid (HA) and the mucin-like glycoprotein proteoglycan 4 (PRG4 or lubricin), interact synergistically to reduce boundary friction. However, the precise manner in which these molecules influence the rheological properties of SF remains unclear. This study aimed to elucidate this by employing confocal microscopy and multiscale rheometry to examine the microstructure and rheology of solutions containing recombinant human PRG4 (rhPRG4) and HA. Contrary to previous assumptions of an extensive HA-rhPRG4 network, it is discovered that rhPRG4 primarily forms stiff, gel-like aggregates. The properties of these aggregates, including their size and stiffness, are found to be influenced by the viscoelastic characteristics of the surrounding HA matrix. Consequently, the rheology of this system is not governed by a single length scale, but instead responds as a disordered, hierarchical network with solid-like rhPRG4 aggregates distributed throughout the continuous HA phase. These findings provide new insights into the biomechanical function of PRG4 in cartilage lubrication and may have implications in the development of HA-based therapies for joint diseases likeosteoarthritis.

Increased level of C3 in synovial fluid in patients with activated osteoarthritis as a diagnostic and therapeutic target – pilot group of patients from the Rheumatology Department at UMHAT Burgas

The clinical course of osteoarthritis (OA) indicates the role of low-grade synovitis as the main driver of the degenerative process. Components of the extracellular matrix, fibronectin isoforms, and fragments of hyaluronic acid are presumed ligands for DAMPs (particularly TLR). Complement fractions bind to the corresponding receptors on the cell membranes of chondrocytes and synoviocytes through TLR. Does the complement cascade play a role only as a clearing system and/or a leading pathogenetic factor in activated OA? The aim of this study is to answer this question. The study included 50 patients with activated OA of the knee joint. We examined the levels of C3 and C4 complement fractions in the blood plasma and synovial fluid. We found that the values of these proteins in synovial fluid were on average 34.90% for C3 and 30.97% for C4 of their values in blood plasma, with a generally accepted norm of 10% for complement levels in a healthy joint. The observation regarding the strength of correlation between the above results and the radiological stage confirmed a stronger correlation of the obtained results in the earlier stages of the disease when the activity of the repair processes is more pronounced. In this way, we objectified the pathogenetic role of complement in the arthritic process, as well as its role in clearing the joint space from degradation products. The question arises whether pharmacological intervention to balance complement activation could represent a future therapeutic strategy in the treatment of OA and prevent its progression.

The Preparation of Silver and Gold Nanoparticles in Hyaluronic Acid and the Influence of Low-Pressure Plasma Treatment on Their Physicochemical and Microbiological Properties.

Nanometals constitute a rapidly growing area of research within nanotechnology. Nanosilver and nanogold exhibit significant antimicrobial, antifungal, antiviral, anti-inflammatory, anti-angiogenic, and anticancer properties. The size and shape of nanoparticles are critical for determining their antimicrobial activity. In this study, silver and gold nanoparticles were synthesized within a hyaluronic acid matrix utilizing distilled water and distilled water treated with low-pressure, low-temperature glow plasma in an environment of air and argon. Electron microscopy, UV-Vis and FTIR spectra, water, and mechanical measurements were conducted to investigate the properties of nanometallic composites. This study also examined their microbiological properties. This study demonstrated that the properties of the composites differed depending on the preparation conditions, encompassing physicochemical and microbiological properties. The application of plasma-treated water under both air and argon had a significant effect on the size and distribution of nanometals. Silver nanoparticles were obtained between the range of 5 to 25 nm, while gold nanoparticles varied between 10 to 35 nm. The results indicate that the conditions under which silver and gold nanoparticles are produced have a significant effect on their mechanical and antibacterial properties.

3D Bioprinting and Characterization of Bioinks with Different Concentrations of Hyaluronic Acid Methacrylate (AHMA)

The 3D Bioprinting technique for tissue engineering has been constantly developed and generating different results due to the range of applicability of the technique. It is necessary to study and analyze matrices to use this technology, as an example of hydrogels, which are viable for use in conjunction with cells to create the bioink used in bioprinting, verifying their physicochemical properties, cellular reviews, and properties mechanics for the desired application. Based on this, this work aims to analyze these properties, focusing on the hyaluronic acid (HA) matrix in different concentrations during the manufacture of bioink for 3D bioprinting for future application in tissue engineering.

Development of hyaluronic acid-silica composites via in situ precipitation for improved penetration efficiency in fast-dissolving microneedle systems

Fast-dissolving microneedles (DMNs) hold significant promise for transdermal drug delivery, offering improved patient compliance, biocompatibility, and functional adaptability for various therapeutic purposes. However, the mechanical strength of the biodegradable polymers used in DMNs often proves insufficient for effective penetration into human skin, especially under high humidity conditions. While many composite strategies have been developed to reinforce polymer-based DMNs, simple mixing of the reinforcements with polymers often results in ineffective penetration due to inhomogeneous dispersion of the reinforcements and the formation of undesired micropores. In response to this challenge, this study aimed to enhance the mechanical performance of hyaluronic acid (HA)-based microneedles (MNs), one of the most commonly used DMN systems. We introduced in situ precipitation of silica nanoparticles (Si) into the HA matrix in conjunction with conventional micromolding. The precipitated silica nanoparticles were uniformly distributed, forming an interconnected network within the HA matrix. Experimental results demonstrated that the mechanical properties of the HA–Si composite MNs with up to 20 vol% Si significantly improved, leading to higher penetration efficiency compared to pure HA MNs, while maintaining structural integrity without any critical defects. The composite MNs also showed reduced degradation rates and preserved their drug delivery capabilities and biocompatibility. Thus, the developed HA–Si composite MNs present a promising solution for efficient transdermal drug delivery and address the mechanical limitations inherent in DMN systems. Statement of significanceHA–Si composite dissolving microneedle (DMN) systems were successfully fabricated through in situ precipitation and conventional micromolding processes. The precipitated silica nanoparticles formed an interconnected network within the HA matrix, ranging in size from 25 to 230 nm. The optimal silica content for HA–Si composite MN systems should be up to 20 % by volume to maintain structural integrity and mechanical properties. HA–Si composite MNs with up to 20 % Si showed improved penetration efficiency and reduced degradation rates compared to pure HA MNs, thereby expanding the operational window. The HA–Si composite MNs retained good drug delivery capabilities and biocompatibility.

Development of Thiol-Ene Reaction-Based HA Hydrogel with Sustained Release of EGF for Enhanced Skin Wound Healing.

This study develops a novel drug delivery system using a hyaluronic acid (HA) hydrogel for controlled release of epidermal growth factor (EGF) to enhance skin wound healing. Conventional hydrogel-based methods suffer from a burst release and limited drug delivery times. To address this, we employ bioconjugation to introduce an acrylate group to EGF, enabling chemical bonding to the HA hydrogel matrix through thiol-ene cross-linking. This approach results in sustained-release delivery of EGF based on the degradation rate of the HA matrix, overcoming diffusion-based limitations. We confirm the introduction of the acrylate group using matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry. We evaluated the hydrogel morphology and rheological properties following binding of acrylate-conjugated EGF to the HA matrix. Assessment of the EGF release profile demonstrates delayed release compared to unconjugated EGF. We evaluate the impact on cells through cell proliferation and scratch assays, indicating the system's efficacy. In a rat wound healing model, the sustained release of EGF from the hydrogel system promotes appropriate tissue healing and restores it to a normal state. These findings suggest that this practical drug delivery system, involving the modification of growth factors or drugs to chemically bind healing factors to hydrogels, can achieve long-lasting effects.

Use of hyaluronic acid matrix in dorsal augmentation rhinoplasty

ABSTRACT Augmentation rhinoplasty sometimes is required for patients with saddle nose deformity caused by failed rhinoplasty or facial trauma; finding appropriate grafting material remains a significant problem for this procedure. We investigated hyaluronic acid matrix as an allograft for dorsal augmentation rhinoplasty in a rabbit model. We performed an osteotomy on the nasal bones of eight rabbits. Four animals were sham operated as the control group and four were administered a mixture of saline-gelled hyaluronic acid matrix and sliced cartilage. Ultrasonography and three-dimensional reconstruction tomography were performed at the end of the experimental period. After sacrifice of the animals, nasal tissues were examined for histopathology, and both collagen scores and number of capillaries were compared between the two groups. Increased collagen and capillaries were apparent in the hyaluronic acid matrix group compared to controls. The median collagen score was significantly greater for the hyaluronic acid matrix group than for the control group. Although the number of capillaries for the hyaluronic acid matrix group was greater than for the control group, the difference was not statistically significant. Three weeks is sufficient for adhesion of ends of fractures in clinical practice; however, we found no ossification at this time in either group. A hyaluronic acid matrix may be a useful alternative supplement for dorsal augmentation rhinoplasty. Development of collagen was commensurate with membranous ossification; however, assessment of complete ossification requires a longer experimental period.

In Situ Cross-Linkable Hyaluronic-Ferulic Acid Conjugate Containing Bucladesine Nanoparticles Promotes Neural Regeneration after Spinal Cord Injury.

Dysfunctional clinical outcomes following spinal cord injury (SCI) result from glial scar formation, leading to the inhibition of new axon growth and impaired regeneration. Nevertheless, nerve regeneration after SCI is possible, provided that the state of neuron development in the injured environment is improved. Hence, biomaterial-based therapy would be a promising strategy to endow a desirable environment for tissue repair. Herein, we designed a novel multifunctional injectable hydrogel with antioxidant, neuroprotective, and neuroregenerative effects. Bucladesine-encapsulated chitosan nanoparticles (BCS NPs) were first prepared and embedded in a matrix of thiol-functionalized hyaluronic acid modified with ferulic acid (HASH-FA). The target hydrogel (HSP-F/BCS) was then created through Michael-type addition between HASH-FA containing BCS NPs and four-arm polyethylene glycol-maleimide (4-Arm-PEG-Mal). The obtained hydrogel with shear thinning behavior showed viscoelastic and mechanical properties similar to the normal nerve tissue. FA conjugation significantly improved the antioxidant activity of HA, and suppressed intracellular ROS formation. In situ injection of the HSP-F/BCS hydrogel in a rat contusion model of SCI inhibited glial scar progression, reduced microglia/macrophage infiltration, promoted angiogenesis, and induced myelinated axon regeneration. As a result, a significant improvement in motor performance was observed compared to other experimental groups. Taken together, the HSP-F/BCS hydrogel developed in this study could be a promising system for SCI repair.

Immune-microenvironment modulatory polyurethane-hyaluronic acid hybrid hydrogel scaffolds for diabetic wound treatment

The healing of wounds in diabetic patients is a huge challenge issue in clinical medicine due to the disordered immune. Recruiting endogenous cells to play a role in the early stage and timely reducing inflammation to promote healing in the middle or late of injuring are both prerequisites for effective treatment. Here, inspired by natural extracellular matrix, three-dimensional porous polyurethane-hyaluronic acid hybrid hydrogel scaffolds (PUHA) were prepared to repair diabetic wound through activate cell immunity by moderate foreign body reaction, provide cell adhesion growth extracellular matrix of hyaluronic acid (HA) and exhibit anti-inflammatory effect of polyurethane (PU). The interaction between PU and HA alters the compact PU hydrogel into macroporous PUHA hydrogel scaffolds with super-swelling, elastic mechanical properties, and controllable degradation, which are suitable for endogenous cells infiltration, growth and immune activation. Additionally, incorporating with RGD, PUHA hydrogel scaffolds with bioactive physicochemical features can evidently reduce the inflammation and modulate the polarization of macrophage apparently both in vitro and in vivo, mainly through downregulation of cytokine-cytokine receptor interaction genes, leading to reprogramming immune-microenvironment and rapid diabetic wound healing. This method of gathering cells initially and intervening immune-microenvironment in time provides an expected way to design biomaterials for chronic wound healing.

Concentration-dependent diffusion of unlabeled protein within an in vitro hyaluronic acid matrix.

Diffusion and movement of subcutaneously injected biologics and high-concentration immunoglobulin G (IgG) therapeutics away from the injection site and through the subcutaneous (SC) tissue may be concentration dependent. This possibility was confirmed by in situ measurement of diffusion coefficients of unlabeled bovine IgG in phosphate-buffered saline within an in vitro hyaluronic acid matrix that represents the SC electrostatic environment. Diffusion decreased from 2.67 to 0.05 × 10-7 cm2 /s when IgG concentration increased from 25 to 73 mg/mL. The results demonstrated that in situ detection of unlabeled proteins within an in vitro SC environment provides another useful tool for the preclinical characterization of injectable biologics.

Cartilage regeneration and inflammation modulation in knee osteoarthritis following injection of allogeneic adipose-derived mesenchymal stromal cells: a phase II, triple-blinded, placebo controlled, randomized trial

BackgroundIntra-articular injection of mesenchymal stromal cells (MSCs) with immunomodulatory features and their paracrine secretion of regenerative factors proposed a noninvasive therapeutic modality for cartilage regeneration in knee osteoarthritis (KOA).MethodsTotal number of 40 patients with KOA enrolled in two groups. Twenty patients received intra-articular injection of 100 × 106 allogeneic adipose-derived mesenchymal stromal cells (AD-MSCs), and 20 patients as control group received placebo (normal saline). Questionnaire-based measurements, certain serum biomarkers, and some cell surface markers were evaluated for 1 year. Magnetic resonance imaging (MRI) before and 1 year after injection was performed to measure possible changes in the articular cartilage.ResultsForty patients allocated including 4 men (10%) and 36 women (90%) with average age of 56.1 ± 7.2 years in control group and 52.8 ± 7.5 years in AD-MSCs group. Four patients (two patients from AD-MSCs group and two patients from the control group) excluded during the study. Clinical outcome measures showed improvement in AD-MSCs group. Hyaluronic acid and cartilage oligomeric matrix protein levels in blood serum decreased significantly in patients who received AD-MSCs (P < 0.05). Although IL-10 level significantly increased after 1 week (P < 0.05), the serum level of inflammatory markers dramatically decreased after 3 months (P < 0.001). Expressions of CD3, CD4, and CD8 have a decreasing trend during 6-month follow-up (P < 0.05), (P < 0.001), and (P < 0.001), respectively. However, the number of CD25+ cells increased remarkably in the treatment group 3 months after intervention (P < 0.005). MRI findings showed a slight increase in the thickness of tibial and femoral articular cartilages in AD-MSCs group. The changes were significant in the medial posterior and medial anterior areas of ​​the tibia with P < 0.01 and P < 0.05, respectively.ConclusionInter-articular injection of AD-MSCs in patients with KOA is safe. Laboratory data, MRI findings, and clinical examination of patients at different time points showed notable articular cartilage regeneration and significant improvement in the treatment group.Trial registration: Iranian registry of clinical trials (IRCT, https://en.irct.ir/trial/46), IRCT20080728001031N23. Registered 24 April 2018.

A novel thermoresponsive nano carrier matrix of hyaluronic acid, methotrexate and chitosan to target the cluster of differentiation 44 receptors in tumors

Major challenges in current cancer chemotherapy include drug resistance, low efficacy and non-selectivity, resulting in undesirable side effects. In this study, we demonstrate a solution to these challenges that involves a dual targeting approach for tumors that overexpress CD44 receptors. The approach employs a nano-formulation (tHAC-MTX nano assembly), fabricated from hyaluronic acid (HA), the natural ligand for CD44, conjugated with methotrexate (MTX) and complexed with the thermoresponsive polymer 6-O-carboxymethylchitosan (6-OCMC) graft poly(N-isopropylacrylamide) [6-OCMC-g-PNIPAAm]. The thermoresponsive component was designed to have a lower critical solution temperature of 39 °C (the temperature of tumor tissues). In-vitro drug release studies reveal faster release of the drug at the higher temperatures of the tumor tissue likely due to the conformation changes in the thermoresponsive component of the nano assembly. Drug release was also enhanced in the presence of hyaluronidase enzyme. Higher cellular uptake and greater cytotoxicity of the nanoparticles were demonstrated in cancer cells that overexpress CD44 receptors suggesting a receptor binding and cellular uptake mechanism. Such nano-assemblies which incorporate multiple targeting mechanisms have the potential to improve efficacy and decrease side effects of cancer chemotherapy.