Long-acting bulleyaconitine A microspheres via intra-articular delivery for multidimensional therapy of rheumatoid arthritis.

Bulleyaconitine A (BLA) is a promising candidate for treating rheumatoid arthritis (RA) with diverse pharmacological activities, including anti-inflammatory, analgesic and bone repair. Herein, the long-acting bulleyaconitine A microspheres (BLA-MS) were developed to treat RA comprehensively by forming drug reservoirs in joint cavities. The BLA-MS were prepared by emulsion/solvent evaporation method. The particle size and distribution were assessed by SEM. The crystalline state was investigated by DSC and PXRD. The drug loading (DL), encapsulation efficiency (EE) and cumulative release in vitro were determined by HPLC. The DL and EE were 23.93 ± 0.38 % and 95.73 ± 1.56 % respectively, and the cumulative release was up to 69 days with a stable release curve. The pharmacodynamic results in collagen induced arthritis (CIA) rats showed a noticeable reduction in paw thickness (5.66 ± 0.32 mm), and the decreasing expression level of PGE2, TNF-α and IL-6 which diminished the infiltration of inflammatory cells, thereby alleviating the progression of erosion and repairing the damaged bones (BV/TV (Bone Volume / Total Volume): 81.97 %, BS/BV (Bone Surface / Bone Volume): 6.08 mm-1). In conclusion, intra-articular injection of BLA-MS should have a promising application in the treatment of RA and may achieve clinical transformation in the future.

Efficacy Analysis of Arthroscopic Surgery Combined with Intra-articular Chitosan Injection for Stage II-III Knee Osteoarthritis in Patients with Abnormal Body Weight.

OBJECTIVE: Weight is an influential factor in knee osteoarthritis (KOA). However, the effect of abnormal body weight on chitosan's efficacy in treating KOA is unclear. This study aimed to explore the differences in the effectiveness of arthroscopic surgery combined with intra-articular chitosan injection for KOA in patients with abnormal body weight. METHODS: Patients with stage II-III KOA (Kellgren-Lawrence rating, K-L) undergoing arthroscopic surgery were recruited for this clinical study from January 2020 to September 2021. Based on body mass index (BMI) and intra-articular chitosan injection, patients with KOA undergoing arthroscopic surgery (138 patients) were divided into four groups: low-weight-non-injection (Lw-N, BMI <18.5); low-weight-chitosan injection (Lw-CS, BMI <18.5); overweight-non-injection (Ow-N, BMI ≥25); overweight-chitosan injection (Ow-CS, BMI ≥25). A 2-year follow-up was conducted to evaluate various indicators, including the visual analogue scale (VAS) and the Western Ontario and McMaster Universities osteoarthritis index score (WOMAC). Statistical analyses were performed using relevant parametric or non-parametric tests. RESULTS: In total, 138 patients with KOA were included in this study. There were no significant differences in gender, age, and incidence of chronic residual pain after arthroscopy among the four groups (p > 0.05). The proportion of patients undergoing subsequent knee arthroplasty during the 2-year follow-up period was significantly higher in the Ow-CS group (20/35) than in the Lw-CS group (12/39) (p < 0.05). The K-L rating showed an overall increasing trend over time, with the K-L rating in the Ow-N and Ow-CS groups significantly higher than that in the Lw-CS group at the final follow-up (p < 0.05). VAS and WOMAC scores significantly decreased at 1 and 3 months post-arthroscopy and then increased. One month after arthroscopy, VAS was significantly lower (p < 0.05) in the intra-articular chitosan injection groups (Lw-CS and Ow-CS) compared with the non-injection groups (Lw-N and Ow-N). VAS was lower in the Ow-CS group than in the Lw-CS group (p < 0.05). There was no significant difference in WOMAC between the intra-articular chitosan injection and non-injection groups at each time point (Lw-N vs. Lw-CS, Ow-N vs. Ow-CS, p > 0.05). CONCLUSION: Arthroscopic surgery combined with intra-articular chitosan injection shows short-term positive effects in treating KOA. Intra-articular chitosan injection appears to have a greater short-term pain relief effect in obese patients.

The ICHI-FIXATOR® system, a novel wire-connected external fixator, demonstrates efficacy in managing intra-articular fractures involving the proximal phalanx of the big toe.

Proximal phalanx fractures of the big toe involving angulation or dislocation of the articular surface require repositioning and fixation. We treated a patient with such a fracture using a novel wire-connected external fixator, the ICHI-FIXATOR® system. A 45-year-old male sustained an injury when slipping down the stairs and impacting his left big toe. Plain radiography and computed tomography revealed a proximal phalangeal fracture of the left big toe with dislocation of the articular surface and comminution. The surgical intervention was performed using 1.1-mm diameter C-wires and an external fixator. The patient regained ambulation and resumed work immediately after surgery. Four weeks postoperatively, all wires were removed on an outpatient basis. Eight months postoperatively, the patient experienced no pain during strenuous activities or exercises. This novel wire-connected external fixator provides reliable and secure fixation, facilitating a prompt return to normal daily activities. This technique may be an effective option for managing toe fractures.

Chondrotoxicity of Intra-Articular Injection Treatment: A Scoping Review.

The purpose of this scoping review was to identify possible chondrotoxic effects caused by drugs usually used for intra-articular injections. PubMed, Scopus, Web of Science and Cochrane were searched. Inclusion criteria required randomized controlled trials written in English that evaluate the toxic effect that damages the cartilage. The literature search resulted in 185 unique articles. 133 full-text articles were screened for inclusion, of which 65 were included. Corticosteroids, with the exception of triamcinolone, along with local anaesthetics, potentially excluding ropivacaine and liposomal bupivacaine, and nonsteroidal anti-inflammatory drugs, exhibited insufficient safety profiles to warrant casual use in clinical settings. Hyaluronic acid, on the other hand, appears to demonstrate safety while also mitigating risks associated with concurrent compounds, thereby facilitating therapeutic combinations. Additionally, there remains a paucity of data regarding platelet-rich plasma, necessitating further evaluation of its potential efficacy and safety. Overall, it seems that results are significantly influenced by the dosage and frequency of injections administered, observed in both human and animal studies.

Primary Reconstruction Using Fibular Strut Allograft for Distal Humerus Intra-articular Comminuted Open Fracture (AO/OTA13C2, G-A type IIIA): A Case Report.

Distal humerus intra-articular comminuted open fracture is a challenging injury, with nonunion, infection and stiffness considered as major concerns. We report a 58-year-old woman who was admitted to the emergency department from a car accident, sustaining an open wound with severe comminution of distal humerus and complete articular fracture, classified as AO/OTA 13C2 and Gustillo Anderson type IIIA. Debridement and external fixation was done first, followed by open reduction and internal fixation with fibular strut allograft. The patient showed excellent results in radiological and functional outcomes. Level of Evidence: Level V (Therapeutic).

Pins and Rubber Band Traction System Combined with Internal Fixation for Intra-articular Fractures of the Proximal Interphalangeal Joints.

Background: Intra-articular fractures of the proximal interphalangeal joint (PIPJ) can result in poor outcomes if inadequately treated. Dynamic external fixation and internal fixation with plates and/or screws are two treatment options. The role of combining these two methods is unclear. The aim of this study is to determine the outcomes of patients with intra-articular fractures of the PIPJ treated with a combination of dynamic external fixation with a plate and/or screws. Methods: A retrospective review was conducted on 18 consecutive cases of intra-articular fractures of the PIPJ treated with pins and rubber band traction system (PRTS) combined with dorsal internal fixation with plates and/or screws. The patients' average age was 51 years (range: 20-81 years). The fracture patterns were volar-type (n = 2), dorsal-type (n = 4) and pilon-type (n = 12). Data with regard to time to surgery, interphalangeal joint range of motion, grip strength, VAS for pain, Quick DASH score, complications, duration of follow-up and return to work were collected. Results: The levels of articular involvement were stable (n = 1), tenuous (n = 5) and unstable (n = 12). The average time to surgery was 9 days, and the average follow-up period was 15 months. The fracture was fixed with a dorsal plate and screws in 10 patients and with only screws in eight patients. All patients had PRTS. All patients returned to their original occupation and the fractures united in good alignment. The average grip strength was 86% of that of the unaffected side. The average active PIPJ motion was 85° (range: 50°-106°), and the average active distal interphalangeal joint (DIPJ) motion was 48° (range: 10°-90°). Conclusions: Our results show that a combination of PRTS and open reduction and fixation with plate and/or screws achieved a good range of motion and articular reduction. Level of Evidence: Level IV (Therapeutic).

Time to Total Knee Arthroplasty (TKA) Post Intra-Articular Injection.

Background: Disease-modifying treatments are not currently developed to target the underlying causes of knee osteoarthritis (KOA). Corticosteroids (CS), hyaluronic acid (HA), and platelet-rich plasma (PRP) intra-articular (IA) injections are commonly used for patients that do not respond to non-pharmacological treatments, oral nonsteroidal anti-inflammatory, or pain medications to address solely KOA symptoms. Utilizing TKA as an endpoint in the KOA disease progression provides a basis to determine efficacy of this treatment pathway. The primary objective is to evaluate a large national database to determine the time between first injection and total knee arthroplasty in patients solely administered intra-articular IA, CS, and HA. Methods: A retrospective query was performed on a national, all-payer claims database (PearlDiver, Colorado Springs, CO, USA), a composite of over 160 million Health Insurance Portability and Accountability Act compliant orthopedic records across all states and territories of the United States spanning 2016 to 2022. The database was queried to produce three distinct cohorts for analysis (PRP, HA, and CS). A 4:1 case match was conducted to compare cohorts receiving a subsequent TKA. Kaplan-Meier survival analysis analyzed the TKA-free survival of patients within each group at 6 months and 1 to 4 years. The log-rank test was performed for comparisons between survival cohorts. Results: The PRP cohort had a total population of 3240 patients, of which 71 (2.2%) received a subsequent TKA. The corticosteroid cohort had a total population of 1,382,572, of which 81,271 (5.9%) received a subsequent TKA. The HA cohort had a total population of 164,000, of which 13,044 (8.0%) received a subsequent TKA. Due to the low population within the PRP group, this group was excluded from comparison. The mean time to TKA from first injection in the HA group was 377.8 days, while in the corticosteroid group it was 370.0 days. The proportions of TKA-free survival for CS and HA when compared at 4 years post-injection was similar between groups (p = 0.05). Discussion and Conclusion: Patients that received only IA-corticosteroids or IA-hyaluronic acid had a similar length of time between the first injection and the total knee arthroplasty associated with the injected joint. This evidence provides information for clinicians and patients alike when contemplating these non-surgical injection modalities for KOA. The similarity observed between these treatments supports the need for future research to determine whether there is any potential for reduction in healthcare costs for KOA treatment prior to TKA.

Adding Dexmedetomidine to Intra-articular Local Anesthetics Results in Prolonged Analgesia after Knee Arthroscopy: A Systematic Review and Meta-Analysis.

PURPOSE: This systematic review and meta-analysis aims to assess the efficacy and safety of dexmedetomidine as an adjuvant to intra-articular (IA) injections of local anesthetics (LA) in adult patients undergoing knee arthroscopy. METHODS: We searched MEDLINE, Embase, and Cochrane Library for randomized controlled trials (RCTs) comparing IA dexmedetomidine plus LA versus LA alone for knee arthroscopy in adults. We used the DerSimonian and Laird random-effects model for all outcomes, and conducted a sensitivity analysis with the leave-one-out method, as well as a subgroup analysis for the type of LA. We used R version 4.1.2 for all statistical analyses. RESULTS: We included 16 RCT encompassing 799 patients, of whom 49.8% received IA dexmedetomidine. In the pooled analysis, time to first analgesia rescue was prolonged in almost 4 hours with the use of dexmedetomidine (MD 229 min; p<0.001). We found statistically significant differences favoring dexmedetomidine in pain scores at rest and movement throughout the first 2, 6, 12 and 24 hours postoperatively (p<0.001). Although the mean difference (MD) ranged from -0.3 to -0.9 cm, corresponding to a 3 to 9% reduction in pain scores, this change is not clinically significant when compared to the minimal clinically important difference (MCID). Additionally, the intervention group showed a statistically significant reduction in cumulative opioid consumption over 24 hours (MD -4.5 mg; p<0.001). However, this reduction did not meet the threshold for the MCID. There was no difference between groups on the incidence of hypotension (p=0.190), bradycardia (p=0.430) and postoperative nausea and vomiting (p=0.550). CONCLUSIONS: Adding dexmedetomidine to LA in IA injections for knee arthroscopy significantly extended analgesia duration. Additionally, it lowered pain scores and opioid use, although these effects did not reach the MCID. Furthermore, this addition did not increase the risk of adverse events.

Synovial mesenchymal stem cells secrete more lubricin than adipose mesenchymal stem cells after injection into rat osteoarthritis knees.

Intra-articular injection of mesenchymal stem cells (MSCs) is envisioned as a solution for knee osteoarthritis (OA). Although synovial MSCs (SyMSCs) are promising for cartilage regeneration, the clinical choice is usually adipose MSCs (AdMSCs). However, the similarities/differences in the mode of action between SyMSCs and AdMSCs remain unclear. Here, we compared factors secreted by human SyMSCs and AdMSCs after injection into OA knees. Human SyMSCs or AdMSCs were injected into the knees of rat partial meniscectomy models. The next day, the knee joints were collected to analyze the distribution of injected MSCs and transcriptome changes in the human MSCs and rat synovium. Non-injected MSCs were mixed with rat synovium as a control. After injection, no difference was apparent in intra-articular distribution of the SyMSCs or AdMSCs. RNA sequencing demonstrated an enrichment of cytokine-cytokine receptor interaction-related genes in both human SyMSCs and AdMSCs after injection. Differentially expressed genes (DEGs) specific to SyMSCs were associated with cartilage matrix synthesis and homeostasis. PCR analysis of the matrisome-related DEGs showed significantly higher expression of PRG4 in SyMSCs than in AdMSCs after injection. Immunostaining also confirmed a significantly greater expression of lubricin by SyMSCs than by AdMSCs. These findings indicate that SyMSCs will be a more promising treatment for OA.

Postoperative Infection Following Hip Arthroscopy in Patients Receiving Preoperative Intra-articular Injections: A Systematic Review and Meta-Analysis.

Intra-articular injections prior to hip arthroscopy are often used to diagnose and conservatively manage hip pathologies, such as femoroacetabular impingement, labral tears, and chondral lesions. As a diagnostic tool, the relief of hip pain following an intra-articular injection helps pinpoint the primary source of pain and assists surgeons in recommending arthroscopic intervention for underlying intra-articular pathologies. However, when injections are not sufficiently spaced apart in time prior to hip arthroscopy, there is an elevated risk of postoperative infection. This systematic review aims to assess whether preoperative intra-articular injections prior to hip arthroscopy are associated with an increased risk of postoperative infection and to determine the safety timeframe for administering such injections prior to the procedure. A comprehensive search was conducted in the PubMed, Embase, and Cochrane Library databases to identify studies examining the relationship between preoperative intra-articular injections and postoperative infection following hip arthroscopy. A meta-analysis was conducted to compare the risk of infection between patients who received injections prior to hip arthroscopy at varying intervals and those who did not receive any preoperative injections. Five studies were included (four level III and one level IV), which consisted of 58,576 patients (58.4% female). Injections administered anytime prior to hip arthroscopy posed a significantly higher risk of infection compared to no history of prior injections (risk ratio: 1.45, 95% confidence interval: 1.14-1.85, P = 0.003). However, upon subanalysis, the risk of infection was significantly higher among patients who received injections within three months prior to hip arthroscopy compared to those who did not receive injections (risk ratio: 1.55, 95% confidence interval: 1.19-2.01, P = 0.001). Additionally, no significant difference in infection risk was observed when injections were administered more than three months before hip arthroscopy compared to no injections (risk ratio: 1.05, 95% confidence interval: 0.56-1.99, P = 0.87). The findings suggest that patients undergoing hip arthroscopy who have previously received intra-articular injections may face a statistically higher risk of postoperative infection, particularly when the injection is administered within three months prior to hip arthroscopy. Consequently, surgeons should exercise caution and avoid administering intra-articular injections to patients scheduled for hip arthroscopy within the subsequent three months to mitigate the increased risk of infection.

Integrated Nail and Plate Fixation with Allograft in the Management of Osteoporotic Intra-articular Distal Femur Fracture - A Case Report.

Introduction: Securing stable internal fixation for fractures in osteoporotic intra-articular distal femur proves to be a demanding task due to thin cortices, a wide medullary canal, diminished bone stock, and fracture comminution. No singular therapeutic approach has successfully tackled all facets of this injury. Consequently, we now introduce a pioneering fixation method in our report, aiming to offer a holistic solution to the intricate challenges associated with this scenario. Case Report: A 60-year-old female presented with an intra-articular distal femur fracture, and underwent a combination fixation of distal femur plate and intramedullary interlocking nailing. The patient was rehabilitated with active knee range of motion on post-operative day 7 and has now attained full knee range of motion. Conclusion: The utilization of anatomical plates with locking mechanisms, in tandem with intramedullary interlocking nailing, holds promise for the secure stabilization and fixation of osteoporotic distal femur fractures, potentially leading to an expedited recovery process.

Advancements in pH-Responsive nanoparticles for osteoarthritis treatment: Opportunities and challenges.

Osteoarthritis (OA) is a degenerative disease linked to aging and obesity. The global aging population has led to an increasing number of OA patients, imposing a significant economic burden on society. Traditional drugs treatment methods often fail to achieve satisfactory outcomes. With the rapid advancement of nanomaterial delivery systems, numerous studies have focused on utilizing nanomaterials as carriers to achieve efficient OA treatment by effectively loading and delivering bioactive ingredients (e.g., drugs, nucleic acids) tailored to the unique pathological conditions, such as the weakly acidic microenvironment of synovial fluid in OA patients. This review highlights the latest advancements in the use of pH-responsive nanoparticles for OA treatment, emphasizing the principle of targeted drug delivery leveraging the acidic microenvironment of inflamed joints. It further discusses the composition, synthesis, response mechanism, target selection, application, and recent research findings of nanoparticles, while also addressing the challenges and future directions in this promising field.

Analogies Between Platelet-Rich Plasma Versus Hyaluronic Acid Intra-articular Injections in the Treatment of Advanced Knee Arthritis: A Single-Center Study.

Background Knee osteoarthritis (KOA), a degenerative joint disease, is a common cause of chronic knee pain and disability in adults. Conservative management options are the first-line approach, but intra-articular injections, such as platelet-rich plasma (PRP) and hyaluronic acid (HA), are considered for advanced cases. This study aims to compare the efficacy of PRP versus HA injections in patients with advanced KOA. Methods A retrospective study was conducted on 145 patients with advanced KOA. Seventy patients received PRP injections, while 75 patients received HA injections. The Visual Analog Scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and International Knee Documentation Committee (IKDC) score were employed to evaluate the treatment's efficacy. Adverse events associated with these injections were also recorded. Results Both PRP and HA injections significantly reduced pain and improved joint function in patients with advanced KOA. PRP injections were slightly more effective than HA injections in reducing pain scores. Both treatments showed similar improvements in functional outcomes. Adverse events were minimal and self-limiting for both treatments. Conclusions Both PRP and HA injections effectively ameliorate advanced KOA by reducing pain and improving function. PRP injections showed a slightly greater improvement in pain scores and functional outcomes. The choice between PRP and HA injections may depend on factors like cost, availability, and patient preference. Further research is needed to validate these findings and understand treatment suitability for different patient populations.

Intra-articular corticosteroids for the treatment of osteoarthritis: A systematic review and meta-analysis on the comparison of different molecules and doses.

Purpose: The purpose of this study was to quantify and compare the clinical relevance of the different intra-articular corticosteroids (CS) effects in vivo for osteoarthritis (OA) treatment. Methods: The search was conducted on PubMed, Cochrane, and Web of Science in October 2023. The PRISMA guidelines were used. Inclusion criteria: animal or human randomized controlled trials (RCTs), English language and no time limitation, on the comparison of different intra-articular CS for OA treatment. The articles' quality was assessed using the Cochrane RoB2 and GRADE guidelines for human RCTs, and SYRCLE's tool for animal RCTs. Results: Eighteen RCTs were selected (16 human and 2 animal studies), including 1577 patients (1837 joints) and 31 animals (51 joints). The CS used were triamcinolone (14 human and 2 animal studies), methylprednisolone (7 human and 1 animal study), betamethasone (3 human studies) and dexamethasone (1 human study). All studies addressed knee OA except for three human and one animal study. A meta-analysis was performed on the comparison of methylprednisolone and triamcinolone in humans with knee OA analysing VAS pain at very short- (≤2 weeks), short- (>2 and ≤4 weeks), mid- (>4 and ≤8 weeks), long- (>8 and ≤ 12 weeks), and very long-term (>12 and ≤24 weeks). Triamcinolone showed better post-injection values compared to methylprednisolone at very short-term (p = 0.028). No difference in terms of VAS improvement was observed at any follow-up. Conclusions: The available preclinical and clinical literature provides limited evidence on the comparison of different CS, hindering the possibility of determining the best CS approach in terms of molecule and dose for the intra-articular injection of OA joints. Level of Evidence: Level I.

Updates in the Treatment of Knee Osteoarthritis.

Knee osteoarthritis (OA) is an inflammatory and degenerative condition resulting in articular cartilage destruction and functional loss. Its prevalence has grown considerably due to increased life expectancy and obesity, and its diagnosis relies on evaluation, medical examination, and confirmation by supplementary radiographic images. Knee OA is multifactorial and influenced by several local, systemic, and external aspects. In addition, its progress and therapeutic responses highly depend on the characteristics of each subject. The initial recommendation is drug treatment and alternative therapies to improve quality of life. However, if these treatments are unsuccessful, one must consider surgical treatment. Surgical options include arthroscopies, osteotomies, and partial and total arthroplasties, while non-surgical treatments include medications and alternative therapies such as infiltrations, acupuncture, and physical exercise. It is worth highlighting that biomarkers can be a significant strategy for early disease detection, assessment of disease activity, prediction of prognosis, and monitoring a better response to therapy. Nevertheless, this topic must be the focus of further research to confirm its findings.

The efficacy and safety of intra-articular injection of corticosteroids in multimodal analgesic cocktails in total knee arthroplasty-a historically controlled study.

Background: Total knee arthroplasty (TKA) is a common and effective procedure. Optimizing pain control and reducing postoperative discomfort are essential for patient satisfaction. No studies have examined the safety and efficacy of intra-articular corticosteroid injections following TKA. This study aims to examine the safety and efficacy of corticosteroids in intra-articular multimodal analgesic injections. Materials and methods: This was a historically controlled study conducted at a single academic institution. Before May 2019, patients received an intra-articular cocktail injection without corticosteroids during surgery, referred to as the non-corticosteroid (NC) group. After June 2019, intraoperatively, patients received an intra-articular cocktail injection containing corticosteroids, referred to as the corticosteroid (C) group. Finally, 738 patients were evaluated, 370 in the C cohort and 368 in the NC cohort. The mean follow-up duration was 30.4 months for the C group and 48.4 months for the NC group. Results: The mean VAS scores at rest on postoperative day (POD) 1 (2.35) and POD3 (3.88) were significantly lower in the C group than those in the NC group, which were 2.86 (POD1) and 5.26 (POD3) (p < 0.05). Walking pain in the C group (4.42) was also significantly lower than that (5.96) in the NC group on POD3 (p < 0.05). Patients in the C group had a significantly higher mean range of motion (ROM) (92.55) on POD3 than that (86.38) in the NC group. The mean time to straight leg raise for group C (2.77) was significantly shorter than that (3.61) for the NC group (p < 0.05). The C group also had significantly fewer rescue morphine (1.9) and metoclopramide (0.21) uses per patient than the NC group, which were 3.1 and 0.24, respectively. No significant differences in fever or vomiting rates between groups were found. Patients in neither group developed periprosthetic joint infections or skin necrosis. One patient in the C group suffered from wound dehiscence, and the wound healed well after debridement. No patient died or had a re-operation in either group. Conclusions: This pilot trial found that intra-articular injection of multimodal analgesia (including corticosteroids) reduced initial postoperative pain, increased ROM in the early postoperative days (up to POD3), and did not increase wound complications or infection rates in approximately 30 months of follow-up.

Intra-articular hydrogel formulation prolongs the in vivo stability of Toll-like receptor antagonistic peptides for rheumatoid arthritis treatment.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by systemic inflammation that primarily affects joint tissue and requires frequent medication. Recently, we developed cyclic phage-display-derived inhibitory peptides (CPs), which act as Toll-like Receptor 4 antagonists. These CPs exhibited therapeutic efficacy against joint diseases by alleviating inflammatory factors. Nonetheless, CP exhibits in vivo instability and a short half-life. Therefore, this study sought to improve the in vivo stability of CP, thereby reducing the frequency of CP administration through the development of an injectable hydrogel depot formulation. To improve in vivo stability, CP was chemically conjugated to hyaluronic acid (HA-CP) and subsequently mixed into a temperature-sensitive hydrogel [methoxy polyethylene glycol-b-poly(ε-caprolactone)-ran-poly(lactide) (PC)] as an injectable depot (PC+(HA-CP)). For comparison, CP was physically mixed with HA and PC (PC+(HA+CP)). Both PC+(HA-CP) and PC+(HA+CP) were found to rapidly form depots upon injection into the joint space. Cell viability assays confirmed the non-toxic nature of PC+(HA-CP) and PC+(HA+CP), whereas both formulations exhibited inhibition of inflammatory factors. Furthermore, PC+(HA-CP) retained CP for a longer duration compared to PC+(HA+CP) in the presence of hyaluronidase and within the RA joint space. Following intra-articular injection, both the PC+(HA-CP) and PC+(HA+CP) depots exhibited reductions in RA symptoms, cartilage regeneration, and suppression of pro-inflammatory cytokine levels. Specifically, by extending the in vivo retention of CP, PC+(HA-CP) demonstrated superior RA treatment efficacy compared to PC+(HA+CP). In conclusion, intra-articular injection of PC+(HA-CP) was validated as an effective strategy for treating RA, owing to its ability to prolong the in vivo retention of CP. This approach holds promise for improving RA management and patient outcomes.

Intra-articular injection of an extended-release flavopiridol formulation represents a potential alternative to other intra-articular medications for treating equine joint disease.

OBJECTIVE: To establish the pharmacokinetics of the cyclin-dependent kinase-9 inhibitor flavopiridol in equine middle carpal joints, using an extended-release poly lactic-co-glycolic acid (PLGA) microparticle formulation. ANIMALS: 4 healthy horses without evidence of forelimb lameness. METHODS: A 6-week longitudinal pharmacokinetic study was conducted in 2 phases (6 weeks each) in 4 healthy horses. The PLGA microparticles containing 122 µg flavopiridol in 3 mL saline were administered by intra-articular injection into 1 middle carpal joint, with empty PLGA microparticles injected into the contralateral joint as a control. Synovial fluid and plasma were collected at time points out to 6 weeks, and drug concentrations in synovial fluid and plasma were determined using validated protocols. Synovial fluid total protein and total nucleated cell count and differential, CBC, serum biochemistry, and lameness exams were performed at each of the time points. RESULTS: Synovial fluid flavopiridol averaged 19 nM at week 1, gradually reduced to 1.4 nM by 4 weeks, and was generally below the detection limit at 5 and 6 weeks. There was no detectable flavopiridol in the plasma samples, and no adverse effects were observed at any time point. CLINICAL RELEVANCE: Intra-articular injection of PLGA microparticle-encapsulated flavopiridol was well tolerated in horses, with detectable levels of flavopiridol in the synovial fluid out to 4 weeks with negligible systemic exposure. Flavopiridol is a cyclin-dependent kinase-9 inhibitor with potent anti-inflammatory and analgesic activity. The extended-release microparticle formulation promotes intra-articular retention of the drug and it may be an alternative to other intra-articular medications for treatment of equine joint disease.

The necessity of suction drainage when intra-articular injection of tranexamic acid is used during primary total knee arthroplasty: a retrospective study.

BACKGROUND: Suction drainages are commonly used after total knee arthroplasty (TKA) procedures; however, their use is somewhat controversial. Recently, some reports have claimed that the administration of tranexamic acid (TXA) may prevent postoperative bleeding following TKAs. Although numerous studies have reported regarding different dosages, timings of administration, or drain clamping times for intravenous and intra-articular TXA injections (IA-TXAs), few have examined whether suction drainage is necessary when TXA is administered. In this study, we compared using suction drainage without TXA administration and IA-TXA without suction drainage and aimed to examine the need for suction drainage during IA-TXA. METHODS: This retrospective study was conducted on 217 patients who had received TKA for osteoarthritis; 104 were placed on suction drainage after TKA without TXA (Group A), whereas the remaining 113 received IA-TXA immediately after surgery without suction drainage (Group B). Our clinical evaluation included assessments of the need for transfusion, presence of postoperative complications, incidence of deep vein thrombosis (DVT), and changes in hemoglobin (Hb), hematocrit (Hct), and D-dimer levels. RESULTS: No significant differences were observed in terms of postoperative complications and preoperative Hb, Hct, or D-dimer levels between the two groups. Although the prevalence of DVT was significantly higher in Group B (p < 0.05), all cases were asymptomatic. Hb and Hct levels were significantly lower in Group A than in Group B at 1, 3, 7, and 14 days postoperatively (p < 0.05), although none of the cases required blood transfusions. D-dimer levels were significantly higher in Group A than in Group B at 1 and 3 days postoperatively (p < 0.05). CONCLUSION: Suction drainage might not be necessary when IA-TXA is administered after TKA procedures.

Prospects of Disease-Modifying Osteoarthritis Drugs.

Osteoarthritis (OA) causes a massive disease burden with a global prevalence of nearly 23% in 2020 and an unmet need for adequate treatment, given a lack of disease-modifying drugs (DMOADs). The author reviews the prospects of active DMOAD candidates in the phase 2/3 clinical trials of drug development pipeline based on key OA pathogenetic mechanisms directed to inflammation-driven, bone-driven, and cartilage-driven endotypes. The challenges and possible research opportunities are stated in terms of the formulation of a research question known as the PICO approach: (1) population, (2) interventions, (3) comparison or placebo, and (4) outcomes.