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Background: Osteoarthritis (OA) standing as the most prevalent form of arthritis, closely associates with heightened levels of reactive oxygen species, particularly hypochlorous acid (HOCl). Although there are numerous probes available for detecting HOCl in the OA region, probes with dual functions of diagnostic and therapeutic capabilities are still significantly lacking. While this type of probe can reduce the time gap between diagnosis and treatment, which is clinically needed. Methods: We developed a fluorescent probe (DHU-CBA1) toward HOCl with theranostics functions through the release of methylene blue (MB) and ibuprofen (IBP) in this work. DHU-CBA1 can detect HOCl with high specificity and sensitivity, releasing MB and IBP with an impressive efficiency of ≥ 95% in vitro. Results: DHU-CBA1 exhibits good biosafety, enabling in vivo imaging of endogenous HOCl, along with reducing arthritis scores, improving synovitis and cartilage damage, and maintaining catabolic balance while alleviating senescence in cartilage. Conclusions: This study proposes a novel approach to enhance osteoarthritis therapy by releasing IBP via a smart HOCl-enabled fluorescent probe.
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Colorantes Fluorescentes , Ácido Hipocloroso , Ibuprofeno , Azul de Metileno , Osteoartritis , Osteoartritis/tratamiento farmacológico , Colorantes Fluorescentes/química , Ibuprofeno/administración & dosificación , Animales , Azul de Metileno/química , Ratones , Humanos , Nanomedicina Teranóstica/métodos , Masculino , Imagen Óptica/métodos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Osteoarthritis (OA) is a prevalent joint disease that affects all the tissues within the joint and currently lacks disease-modifying treatments in clinical practice. Despite the potential of rapamycin for OA disease alleviation, its clinical application is hindered by the challenge of achieving therapeutic concentrations, which necessitates multiple injections per week. To address this issue, rapamycin was loaded into poly(lactic-co-glycolic acid) nanoparticles (RNPs), which are nontoxic, have a high encapsulation efficiency and exhibit sustained release properties for OA treatment. The RNPs were found to promote chondrogenic differentiation of ATDC5 cells and prevent senescence caused by oxidative stress in primary mouse articular chondrocytes. Moreover, RNPs were capable to alleviate metabolism homeostatic imbalance of primary mouse articular chondrocytes in both monolayer and 3D cultures under inflammatory or oxidative stress. In the mouse destabilization of the medial meniscus (DMM) model, intra-articular injection of RNPs effectively mitigated joint cartilage destruction, osteophyte formation, chondrocytes hypertrophy, synovial inflammation, and pain. Our study demonstrates the feasibility of using RNPs as a potential clinically translational therapy to prevent the progression of post-traumatic OA.
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Cartílago Articular , Nanopartículas , Osteoartritis , Ratones , Animales , Sirolimus/farmacología , Cartílago Articular/metabolismo , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Modelos Animales de EnfermedadRESUMEN
Osteoarthritis (OA) is associated with lubrication failure of articular cartilage and severe inflammatory response of joint capsule. Synergistic therapy combining joint lubrication and anti-inflammation emerges as a novel treatment of OA. In this study, bioinspired by ultralow friction of natural articular synovial fluid and mussel adhesion chemistry, a biomimetic nanosystem with dual functions of enhanced lubrication and stimuli-responsive drug release is developed. A dopamine mediated strategy realizes one step biomimetic grafting of hyaluronic acid (HA) on fluorinated graphene. The polymer modified sheets exhibit highly efficient near-infrared absorption, and show steady lubrication with a long time under various working conditions, in which the coefficient of friction is reduced by 75% compared to H2 O. Diclofenac sodium (DS) with a high loading capacity of 29.2% is controllably loaded, and responsive and sustained drug release is adjusted by near-infrared light. Cell experiments reveal that the lubricating nanosystem is taken up by endocytosis, and anti-inflammation results confirm that the nanosystem inhibits osteoarthritis deterioration by upregulating cartilage anabolic gene and downregulating catabolic proteases and pain-related gene. This work proposes a promising biomimetic approach to integrate polymer modified fluorinated graphene as a dual-functional nanosystem for effective synergistic therapy of OA.
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Cartílago Articular , Grafito , Osteoartritis , Humanos , Biomimética , Liberación de Fármacos , Grafito/farmacología , Osteoartritis/tratamiento farmacológico , Cartílago Articular/metabolismo , Ácido Hialurónico/farmacología , Polímeros/farmacología , FricciónRESUMEN
The occurrence of osteoarthritis (OA) is highly correlated with the reduction of joint lubrication performance, in which persistent excessive inflammation and irreversible destruction of cartilage dominate the mechanism. The inadequate response to monotherapy methods, suboptimal efficacy caused by undesirable bioavailability, short retention, and lack of stimulus-responsiveness, are few unresolved issues. Herein, we report a pH-responsive metal-organic framework (MOF), namely, MIL-101-NH2, for the co-delivery of anti-inflammatory drug curcumin (CCM) and small interfering RNA (siRNA) for hypoxia inducible factor (HIF-2α). CCM and siRNA were loaded via encapsulation and surface coordination ability of MIL-101-NH2. Our vitro tests showed that MIL-101-NH2 protected siRNA from nuclease degradation by lysosomal escape. The pH-responsive MIL-101-NH2 gradually collapsed in an acidic OA microenvironment to release the CCM payloads to down-regulate the level of pro-inflammatory cytokines, and to release the siRNA payloads to cleave the target HIF-2α mRNA for gene-silencing therapy, ultimately exhibiting the synergetic therapeutic efficacy by silencing HIF-2α genes accompanied by inhibiting the inflammation response and cartilage degeneration of OA. The hybrid material reported herein exhibited promising potential performance for OA therapy as supported by both in vitro and in vivo studies and may offer an efficacious therapeutic strategy for OA utilizing MOFs as host materials.
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Curcumina , Estructuras Metalorgánicas , Osteoartritis , Humanos , Curcumina/farmacología , Condrocitos/metabolismo , ARN Interferente Pequeño/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Inflamación/metabolismo , Concentración de Iones de HidrógenoRESUMEN
Due to the avascular characteristic of articular cartilage, its self-repair capacity is limited. When cartilage is damaged or forms osteoarthritis (OA), clinical treatment is necessary. However, conventional treatments, including joint replacement, microfracture, cell and drug therapies, have certain limits. Lately, the exosomes derived from mesenchymal stem cells (MSCs-EXO), which consist of complex transcription factors, proteins and targeting ligand components, have shown great therapeutic potentials. With recent advancements in various biomaterials to extend MSCs-EXO's retention time and control the release propertiesin vivo, biomaterials-assisted exosomes therapy has been soon becoming a practically powerful tool in treating OA. This review analyzes the effects of MSCs-EXO on OA inflammation, metabolism, ageing and apoptosis, and introduces the combinational systems of MSCs-EXO with biomaterials to enhance the repair, anti-inflammatory, and homeostasis regulation functions. Moreover, different types of natural or synthetic biomaterials and their applications with MSCs-EXO were also described and discussed. And finally, we presage the future perspective in the development of biomaterial-assisted exosome therapies, as well as the potential to incorporate with other treatments to enhance their therapeutic effects in OA.
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Materiales Biocompatibles , Exosomas , Osteoartritis/terapia , Animales , Materiales Biocompatibles/administración & dosificación , Materiales Biocompatibles/uso terapéutico , Células Cultivadas , Humanos , Inyecciones Intraarticulares , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Ratones , RatasRESUMEN
Osteoarthritis (OA) is a serious chronic and degenerative disease that increasingly occurs in the aged population. Its current clinical treatments are limited to symptom relief and cannot regenerate cartilage. Although a better understanding of OA pathophysiology has been facilitating the development of novel therapeutic regimen, delivery of therapeutics to target sites with minimal invasiveness, high retention, and minimal side effects remains a challenge. Biocompatible hydrogels have been recognized to be highly promising for controlled delivery and release of therapeutics and biologics for tissue repair. In this review, the current approaches and the challenges in OA treatment, and unique properties of injectable natural polymer hydrogels as delivery system to overcome the challenges are presented. The common methods for fabrication of injectable polysaccharide-based hydrogels and the effects of their composition and properties on the OA treatment are detailed. The strategies of the use of hydrogels for loading and release cargos are also covered. Finally, recent efforts on the development of injectable polysaccharide-based hydrogels for OA treatment are highlighted, and their current limitations are discussed.
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Hidrogeles , Osteoartritis de la Rodilla , Anciano , Cartílago , Humanos , Osteoartritis de la Rodilla/tratamiento farmacológico , Polímeros , PolisacáridosRESUMEN
The aim of this study was to evaluate the long-term efficacy and safety of single or 1-3 weekly injections of hylan G-F 20 at 1 year following the first injection for knee osteoarthritis (OA). Searches were conducted in PubMed/MEDLINE, Embase, and CENTRAL and included relevant conference proceedings (January 1, 1995-August 17, 2020). Randomized controlled trials (RCTs), non-randomized trials, and observational studies investigating 1-year efficacy and safety of 1-3 weekly injections or single hylan G-F 20 injection for knee OA were included. Primary outcomes were WOMAC pain, physical function, and stiffness. Meta-analyses of RCTs and non-randomized studies were conducted separately. Our search identified 24 eligible studies. Hylan G-F 20, in the meta-analyses of RCTs, showed statistically significant improvement in WOMAC pain (SMCC - 0.98, 95% CI - 1.50, - 0.46), physical function (SMCC - 1.05, 95% CI - 1.28, - 0.83), and stiffness (SMCC - 1.07, 95% CI -1.28, -0.86). Improvement was also seen for VAS pain, SF-36 MCS (mental component summary), and SF-36 PCS (physical component summary). Analyses of non-randomized studies showed similar efficacy estimates. There were no significant differences in efficacy based on injection schedule, nor between RCT and non-randomized studies. Rates of adverse events (AEs) were low for most types of AEs. Hylan G-F 20 (either as single or 1-3 weekly injections) showed improvement in 1-year efficacy outcomes in comparison to baseline and was generally well tolerated. While further research will inform the medical field regarding viscosupplementation treatment options for knee OA, these findings show that hylan G-F 20 at both frequencies/dosages are efficacious and generally well tolerated for long-term use.
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Osteoartritis de la Rodilla , Humanos , Ácido Hialurónico/efectos adversos , Ácido Hialurónico/análogos & derivados , Inyecciones Intraarticulares , Osteoartritis de la Rodilla/tratamiento farmacológico , Dolor , Resultado del TratamientoRESUMEN
BACKGROUND: Osteoarthritis is the most common form of arthritis, principally affecting the older population. Highly prevalent, disabling diseases such as osteoarthritis strain the capacity of health systems, and can result in unmet need for services. The Joint Clinic was initiated to provide secondary care consultations and access to outpatient services for people with advanced hip or knee osteoarthritis, who were referred by their general practitioner for orthopaedic consultation but not offered an orthopaedic specialist appointment. METHODS: This longitudinal programme evaluation comprised four components: a proof-of-concept evaluation; an implementation evaluation; a process evaluation; and an outcomes evaluation. Interviews and surveys of general practitioners, staff, and patients were conducted pre- and post-implementation. Interviews were transcribed, and thematic analysis was completed. In addition, Joint Clinic patient visits and outcomes were reviewed. RESULTS: One hundred and eleven primary care physicians (GPs) and 66 patients were surveyed, and 28 semi-structured interviews of hospital staff and GPs were conducted. Proof of concept was satisfied. Interim and final implementation evaluations indicated adherence to the concept model, high levels of acceptance of and confidence in the programme and its staff, and timely completion within budget. Process evaluation revealed positive impacts of the programme and positive stakeholder perceptions, with some weaknesses in communication to the outer context of primary care. The Joint Clinic saw a total of 637 patient visits during 2 years of operation. Unmet need was reduced by 90%. Patient and referring physician satisfaction was high. Hospital management confirmed that the programme will continue. CONCLUSIONS: This evaluation indicates that the Joint Clinic concept model is fit for purpose, functioned well within the organisation, and achieved its primary objective of reducing unmet need of secondary care consultation for those suffering advanced hip or knee osteoarthritis.
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Instituciones de Atención Ambulatoria/organización & administración , Atención Ambulatoria/organización & administración , Osteoartritis de la Cadera/diagnóstico , Osteoartritis de la Rodilla/diagnóstico , Derivación y Consulta/organización & administración , Anciano , Anciano de 80 o más Años , Atención Ambulatoria/estadística & datos numéricos , Instituciones de Atención Ambulatoria/estadística & datos numéricos , Femenino , Necesidades y Demandas de Servicios de Salud , Humanos , Estudios Longitudinales , Masculino , Osteoartritis de la Cadera/terapia , Osteoartritis de la Rodilla/terapia , Aceptación de la Atención de Salud/estadística & datos numéricos , Evaluación de Programas y Proyectos de Salud , Calidad de VidaRESUMEN
OBJECTIVE: To evaluate the effect of intra-articular injections of sodium bicarbonate with a single (SBCG1) or double dose (SBCG2) of calcium gluconate administered monthly compared with methylprednisolone (MP) for treatment of knee osteoarthritis. METHODS: A 3-month, randomized, double-blind clinical trial with patients diagnosed with knee osteoarthritis (OA). The outcome variables were the Western Ontario-McMaster University Osteoarthritis Index (WOMAC) and the Lequesne functional index. RESULTS: After 3 months, all treatments significantly improved in overall WOMAC and Lequesne scores. Mean changes (95% confidence interval) in WOMAC total score and the Lequesne index, respectively, for SBCG1 (-12.5 [-14.3, -10.7]; -9.0 [-11.4, -6.7]) and SBCG2 (-12.3 [-14.3, -10.4]; -8.9 [-10.4, -7.4]) were significantly greater than for MP (-5.0 [-7.2, -2.8]; -3.2 [-4.9, -1.5]) (P < .001). CONCLUSIONS: Intra-articular injections of sodium bicarbonate and calcium gluconate are useful for short-term relief of OA symptoms in patients with bilateral knee osteoarthritis. Both treatments are more effective than MP injections in the reduction of knee OA symptoms. TRIAL REGISTRATION: Clinicaltrials.gov NCT00977444.
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The lubricating proteoglycan, lubricin, facilitates the remarkable low friction and wear properties of articular cartilage in the synovial joints of the body. Lubricin lines the joint surfaces and plays a protective role as a boundary lubricant in sliding contact; decreased expression of lubricin is associated with cartilage degradation and the pathogenesis of osteoarthritis. An unmet need for early osteoarthritis treatment is the development of therapeutic molecules that mimic lubricin function and yet are also resistant to enzymatic degradation common in the damaged joint. Here, we engineered a lubricin mimic (mLub) that is less susceptible to enzymatic degradation and binds to the articular surface to reduce friction. mLub was synthesized using a chondroitin sulfate backbone with type II collagen and hyaluronic acid (HA) binding peptides to promote interaction with the articular surface and synovial fluid constituents. In vitro and in vivo characterization confirmed the binding ability of mLub to isolated type II collagen and HA, and to the cartilage surface. Following trypsin treatment to the cartilage surface, application of mLub, in combination with purified or commercially available hyaluronan, reduced the coefficient of friction, and adhesion, to control levels as assessed over macro-to micro-scales by rheometry and atomic force microscopy. In vivo studies demonstrate an mLub residency time of less than 1 week. Enhanced lubrication by mLub reduces surface friction and adhesion, which may suppress the progression of degradation and cartilage loss in the joint. mLub therefore shows potential for treatment in early osteoarthritis following injury.