Intra-articular Administration Research Articles

Effect of repeated intra-articular administration of collagen as a treatment for knee osteoarthritis: a case report.

Intra-articular injections aimed at correcting underlying pathophysiological processes and providing pain relief are essential for managing knee osteoarthritis (KOA). Collagen, the primary component of articular cartilage, has a long half-life, making it a promising candidate for intra-articular injections with a low risk of serious side effects. The first of the two cases in this report involved a woman in her early 70s with a 6-year history of persistent left knee pain. The second case involved a woman in her mid-50 s with a >7-year history of right knee pain. Both patients received hyaluronic acid injections every 6 months, totaling 10 injections over 5 years. They were diagnosed with Kellgren-Lawrence grade 2 KOA. The patients received two 3-mL intra-articular injections of 6% collagen, administered at baseline and 6 months later. Improvements in clinical outcomes, including visual analog scale scores and Western Ontario and McMaster Universities Osteoarthritis Index scores, were observed and maintained in both patients, with no side effects reported. In summary, when collagen injections were administered to these two patients with KOA, clinical improvements lasted approximately 6 months, and repeated treatments demonstrated efficacy and safety similar to the initial course.

Modulation of IFN-γ induced macrophage inflammatory responses via indomethacin-loaded NLCs for OA management

Macrophages are the main cells present in the synovial membrane. They play an important role in the development and progression of osteoarthritis (OA). After the establishment of the disease macrophages mostly adopt a pro-inflammatory secretory phenotype (OA phenotype) further inducing cartilage degradation. Indomethacin (IND) is a non-steroidal anti-inflammatory drug (NSAID) able to inhibit the synthesis of prostaglandins mediated by both cyclooxygenase isoforms depicting a potent anti-inflammatory capacity. However, the lack of specificity and short half-like of free drugs within the joint cavity limits its utility in controlling inflammation after intra-articular administration. This study aims at developing IND loaded glycosylated nanostructured lipid carriers (NLCs) to selectively target macrophages and promote their reprogramming to an anti-inflammatory phenotype. This approach focused on the local administration of the NLCs, offers a promising therapeutic strategy for treating OA by modulating the inflammatory environment within the joint. NLCs will be designed by combining experimental and in silico docking analyses, and thoroughly characterized to obtain drug delivery systems with high stability and suitable physicochemical properties. The proposed mannose-functionalized systems exhibited adequate particle sizes (≈ 70 nm) and positive surface charges (> 20 mV) to be efficiently retained in the joint cavity. Moreover, the developed NLCs demonstrated effective and specific uptake by OA-like macrophages leading to a significant decrease in the secretion of the pro-inflammatory cytokines IL-6, IL-8 and TNF-α similarly to the free drug. Therefore, these systems effectively reprogrammed OA-associated macrophages to adopt a more regenerative phenotype, offering a promising strategy for managing inflammation in OA.

Juvenile idiopathic arthritis management: insights into the utilization of intra-articular corticosteroid injections

ABSTRACT Background Juvenile idiopathic arthritis (JIA) is a common chronic rheumatic disease in children, requiring careful management to reduce both short- and long-term morbidity. In this study, our objective was to assess the clinical features of patients diagnosed with JIA who received intra-articular corticosteroid injections (IACI). Methods In this retrospective study, we evaluated the clinical and laboratory characteristics of 225 JIA patients monitored from January 2012 to October 2023 at a tertiary care center. We focused on patients who underwent intra-articular corticosteroid injections (IACI) as part of their treatment. Triamcinolone hexacetonide (TH) was used due to its demonstrated safety and efficacy. Results Our analysis revealed that IACI, particularly utilizing TH, was a widely employed and effective adjunct therapy, contributing to rapid symptom relief and local disease control. Patients receiving IACI exhibited earlier symptom onset, younger age at diagnosis, longer follow-up durations, and higher cumulative treatment burden (p < 0.001, p < 0.001, p < 0.01, p < 0.001 respectively). Despite inconclusive acute-phase reactants, a higher frequency of ANA positivity and elevated initial lymphocyte counts were associated with increased IACI use (p < 0.001, p < 0.001 respectively). Importantly, on a joint basis, a high percentage of arthritis remission following IACI underscores its efficacy and favorable safety profile. Conclusions Notably, the high percentage of arthritis remission achieved with intra-articular corticosteroid injections (IACI) on a joint-specific basis highlights its efficacy and favorable safety profile. A lymphocyte count exceeding 5000/mm3 at the time of diagnosis may serve as an early indicator for considering intra-articular steroid administration. These findings emphasize the need for nuanced and individualized treatment strategies in JIA management to optimize outcomes for affected children.

Immunotherapeutic potential of collagen V oral administration in mBSA/CFA-induced arthritis.

We hypothesized that after synovial injury, collagen V (Col V) expose occult antigens, and Col V autoantibodies develop, indicating the loss of immune tolerance against this molecule, thus leading to damage to mesenchymal-derived cells as well as the extracellular matrix in experimental arthritis. Thus, the present study investigated the effects of oral administration of Col V on the synovium after the development of inflammation in mBSA/CFA-induced arthritis. After fourteen days of intraarticular administration of mBSA, 10 male Lewis rats were orally administered Col V (500 μg/300 μL) diluted in 0.01 N acetic acid (IA-Col V group). The arthritic group (IA group, n = 10) received only intraarticular mBSA. An intra-articular saline injection (20 μL) was given to the control group (CT-Col V, n = 5). IA group presented damaged synovia, the expansion of the extracellular matrix by cellular infiltrate, which was characterized by T and B lymphocytes, and fibroblastic infiltration. In contrast, after Col V oral immunotherapy IA-Col V group showed a significant reduction in synovial inflammation and intense expression of IL-10+ and FoxP3+ cells, in addition to a reduction in Col V and an increase in Col I in the synovia compared to those in the IA group. Furthermore, an increase in IL-10 production was detected after IA-Col V group spleen cell stimulation with Col V in vitro. PET imaging did not differ between the groups. The evaluation of oral treatment with Col V, after mBSA/CFA-induced arthritis in rats, protects against inflammation and reduces synovial tissue damage, through modulation of the synovial matrix, showing an immunotherapeutic potential in inhibiting synovitis.

Enzyme-responsive microgel with controlled drug release, lubrication and adhesion capability for osteoarthritis attenuation

The treatment of osteoarthritis (OA) remains challenging due to the narrow therapeutic window and rapid clearance of therapeutic agents, even with intra-articular administration, resulting in a low treatment index. Recent advancements in local drug delivery systems have yet to overcome the issues of uncontrolled burst release and short retention time, leading to suboptimal OA treatment outcome. Herein, we developed a methacrylate-crosslinking hyaluronic acid (HA) microgel (abbreviated as CXB-HA-CBP) that covalently conjugates the anti-inflammatory drug celecoxib (CXB) via a metalloproteinase-2 (MMP-2)-responsive peptide linker (GGPLGLAGGC) and a collagen II binding peptide (WYRGRLC). The GGPLGLAGGC linker is specifically cleaved by the overexpressed MMP-2 enzyme within the OA joint, enabling the sustained and on-demand release of CXB entity. The synergistic action of CXB and HA effectively inhibited macrophage activation and reduced the production of pro-inflammatory cytokines, protecting chondrocytes from damage. Furthermore, the collagen II peptide introduced on the microgel surface enabled a cartilage-binding function to form an artificial lubrication microgel layer on the cartilage surface to reduce cartilage wear. The CXB-HA-CBP microgel showed an extended retention time of up to 18 days in the affected joint, leading to an effective OA treatment in rats. This sophistically designed microgel, characterized by the prolonged retention time, sustained drug delivery, and enhanced lubrication, presents a promising biomedicine for OA treatment. Statement of SignificanceA new methacrylate-crosslinking hyaluronic acid (HA) microgel, covalently conjugated with the celecoxib (CXB)-GGPLGLAGGC and the collagen II binding peptide (CBP, peptide sequence: WYRGRLC), was developed. The overexpressed MMP-2 in OA joint cleaved the GGPLGLAGGC linker to trigger the CXB moiety release. Besides, the CBP on the surface of microgels enabled a cartilage-attaching ability, resulting in a prolonged retention time and an improved lubrication property in joint. This advanced drug-loading microgel remarkably reduced macrophage activation and pro-inflammation cytokine production, while protecting the chondrocytes via a dual action of CXB and HA. This study demonstrated that the enzyme-responsive drug-loading microgel could serve as an platform to efficiently attenuate osteoarthritis.

Exploring Intra-Articular Administration of Monoclonal Antibodies as a Novel Approach to Osteoarthritis Treatment: A Systematic Review.

Biological drugs, including monoclonal antibodies, represent a revolutionary strategy in all fields of medicine, offering promising results even in the treatment of osteoarthritis (OA). However, their safety and efficacy have not been fully validated, highlighting the need for in-depth studies. Therefore, we provided a comprehensive systematic review of the intra-articular use of monoclonal antibodies for the treatment of OA in animal models, reflecting ongoing efforts to advance therapeutic strategies and improve patient outcomes. A systematic literature search was conducted in December 2023 following the PRISMA guidelines, using the Web of Science, Google Scholar, and PUBMED databases. Out of a total of 456, 10 articles were included in the study analyzing intra-articular antibodies and focusing on various targets, including vascular endothelial growth factor (VEGF), nerve growth factor (NGF), interleukin 4-10 (IL4-10), tumor necrosis factor α (TNF-α), a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5), and matrix metalloproteinase 13 (MMP-13). Most studies administered the antibodies weekly, ranging from 1 to 10 injections. Animal models varied, with mean follow-up periods of 8.9 ± 4.1 weeks. The methods of assessing outcomes, including pain and morpho-functional changes, varied. Some studies reported only morphological and immunohistochemical data, while others included a quantitative analysis of protein expression. In conclusion, monoclonal antibodies represent a promising avenue in the treatment of OA, offering targeted approaches to modulate disease pathways. Further research and clinical trials are needed to validate their safety and efficacy, with the potential to revolutionize the management of OA and reduce reliance on prosthetic interventions.

Intra-articular injection of platinum nanozyme-loaded silk fibroin/pullulan hydrogels relieves osteoarthritis through ROS scavenging and ferroptosis suppression

Reactive oxygen species (ROS)-mediated ferroptosis plays a critical role in the development of osteoarthritis (OA). Consequently, it is speculated that anti-ferroptosis agents could represent a novel therapeutic strategy for managing OA. In this study, a hydrogel incorporating platinum (Pt) nanozyme was synthesized by dispersing Pt nanoparticles (NPs) within a matrix of silk fibroin (SF) and oxidized pullulan (oxPL). This hydrogel allows for a substantial and sustained release of up to 30 days. The gelation time (from 140.3 ± 42.3 s to 460.0 ± 40.0 s), swelling capacity (from 57.7 ± 3.8 % to 24.0 ± 7.0 %), and degradation rate (from 60.3 ± 4.7 % to 32.0 ± 4.6 %) of the hydrogels can be modulated by adjusting the Pt NP content. The Pt@SF/oxPL hydrogel effectively eliminates ROS due to its catalase-like and superoxide dismutase-like enzymatic properties. In vitro studies demonstrated that Pt@SF/oxPL efficiently mitigated the process of ferroptotic cell death in chondrocytes. More critically, intra-articular administration of Pt@SF/oxPL showcased therapeutic advantages by both protecting and stimulating the regeneration of cartilage throughout the progression of OA. Collectively, this study suggests that Pt@SF/oxPL hydrogels could potentially serve as an effective treatment for OA, presenting a novel nanozyme-based therapeutic approach for this condition.

Leukocyte-Poor Platelet-Rich Plasma for the Management of Knee Osteoarthritis: A Retrospective Study With 12 Months of Follow-Up.

Introduction The knee, the most frequently affected joint in osteoarthritis (OA), impacts the life quality of millions of individuals globally, resulting in a considerable healthcare burden. Conservative treatments are preferred, turning to surgical intervention when necessary. Nonetheless, these conventional modalities have drawbacks. Recently, the use of regenerative medicine therapies, including autologous peripheral blood-derived orthobiologics (APBOs), such as leukocyte-poor platelet-rich plasma (LP-PRP), has evolved and demonstrated the ability to manage knee OA. The primary objective of this investigation was to evaluate the efficacy of LP-PRP via widely used patient-reported outcome measures (PROMs) in grade I or II (on the Kellgren-Lawrence scale) knee OA patients. The secondary objective was to characterize the formulated LP-PRP and determine the efficiency of the leukodepletion filter used for leukocyte removal and platelet recovery. Methods This investigation was a retrospective analysis of data collected from patients treated at a single center over a period of 15 months.Data from 40 patients included in this study were intra-articularly injected with 3mL of formulated LP-PRPunder ultrasound guidance. PROMs questionnaires, including Kujala and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, were used and responses were documented at baseline and up to 12 months follow-up. The characterization of the formulated LP-PRP and the efficiency of the leukodepletion filter in removing leukocytes and recovering platelets were assessed via complete blood count (CBC) analysis. Results The intra-articular administration of LP-PRP resulted in statistically significant improvements in Kujala and WOMAC scores in patients with Grade I or II OA of the knee at all follow-up time points (four to 12 months) compared to the respective baseline scores. The subgroup analysis showed significant improvements in Kujala and WOMAC scores inboth male and female grade I or II knee OA patients with or without comorbidities, including diabetes and/or hypertension. The characterization of formulated PRP showedplatelet concentration to be at least 6x compared to the baseline whole blood levels, the absolute platelet count to be at least 5 billion, and total leukocytes, lymphocytes, neutrophils, and RBCs were depleted by over 88%, 82%, 98%, and 98%, respectively. In addition, the utilization of the PuriBlood leukocyte reduction filter (Puriblood Medical Co. Ltd., Baoshan Township, Taiwan) led to the depletion of approximately 93% of leukocytes and the recovery of about 83% of platelets. Conclusions Administration of LP-PRP resulted in significant improvements in pain and function of patients suffering from grade I or II OA of the knee. In addition, the leukodepletion filter used to formulate LP-PRP, successfully resulted in the depletion of leukocytes while recovering the platelets. More sufficiently powered, multi-center, prospective, non-randomized, and randomized controlled trials with long-term follow-up are needed to further establish the effectiveness of this formulation in knee OA patients.

PSI-18 Intra-articular triamcinolone acetonide administration does not affect microbial culture or synovial fluid volume in young, exercising Quarter Horses

Abstract Intra-articular corticosteroids (IAC) are administered to horses experiencing joint inflammation, at times with a concurrent articular antibiotic for prophylaxis. However, information regarding the biologic effects of IAC and potential for microbial contamination in IAC-administered joints is limited in young, exercising horses. The objective of this study was to evaluate the impact of IAC on traditional microbial culture, synovial fluid (SF) volume, and the presence of IAC; hypothesizing negative microbial culture, no change of SF volume, and detection of IAC in SF post-administration. To test this, 2-yr-old Quarter Horses {n = 24; body weight (BW) = 409 ± 6 kg; 825 ± 21 d of age; 12 fillies, 12 geldings) were stratified by BW, age, and sex, and randomly assigned to 1 of 3 treatment groups for a 56-d trial. Horses were housed individually in stalls with runs and fed concentrate offered at 0.75% BW/d split evenly every 12 h with ad libitum Coastal bermudagrass hay and water. Every 21 d, BW and body condition score (BCS) were recorded, and concentrate was adjusted accordingly. Horses were exercised 5 d/wk, up to 45 min/d in a progressive workload using a free-stall exerciser. Blood was collected post-exercise during wk 1, 4, and 7 via jugular venipuncture and lactate (BL) was measured to monitor increasing workload. Intra-articular treatments consisted of 0 mg (CON; n = 8), 6 mg (CORT6; n = 8), or 12 mg (CORT12; n = 8) of triamcinolone acetonide (TA). On d 0, treatments were administered in one randomly selected radiocarpal joint per horse. Following aseptic preparation, SF from both radiocarpal joints was collected before administration (pre), and on d 7, 14, 28, and 56. Volume of SF was recorded, and standard microbial culture and detection of TA were performed by a commercial laboratory. Data were analyzed using PROC MIXED (BW, BCS, BL, SF volume) and PROC GLM (TA) of SAS. For SF volume, data from the contralateral radiocarpal joint were used as a covariate. Horses increased BW and BCS over time (P ≤ 0.01) across treatments. Post-exercise BL increased from wk 1 to 4 and remained increased through wk 7 (P &amp;lt; 0.01). Microbial culture for all horses and time points were negative. Concentration of TA was not evaluated on d 7 due to limited SF volume, but TA was detected on d 14 and concentration did not differ between CORT6 and CORT12 (P = 0.13). Recorded SF volume did not change from d 0 (pre) to 7 but increased to d 56, regardless of treatment (P &amp;lt; 0.01). These results indicate that, based on standard culture, TA administration did not result in positive microbial culture, or decrease SF volume in young horses undergoing regular exercise, however, TA was detectable to d 14.

Engineering exosomes derived from TNF-α preconditioned IPFP-MSCs enhance both yield and therapeutic efficacy for osteoarthritis

BackgroundThe pathogenesis of osteoarthritis (OA) involves the progressive degradation of articular cartilage. Exosomes derived from mesenchymal stem cells (MSC-EXOs) have been shown to mitigate joint pathological injury by attenuating cartilage destruction. Optimization the yield and therapeutic efficacy of exosomes derived from MSCs is crucial for promoting their clinical translation. The preconditioning of MSCs enhances the therapeutic potential of engineered exosomes, offering promising prospects for application by enabling controlled and quantifiable external stimulation. This study aims to address these issues by employing pro-inflammatory preconditioning of MSCs to enhance exosome production and augment their therapeutic efficacy for OA.MethodsThe exosomes were isolated from the supernatant of infrapatellar fat pad (IPFP)-MSCs preconditioned with a pro-inflammatory factor, TNF-α, and their production was subsequently quantified. The exosome secretion-related pathways in IPFP-MSCs were evaluated through high-throughput transcriptome sequencing analysis, q-PCR and western blot analysis before and after TNF-α preconditioning. Furthermore, exosomes derived from TNF-α preconditioned IPFP-MSCs (IPFP-MSC-EXOsTNF−α) were administered intra-articularly in an OA mouse model, and subsequent evaluations were conducted to assess joint pathology and gait alterations. The expression of proteins involved in the maintenance of cartilage homeostasis within the exosomes was determined through proteomic analysis.ResultsThe preconditioning with TNF-α significantly enhanced the exosome secretion of IPFP-MSCs compared to unpreconditioned MSCs. The potential mechanism involved the activation of the PI3K/AKT signaling pathway in IPFP-MSCs by TNF-α precondition, leading to an up-regulation of autophagy-related protein 16 like 1(ATG16L1) levels, which subsequently facilitated exosome secretion. The intra-articular administration of IPFP-MSC-EXOsTNF−α demonstrated superior efficacy in ameliorating pathological changes in the joints of OA mice. The preconditioning of TNF-α enhanced the up-regulation of low-density lipoprotein receptor-related protein 1 (LRP1) levels in IPFP-MSC-EXOsTNF−α, thereby exerting chondroprotective effects.ConclusionTNF-α preconditioning constitutes an effective and promising method for optimizing the therapeutic effects of IPFP-MSCs derived exosomes in the treatment of OA.Graphical

The role of collagen in joint disorders: Applications in orthopedics, rheumatology, and sports medicine

Joint diseases are prevalent in orthopedic, rheumatological, and sports medicine fields, significantly impacting patients' quality of life. Collagen, a primary component of connective tissues, has emerged as a therapeutic agent for these conditions. This article explores the applications of collagen in joint diseases, comparing oral and intra-articular administration, evaluating optimal dosages, assessing single versus long-term therapies, discussing side effects, and examining the benefits of hydrolyzed versus non-hydrolyzed collagen. Additionally, explore various sources of collagen and their respective advantages for patient care.

Actualización en el manejo de gonartrosis: Revisión bibliográfica

Gonarthrosis is a chronic-degenerative disease that involves the entire joint and its components, mainly affecting the articular cartilage, producing its degeneration and bone hyperplasia. About 50-60% of older adults experience symptoms of OA. The objective of this research is to discover new therapeutic options for gonarthrosis, in addition to expanding knowledge about intra-articular infiltration by describing the substances available for this therapy. An electronic search of scientific articles published from January 2018 to April 2024 was carried out in the PubMed, Scopus, Web of Science and ScieLO databases. Currently there are several options for the treatment of OA, from physiotherapy, pharmacotherapy to surgery. Intra-articular drug administration is a new therapeutic approved by the FDA, among its advantages are local bioavailability, reduced systemic drug exposure, fewer adverse events and reduced costs. Some of the substances used are glucocorticoids, hyaluronic acid, ozone and platelet-rich plasma, which reduce pain and inflammation, increasing the patient's quality of life. It is concluded that botulinum toxin decreases central and peripheral sensitivity, reducing pain in the short term. The use of hyaluronic acid as a vehicle for the application of gold microparticles has decreased symptoms in the short and long term, however, further studies are required to evaluate its effectiveness on the control of other symptoms.

The Disease-Modifying Effects of a Single Intra-Articular Corticosteroid Injection during the Freezing Phase of Frozen Shoulder in an Animal Model.

Although frequently prescribed for frozen shoulder, it is not known if corticosteroid injections improve the course of frozen shoulder. This study aimed to assess the disease-modifying effects of an intra-articular corticosteroid administration at the freezing phase of frozen shoulder. Twenty-four Sprague-Dawley rats were divided into four groups. Their unilateral shoulders were immobilized for the first 3 days in all groups, followed by an intra-articular corticosteroid injection in Group A, an injection and the cessation of immobilization in Group B, no further intervention in Group C, and the cessation of immobilization in Group D. All rats were sacrificed in Week 3 of study, at which point the passive shoulder abduction angles were measured and the axillary recess tissues were retrieved for histological and Western blot analyses. The passive shoulder abduction angles at the time of sacrifice were 138° ± 8° (Group A), 146° ± 5° (Group B), 95° ± 11° (Group C), 132° ± 8° (Group D), and 158° ± 2° (Control). The histological assessments and Western blots showed greater fibrosis and inflammation in the groups that did not receive the corticosteroid injection (Groups C and D) compared to the corticosteroid-injected groups (Groups A and B). These findings demonstrate the anti-inflammatory and disease-modifying effects of corticosteroid injections during the freezing phase of frozen shoulder in an animal model.

Postnatal deletion of Phlpp1 in chondrocytes delays post-traumatic osteoarthritis in male mice

ObjectiveOsteoarthritis is a chronic, debilitating disease that causes long-term pain and immobility. Germline deletion of Phlpp1 or administration of small molecules that inhibit Phlpp1 prevents post-traumatic osteoarthritis (PTOA) in mice. However, the chondrocyte-intrinsic role of Phlpp1 in PTOA progression is unknown. The objective of this study was to determine how postnatal, chondrocyte-directed deletion of Phlpp1 affects PTOA progression in the presence or absence of Phlpp inhibitors. DesignPhlpp1fl/fl; Agc-CreERT2 and Agc-CreERT2 mice were injected with tamoxifen at 12 weeks of age to generate Phlpp1-CKOAgcERT and control (AgcERT) groups. Male mice underwent surgery to destabilize the medial meniscus (DMM) at 17 weeks of age. A separate cohort of male Phlpp1-CKOAgcERT mice were administered an intra-articular injection of NSC117079, a Phlpp1/2 inhibitor, or saline seven weeks after DMM surgery. Activity and mechanical allodynia were monitored throughout the experiment and cartilage damage was evaluated 12 weeks post-surgery. ResultsPhlpp1-CKOAgcERT mice had less cartilage damage than AgcERT littermates 12 weeks after DMM surgery but exhibited no differences in activity. Prg4 expression was also higher in articular chondrocytes of Phlpp1-CKOAgcERT mice. Intra-articular administration of NSC117079 to Phlpp1-CKOAgcERT mice improved cartilage structure, subchondral bone sclerosis, and mechanical allodynia at 12 weeks post-DMM. ConclusionsPostnatal deletion of Phlpp1 in chondrocytes attenuates DMM-induced cartilage damage and subchondral bone sclerosis but does not prevent pain-related behaviors. Intra-articular injection of Phlpp inhibitors delays mechanical allodynia in Phlpp1-CKOAgcERT mice. These data indicate that Phlpp1 in chondrocytes affects articular cartilage structure after injury, but pain-related behaviors are controlled by Phlpp1 or Phlpp2 in other cell types.

Baicalin Ameliorates Cartilage Injury in Rats With Osteoarthritis via Modulating miR-766-3p/AIFM1 Axis

The study aims to elucidate the therapeutic mechanism of Baicalin (BAI) in alleviating cartilage injury in osteoarthritic (OA) rat models, concentrating on its regulation of the miR-766-3p/AIFM1 axis. An OA rat model was developed with unilateral anterior cruciate ligament transection (ACLT). Interventions comprised of BAI treatment and intra-articular administration of miR-766-3p inhibitor. For evaluation, histopathological staining was conducted to investigate the pathological severity of knee cartilage injury. The levels of oxidative stress (OS) indicators including MDA, SOD, and GSH-Px, were quantified using colorimetric assays. Inflammatory factors (IFs; TNF-α, IL-1β, and IL-6) in knee joint lavage fluids were assessed using ELISA, while RT-PCR was employed to quantify miR-766-3p expression. TUNEL apoptosis staining was utilized to detect chondrocyte apoptosis, and western blotting examined autophagy-related markers (LC3, Beclin, p62), extracellular matrix (ECM) synthesis-associated indices (COL2A, ACAN, MMP13), and apoptosis-inducing factor mitochondrion-associated 1 (AIFM1). Histological examination revealed a marked amelioration of cartilage injury in the BAI-treated OA rat models compared to controls. BAI treatment significantly reduced inflammation and OS of knee joint fluid, activated autophagy, and decreased chondrocyte apoptosis and ECM degradation. Interestingly, the inhibitory effects of BAI on these pathological markers were significantly decreased by the miR-766-3p inhibitor. Further assessment revealed that BAI efficiently promoted miR-766-3p expression while inhibiting AIFM1 protein expression. BAI potentially mitigates articular cartilage injury in OA rats, likely through modulation of miR-766-3p/AIFM1 axis.

Identification of formulation parameters that affect the analgesic efficacy of ProGel-Dex – A thermoresponsive polymeric dexamethasone prodrug for chronic arthritis pain relief

The relief of joint pain is one of the main objectives in the clinical management of arthritis. Although significant strides have been made in improving management of rheumatoid and related forms of inflammatory arthritis, there are still major unmet needs for therapies that selectively provide potent, sustained and safe joint pain relief, especially among patients with osteoarthritis (OA), the most common form of arthritis. We have recently developed ProGel-Dex, an N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based thermoresponsive dexamethasone (Dex) prodrug, which forms a hydrogel upon intra-articular administration and provides sustained improvement in pain-related behavior and inflammation in rodent models of arthritis. The focus of the present study was to investigate the impact of ProGel-Dex formulation parameters on its physicochemical properties and in vivo efficacy. The results of this study provide essential knowledge for the future design of ProGel-Dex that can provide more effective, sustained and safe relief of joint pain and inflammation.

Sinapic acid-pullulan based inflammation responsive nanomicelles for the local treatment of experimental inflammatory arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disorder of joints. It is one of the major causes of disability and morbidity worldwide. Administration of conventional drugs through the systemic route restricts the bioavailability of drugs, systemic toxicity, and reduced efficacy. We have introduced Rebamipide (Reb)-loaded Sinapic acid (SA)-Pullulan (PL) nanomicelles (Reb@SA-PL NMs), a nanotechnology based drug delivery system for the treatment of inflammatory arthritis. PL is a polysaccharide obtained from the fungus Aureobasidium pullulans, and SA is a bioactive polyphenol found in various plants. Both are classified by US-FDA Generally Recognised as Safe (GRAS) materials. Reb@SA-PL NMs found to be cytocompatible. Subsequently, intra-articular administration of Reb@SA-PL NMs enhances the anti-arthritic potential compared to free Reb drug in collagen-induced experimental inflammatory arthritis rat model. Reb@SA-PL NMs reduced the expression of RANKL receptor and Nf-κB. Reb@SA-PL NMs reverses the breakdown of type II collagen, MMP-13, and inhibits the pro-inflammatory markers. Reb@SA-PL NMs prevented bone erosion, cartilage degradation, joint oedema, and synovial inflammation. The results of the study demonstrated that Reb@SA-PL NMs, an enzyme-responsive drug delivery system, has excellent potential for alleviating inflammatory arthritis by blocking MMP-13 and RANKL.

Platelet lysate does not have an anti-inflammatory effect on monoiodoacetic acid-induced equine persistent synovitis.

To clarify the anti-inflammatory effect of platelet lysate (PL) on equine persistent synovitis by using a model of synovitis induced by monoiodoacetic acid (MIA). Nonseptic synovitis was induced by administering MIA into both antebrachiocarpal joints of 6 clinically healthy horses on day 0. On days 23, 30, and 37, carpal circumference measurement and synovial fluid collection for assays (leucocytes, LDH, tumor necrosis factor-α, and TGF-β1) were performed, after which PL was injected into 1 antebrachiocarpal joint and saline into the contralateral joint. Synovium and synovial fluid were obtained on day 44 for histological analysis and quantification of inflammation-related genes (matrix metalloproteinase-13, a disintegrin and metalloproteinase with thrombospondin motifs 4, receptor activator of nuclear factor κ-Β ligand, and collagen type I α2 chain) and the abovementioned proteins. The LDH level on day 44 was significantly lower in the PL-injected joint than in the saline-treated one. However, no significant differences were found in the other indices quantified, including osteoclast counts on the synovium. Multiple IA administration of PL does not exert anti-inflammatory effects on the equine persistent synovitis induced by MIA. Intra-articular PL administration did not alter many inflammatory biomarkers, suggesting that PL does not have a direct anti-inflammatory effect. However, the reduction in synovial LDH levels suggests that PL promoted joint tissue repair and may consequently alleviate inflammation at the site of administration.

Study on ultrasound-enhanced molecular transport in articular cartilage.

Local intra-articular administration with minimal side effects and rapid efficacy is a promising strategy for treating osteoarthritis(OA). Most drugs are rapidly cleared from the joint space by capillaries and lymphatic vessels before free diffusion into cartilage. Ultrasound, as a non-invasive therapy, enhances molecular transport within cartilage through the mechanisms of microbubble cavitation and thermal effects. This study investigated the mass transfer behavior of solute molecules with different molecular weights (479 Da, 40 kDa, 150 kDa) within porcine articular cartilage under low-frequency ultrasound conditions of 40 kHz and ultrasound intensities of 0.189 W/cm2 and 0.359 W/cm2. The results revealed that under the conditions of 0.189 W/cm2 ultrasound intensity, the mass transfer concentration of solute molecules were higher compared to passive diffusion, and with an increase in ultrasound intensity to 0.359 W/cm2, the mass transfer effect within the cartilage was further enhanced. Ultrasound promotes molecular transport in different layers of cartilage. Under static conditions, after 2 h of mass transfer, the concentration of small molecules in the superficial layer is lower than that in the middle layer. After applying ultrasound at 0.189 W/cm2, the molecular concentration in the superficial layer significantly increases. Under conditions of 0.359 W/cm2, after 12 h of mass transfer, the concentration of medium and large molecules in the deep layer region increased by more than two times. In addition, this study conducted an assessment of damage to porcine articular cartilage under ultrasound exposure, revealing the significant potential of low-frequency, low-intensity ultrasound in drug delivery and treatment of OA.

Does tranexamic acid reduce elbow swelling and improve early function following arthroscopic arthrolysis? A double-blind randomized controlled trial

BackgroundTranexamic acid (TXA) reduces bleeding and hematoma rates in open elbow arthrolysis. However, its effects on arthroscopic elbow arthrolysis remain unclear. This study aims to evaluate the effect of TXA on elbow arthroscopic procedures and compare bleeding volume, hemarthrosis, visual analog scale (VAS) for pain, range of motion (ROM), and Mayo Elbow Performance Score (MEPS) in the early postoperative period between patients who received intra-articular TXA and those who did not. MethodsA prospective, double-blind, randomized controlled trial enrolling 80 patients with stiff elbows who underwent arthroscopic arthrolysis was performed from January 2021 to December 2022. Intra-articularly, 1 g of TXA in 100 ml of saline or placebo (control group) was administered after the arthroscopic operation according to randomization. Parameters were recorded and compared between the groups, including bleeding volume of drainage, hemoglobin (Hgb) level, ratio of arm and forearm circumference of the surgical side to the contralateral side, grading of hematoma, VAS, ROM and MEPS within one week postoperatively. And during one year follow-up, ROM and MEPS were recorded. ResultsAll patients enrolled in this study demonstrated significant improvements in ROM (flexion-extension) and MEPS one week postoperatively, with no significant differences observed between the two groups. Compared to the control group, the TXA group exhibited significant differences in the bleeding volume of drainage (61.45±47.7 ml vs. 89.8±47.0 ml, p=0.030) and a higher Hgb level 24 hours postoperatively (13.5±1.5 g/dL vs. 12.6±1.8 g/dL p=0.049). While the ratio of arm and forearm circumferences significantly increased 24 hours postoperatively compared to preoperative values in TXA group (1.05±0.06 vs. 1.02±0.04 and 1.02±0.06 vs. 0.98±0.04, with p=0.019 and p=0.005, respectively), this difference vanished one week postoperatively for the ratio of arm circumference. However, it persisted for the ratio of forearm circumference (1.02±0.07 vs. 0.98±0.04, p=0.003). Furthermore, there was no significant difference in MEPS, VAS or ROM between the two groups one week postoperatively. ConclusionPatients with stiff elbows who underwent arthroscopic arthrolysis achieved satisfactory clinical outcomes very early postoperatively. Compared to the control group, patients who underwent arthroscopic elbow arthrolysis with intra-articular administration of TXA exhibited significantly less bleeding volume of drainage and slightly higher Hgb levels postoperatively. One week postoperatively, slightly more swelling in the upper arm region was noted in the control group compared to the TXA group. These findings suggest that the intra-articular injection of TXA after arthroscopic release for elbow stiffness may statistically reduce complications related to postoperative bleeding. However, it’s clinical relevance needs further investigation.