Intra-articular Research Articles

Evaluation of the effectiveness of intra-articular administration of highly purified hyaluronic acid in knee osteoarthritis in real clinical practice

Knee osteoarthritis (kOA) is a common cause of turning for medical advice, associated with chronic pain and disability. One of the methods of OA treatment is the local administration of hyaluronic acid (HA) drugs.Objective: to evaluate the effectiveness of intra-articular (IA) administration of highly purified HA (Armaviskon Plus) in kOA.Patients and methods. The study group consisted of 58 patients (74.1% women and 25.9% men, aged 59.5±11.8 years) with kOA, experiencing moderate/severe pain (≥40 mm on a visual analogue scale, VAS). All patients received IA injection of HA Armaviskon Plus (2 ml of a 1.5% solution), 2 injections with an interval of 7 days. The effectiveness criterion was the dynamics of pain at rest and during movement (VAS 0-100 mm) and the function of the knee joint according to a numerical rating scale (NRS 0-100 points) 2 weeks, 1 and 3 months after administration of therapy.Results and discussion. During the treatment, there was a significant improvement in all indicators. The average severity of pain during movement at baseline, after 2 weeks, 1 and 3 months was 50 [40; 60], 30 [20; 40], 15 [0; 30], 20 [0; 30] mm (p<0.001), at rest 20 [10; 40], 5 [0; 20], 0 [0; 20], 10 [0; 20] mm (p<0.05) by VAS. The average values of functional indicators were 40 [10; 60], 10 [0; 40], 20 [0; 40], 10 [10; 30] scores according to the NRS. A decrease in non-steroidal anti-inflammatory drugs demand was recorded: 67.1% of patients were initially taking them, after 3 months – 36.1% (p<0.001). No serious adverse reactions were noted.Conclusion. IA administration of HA is an effective and safe method for the treatment of kOA. Armaviskon Plus, a highly purified high-molecular- weight HA drug, has shown good results in pain reduction and improvement of function in knee OA as well as a favorable safety profile, which makes it possible to recommend its use in real clinical practice.

Thermoresponsive polymeric dexamethasone prodrug for arthritis pain

Intra-articular (IA) glucocorticoids (GC) are commonly used for clinical management of both osteoarthritis and rheumatoid arthritis, but their efficacy is limited by the relatively short duration of action and associated side effects. To provide sustained efficacy and to improve the safety of GCs, we previously developed a N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-based dexamethasone (Dex) prodrug. Serendipitously, we discovered that, by increasing the Dex content of the prodrug to unusually high levels, the aqueous solution of the polymeric prodrug becomes thermoresponsive, transitioning from a free-flowing liquid at 4 °C to a hydrogel at 30 °C or greater. Upon IA injection, the prodrug solution forms a hydrogel (ProGel-Dex) that is retained in the joint for more than 1 month, where it undergoes gradual dissolution, releasing the water-soluble polymeric prodrug. The released prodrug is swiftly internalized and intracellularly processed by phagocytic synoviocytes to release free Dex, resulting in sustained amelioration of joint inflammation and pain in rodent models of inflammatory arthritis and osteoarthritis. The low molecular weight (6.8 kDa) of the ProGel-Dex ensures rapid renal clearance once it escapes the joint, limiting systemic GC exposure and risk of potential off-target side effects. The present study illustrates the translational potential of ProGel-Dex as a potent opioid-sparing, locally delivered adjuvant analgesic for sustained clinical management of arthritis pain and inflammation. Importantly, the observed thermoresponsive properties of the prodrug establishes ProGel as a platform technology for the local delivery of a broad spectrum of therapeutic agents to treat a diverse array of pathological conditions.

Non-clinical assessment of lubrication and free radical scavenging of an innovative non-animal carboxymethyl chitosan biomaterial for viscosupplementation: An in-vitro and ex-vivo study.

ObjectiveLubrication and free radical scavenging are key features of biomaterials used for viscosupplementation (VS) of joints affected by osteoarthritis (OA). The objective of this study was to describe the non-clinical performance characterization of KiOmedine® CM-Chitosan, a non-animal carboxymethyl chitosan, in order to assess its intended action in VS and to compare it to existing viscosupplements based on crosslinked hyaluronan (HA) formulations.MethodThe lubrication capacity of the tested viscosupplements (VS) was evaluated in-vitro and ex-vivo. In-vitro, the coefficient of friction (COF) was measured using a novel tribological system. Meanwhile, an ex-vivo biomechanical model in ovine hindlimbs was developed to assess the recovery of join mobility after an intra-articular (IA) injection. Free radical scavenging capacity of HA and KiOmedine® CM-Chitosan formulations was evaluated using the Trolox Equivalent Antioxidant Capacity (TEAC) assay.ResultsIn the in-vitro tribological model, KiOmedine® CM-Chitosan showed high lubrication capacity with a significant COF reduction than crosslinked HA formulations. In the ex-vivo model, the lubrication effect of KiOmedine® CM-Chitosan following an IA injection in the injured knee was proven again by a COF reduction. The recovery of joint motion was optimal with an IA injection of 3 ml of KiOmedine® CM-Chitosan, which was significantly better than the crosslinked HA formulation at the same volume. In the in-vitro TEAC assay, KiOmedine® CM-Chitosan showed a significantly higher free radical scavenging capacity than HA formulations.ConclusionOverall, the results provide a first insight into the mechanism of action in terms of lubrication and free radical scavenging for the use of KiOmedine® CM-Chitosan as a VS treatment of OA. KiOmedine® CM-Chitosan demonstrated a higher capacity to scavenge free radicals, and it showed a higher recovery of mobility after a knee lesion than crosslinked HA formulations. This difference could be explained by the difference in chemical structure between KiOmedine® CM-Chitosan and HA and their formulations.

Effects of local infiltration of analgesia and tranexamic acid in total knee replacements: safety and efficacy in reducing blood loss and comparability to intra-articular tranexamic acid.

The use of periarticular (PA) tranexamic acid (TXA) and its efficacy in comparison with intra-articular (IA) TXA have not been well explored in the literature. This retrospective cohort study aimed to compare the effects of IA and PA TXA with analgesic components in reducing blood loss and improving immediate postoperative pain relief and functional outcomes in patients after unilateral primary total knee arthroplasty (TKA). A total of 63 patients underwent TKA, and they were divided into the IA TXA delivery group ( n = 42) and PA TXA delivery group ( n = 21). All patients were administered 1 g of TXA. They also received pericapsular infiltration consisting of 0.5 mL of adrenaline, 0.4 mL of morphine, 1 g of vancomycin, 1 mL of ketorolac and 15 mL of ropivacaine. Outcomes for blood loss and surrogate markers for immediate functional recovery were measured. Of the 63 patients, 54% were female and 46% male. The mean drop in postoperative haemoglobin levels in the PA and IA groups was 2.0 g/dL and 1.6 g/dL, respectively, and this was not statistically significant ( P = 0.10). The mean haematocrit drop in the PA and IA groups was 6.1% and 5.3%, respectively, and this was also not statistically significant ( P = 0.58). The postoperative day (POD) 1 and discharge day flexion angles, POD 1 and POD 2 visual analogue scale (VAS) scores, gait distance on discharge and length of hospitalisation stay were largely similar in the two groups. Our study showed that both IA and PA TXA with analgesic components were equally efficient in reducing blood loss and improving immediate postoperative pain relief and functional outcomes.

Administration of an adeno-associated viral vector expressing interferon-β in patients with inflammatory hand arthritis, results of a phase I/II study

Inflammatory hand arthritis (IHA) results in impaired function. Local gene therapy with ART-I02, a recombinant adeno-associated virus (AAV) serotype 5 vector expressing interferon (IFN)-β, under the transcriptional control of nuclear factor κ-B responsive promoter, was preclinically shown to have favorable effects. This study aimed to investigate the safety and tolerability of local gene therapy with ART-I02 in patients with IHA. In this first-in-human, dose-escalating, cohort study, 12 IHA patients were to receive a single intra-articular (IA) injection of ART-I02 ranging 0.3×1012-1.2×1013 genome copies in an affected hand joint. Adverse events (AEs), routine safety laboratory and the clinical course of disease were periodically evaluated. Baseline- and follow-up contrast enhanced magnetic resonance images (MRIs), shedding of viral vectors in bodily fluids, and AAV5 and IFN-β immune responses were evaluated. A data review committee provided safety recommendations. Four patients were enrolled. Long-lasting local AEs were observed in 3 patients upon IA injection of ART-I02. The AEs were moderate in severity and could be treated conservative. Given the duration of the AEs and their possible or probable relation to ART-I02, no additional patients were enrolled. No systemic treatment emergent AEs were observed. The MRIs reflected the AEs by (peri)arthritis. No T-cell response against AAV5 or IFN-β, nor IFN-β antibodies could be detected. Neutralizing antibody titers against AAV5 raised post-dose. Single IA doses of 0.6×1012 or 1.2×1012 ART-I02 vector genomes were administered without systemic side effects or serious AEs. However, local tolerability was insufficient for continuation. NCT02727764.

Development of PBPK model for intra-articular injection in human: methotrexate solution and rheumatoid arthritis case study

A physiologically based model describing the dissolution, diffusion, and transfer of drug from the intra-articular (IA) space to the plasma, was developed for GastroPlus® v9.8. The model is subdivided into compartments representing the synovial fluid, synovium, and cartilage. The synovium is broken up into two sublayers. The intimal layer acts as a diffusion barrier between the synovial fluid and the subintimal layer. The subintimal layer of the synovium has fenestrated capillaries that allow the free drug to be transported into systemic circulation. The articular cartilage is broken up into 10 diffusion sublayers as it is much thicker than the synovium. The cartilage acts as a depot tissue for the drug to diffuse into from synovial fluid. At later times, the drug will diffuse from the cartilage back into synovial fluid once a portion of the dose enters systemic circulation. In this study, a listing of all relevant details and equations for the model is presented. Methotrexate was chosen as a case study to show the application and utility of the model, based on the availability of intravenous (IV), oral (PO) and IA administration data in patients presenting rheumatoid arthritis (RA) symptoms. Systemic disposition of methotrexate in RA patients was described by compartmental pharmacokinetic (PK) model with PK parameters extracted using the PKPlus™ module in GastroPlus®. The systemic PK parameters were validated by simulating PO administration of methotrexate before being used for simulation of IA administration. For methotrexate, the concentrations of drug in the synovial fluid and plasma were well described after adjustments of physiological parameters to account for RA disease state, and with certain assumptions about binding and diffusion. The results indicate that the model can correctly describe PK profiles resulting from administration in the IA space, however, additional cases studies will be required to evaluate ability of the model to scale between species and/or doses.

Comparison of combined intra-articular and sub-acromial injection with intra-articular injection in adhesive capsulitis

Background: The pain and limitation of shoulder function can disrupt daily activities of patients for months to years. Adhesive capsulitis is considered a self-limiting disease but the duration remains uncertain. The brunt of the disease is focussed on the inflamed joint capsule. On this basis, use of corticosteroid injection is justified. However, injection method is not conclusive. Objectives: To compare clinical benefits of intra-articular injection alone versus combined intra-articular and subacromial injections in management of adhesive capsulitis. Methods: Fifty-nine patients with diagnostic criteria for adhesive capsulitis were included in the study from March 2019 to September 2020. Patients were divided into two groups; patients who underwent intra-articular (IA) injection alone (Group 1) and those who received both intra-articular and sub-acromial (IA+SA) injection (Group 2). The injections were landmark guided. Patients were followed up at three, six, and 12 weeks. Pain was recorded using visual analogue scale (VAS) and subjective function using Constant-Murley score. Results: Twenty-eight patients were included in Group 1 (IA) and 31 in Group 2 (IA+SA). Thirty-six patients were female (18 each in Group 1 and Group 2) and 23 patients were male (Group 1 = 13; Group 2 = 10). In the twelfth week, VAS score was reduced in both the groups. On comparing the mean value of Constant-Murley score between the two groups there is significant difference in value recorded at the sixth and twelfth week. Conclusion: The IA+SA injection provides significant reduction in pain and better function in the short term over the IA injection.

Intra-articular therapy with methotrexate or tumor necrosis factor inhibitors in rheumatoid arthritis: a systematic review

BackgroundPersistent monoarthritis in otherwise well-controlled rheumatoid arthritis presents a therapeutic challenge. Intra-articular (IA) steroids are a mainstay of treatment, though some have queried whether IA disease modifying anti-rheumatic drugs (DMARD) and biologics can be used in those who fail steroid injections.MethodsA systematic literature review was conducted using four medical databases to identify randomized, controlled trials assessing IA therapies in RA patients. Included studies underwent Cochrane Risk of Bias 2 assessment for quality.ResultsTwelve studies were included, 6 of which examined intra-articular (IA) TNF inhibitors (TNFi), and 6 studies evaluating IA methotrexate. Of those evaluating IA TNFi, one study reported statistical improvement in TNFi therapy when compared with placebo. The remaining 5 studies compared IA TNFi therapy with steroid injections. IA TNFi had statistically improved symptom scores and clinical assessments comparable with IA steroid treatments.In the 6 studies evaluating IA methotrexate, the addition of methotrexate to steroid intra-articular therapy was not found to be beneficial, and singular methotrexate injection was not superior to the control arms (saline or triamcinolone). Risk-of-bias (ROB) assessment with the Revised Cochrane ROB tool indicated that 2 of 6 TNFi studies were at some risk or high risk for bias, compared with 5 out of 6 methotrexate studies.ConclusionFor persistent monoarthritis in rheumatoid arthritis, IA methotrexate was not found to have clinical utility. Intra-articular TNFi therapy appears to have equal efficacy to IA steroids, though the optimal dose and frequency of injections is yet unknown.

Risk of Severe Acute Localized Reactions for Different Intraarticular Hyaluronic Acid Knee Injections in a Real-World Setting.

Objective:Case reports of severe acute localized reactions (SALR) following intraarticular (IA) hyaluronic acid (HA) injections for knee osteoarthritis (OA) have been described. We compared surrogate SALR measures between patients using hylan G-F 20 and specific non-hylan G-F 20 HA products.Design:Knee OA patients were identified from the Optum Clinformatics dataset (January 2006 to June 2016), stratified into hylan G-F 20 and non-hylan G-F 20 HA users, matched by single or multiple injection products. Occurrences of surrogate SALR measures including inflammation/infection, intraarticular corticosteroid (CS) injections, arthrocentesis/aspiration, arthrotomy/incision and drainage, and arthroscopy were evaluated within 3 days post-HA.Results:Based on 694,404 HA injections, inflammation/infection rate was rare within 3 days of HA (up to 0.03%), with no statistical differences between hylan G-F 20 and non-hylan G-F 20 groups (matched by single or multiple injection products). The risk of knee arthrotomy/incision and drainage, arthroscopy, or arthrocentesis for hylan G-F 20 (2 mL) 3 weekly injection patients was lower than Hyalgan/Supartz and Orthovisc patients, but greater than Euflexxa patients. Overall, we found that Hylan G-F 20 (2 mL) 3 weekly injection had lower SALR rates compared to Hyalgan/Supartz and Orthovisc. However, Hylan G-F 20 (2 mL) 3 weekly injection had slightly higher rates of SALR when compared to Euflexxa. Among the single injection products, Hylan G-F 20 (6 mL) single injection had lower rates of SALR than Monovisc and Gel-One.Conclusions:This study shows no clear correlation between avian-derived or cross-linked products and SALR and provides evidence against avian-derived products or crosslinking as a source for these reactions.

Safety and pharmacokinetics of EP-104IAR (sustained-release fluticasone propionate) in knee osteoarthritis: A randomized, double-blind, placebo-controlled phase 1 trial

ObjectiveEP-104IAR is a novel, sustained-release, intra-articular (IA) formulation of the corticosteroid fluticasone propionate (FP), in development for the treatment of osteoarthritis (OA) pain. This study evaluated the safety, pharmacokinetics (PK) and efficacy of a single dose of EP-104IAR in patients with OA of the knee. DesignThis was a multi-center, randomized, double-blind, placebo-controlled trial performed at 3 sites in Canada. Subjects with moderate to severe pain received either a single dose of the investigational product EP-104IAR (15 ​mg) or placebo (vehicle) and were evaluated for up to 42 weeks. The primary outcome measures were safety and PK. The study was not powered to assess efficacy, however patient reported outcome measures were analyzed to evaluate pain and symptom relief. ResultsThirty-two subjects were randomized (21 women, 11 men, mean age: 64.8 years). EP-104IAR was well tolerated. Average serum cortisol levels showed no clinically significant deviations compared to placebo and remained within the normal range of cortisol variation. Plasma PK concentrations were within acceptable safety margins, compared to marketed FP products. Synovial fluid FP levels were approximately 2 orders of magnitude higher and at efficacious concentrations for most subjects. Efficacy evaluations indicated that EP-104IAR provided an immediate improvement of OA symptoms and these effects persisted for 8–12 weeks consistently across all measures. ConclusionsThis study provides evidence that 15 ​mg of EP-104IAR is well tolerated and has the potential for efficacy in OA patients. These data support further examination of EP-104IAR in larger clinical studies.

Relative Efficacy of Intra-articular Injections in the Treatment of Knee Osteoarthritis: A Systematic Review and Network Meta-analysis

Background: In younger patients and those without severe degenerative changes, the efficacy of intra-articular (IA) injections as a nonoperative modality for treating symptomatic knee osteoarthritis (OA)–related pain while maintaining function has become a subject of increasing interest. Purpose: To assess and compare the efficacy of different IA injections used for the treatment of knee OA, including hyaluronic acid (HA), corticosteroids (CS), platelet-rich plasma (PRP), and plasma rich in growth factors (PRGF), with a minimum 6-month patient follow-up. Study Design: Meta-analysis of randomized controlled trials; Level of evidence, 1. Methods: A systematic review was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines using the following databases: PubMed/MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Google Scholar. Mean or mean change from baseline and standard deviation for outcome scores regarding pain and function were recorded at the 6-month follow-up and converted to either a 0 to 100 visual analog scale score for pain or a 0 to 100 Western Ontario and McMaster Universities Osteoarthritis Index score for function. A frequentist network meta-analysis model was developed to compare the effects of HA, CS, PRP, PRGF, and placebo on patient-reported outcomes. Results: All IA treatments except CS were found to result in a statistically significant improvement in outcomes when compared with placebo. PRP demonstrated a clinically meaningful difference in function-related improvement when compared with CS and placebo due to large effect sizes. Studies evaluating outcomes of PRGF reported significant improvement when compared with placebo due to large effect sizes, whereas a potential clinically significant difference was detected in the same comparison parameters in pain evaluation. With regard to improvements in pain, function, and both combined, PRP was found to possess the highest probability of efficacy, followed by PRGF, HA, CS, and placebo. Conclusion: PRP yielded improved outcomes when compared with PRGF, HA, CS, and placebo for the treatment of symptomatic knee OA at a minimum 6-month follow-up. Further investigations evaluating different IA and other nonoperative treatment options for patients with knee OA are warranted to better understand the true clinical efficacy and long-term outcomes of nonsurgical OA management.

Efficacy and Systemic Absorption of Peri-articular Versus Intra-articular Administration of Tranexamic Acid in Total Knee Arthroplasty: A Prospective Randomized Controlled Trial.

BackgroundTranexamic acid (TXA) is widely accepted as an effective method for reducing blood loss after total knee arthroplasty (TKA). As different routes of local TXA administration have been proposed to minimize systemic complications, we aimed to investigate the effectiveness and systemic absorption of peri-articular (PA) and intra-articular (IA) administration of TXA after primary TKA.MethodsIn a randomized controlled trial of patients scheduled for unilateral primary TKA, 108 were assigned to receive PA-TXA (15 mg/kg), IA-TXA (2 g), or no TXA injection. We assessed total blood loss, blood transfusion rate, and hemoglobin level changes 48 hours after surgery. Postoperative serum TXA levels, complications, and clinical symptoms of venous thromboembolism events were also evaluated.ResultsTotal blood loss, hemoglobin level decreases, and blood transfusion rates in both TXA groups were significantly lower than those in the control group (P < .05), without significant differences between PA and IA groups 48 hours after surgery. Serum TXA levels in the IA group were significantly higher than those in the PA cohort at 2 hours (28.2 mg/L vs 15.6 mg/L, P < .01) and 24 hours (4.4 mg/L vs 1.7 mg/L, P < .01) postoperatively. No wound complications were found in both TXA groups, but 14% of the control group developed subcutaneous ecchymoses. No evidence of venous thromboembolism events was reported.ConclusionsPA-TXA is an excellent alternative route of local TXA injection to decrease postoperative blood loss after TKA. PA-TXA demonstrated lower levels of postoperative serum TXA, which may be beneficial for high-risk patients.

Safety and Systemic Exposure of Triamcinolone Acetonide Following Ultrasound-Guided Intra-Articular Injection of Triamcinolone Extended-Release or Standard Triamcinolone Acetonide in Patients with Shoulder Osteoarthritis: An Open-Label, Randomized Study.

Background and ObjectivesOsteoarthritis (OA) is a major public health burden. While knee and hip joints are most commonly affected, the glenohumoral (shoulder) joint is also frequently involved. We evaluated the pharmacokinetics and safety/tolerability of triamcinolone acetonide extended-release (TA-ER) and triamcinolone acetonide crystalline suspension (TAcs) in patients with shoulder OA.MethodsIn this phase 2, randomized, open-label, single-dose study (NCT03382262), adults with moderately-to-severely symptomatic shoulder OA for ≥ 6 months randomly received a single ultrasound-guided intra-articular (IA) injection of TA-ER 32 mg or TAcs 40 mg. Safety was evaluated throughout 12 weeks post-injection; blood samples for pharmacokinetic evaluations were collected pre-injection and through Day 85 post-injection.ResultsAmong 25 randomized patients, 12 received TA-ER and 13 received TAcs. Most patients were female (60%), and all had moderate (72%) or severe (28%) shoulder OA. Adverse events (AEs) were reported by four (33%) patients following TA-ER and three (23%) following TAcs injection. No AE was serious or led to study discontinuation. Systemic exposure following TAcs was approximately 1.5-fold higher than that following TA-ER injection (geometric mean [GM] AUC0–last 873,543 vs 557,602 h × pg/mL). GM Cmax was also higher in TAcs- than TA-ER-treated patients (2034 vs 1283 pg/mL). Bioequivalence testing confirmed lower systemic TA exposure following TA-ER than TAcs IA injection.ConclusionThese pharmacokinetic data confirm protracted release of TA from TA-ER following IA injection in patients with shoulder OA. Lower peak and systemic TA exposure following TA-ER suggests TA-ER could potentially confer an improved systemic safety profile over TAcs.Trial Registration NumberNCT03382262 (December 22, 2017 retrospectively registered).

Intra-articular injection in the hind limb joints of dromedary camels (Camelus dromedarius) using anatomical and arthrographic-guided landmarks.

Background and Aim:A healthy joint is an important structure for the proper movement of the camel limb. Intra-articular (IA) injection is frequently used in veterinary practice for diagnostic and therapeutic purposes of joint injuries. Thus, the current study aimed to describe the injection of the hindlimb joints in dromedary camels based on the anatomical and arthrographic-guided landmarks.Materials and Methods:Eighteen orthopedically sound adult camels (mean±standard deviation age: 78±12 months) of both sexes were included in this study. Three camels were euthanized to identify anatomical features in the hindlimb joints and related structures. IA injections were performed in the hindlimbs of 5 camel cadavers to evaluate the optimal IA injection site, which was confirmed by arthrography. The optimized IA injection technique was applied in 10 live camels and confirmed by arthrocentesis and arthrography. For each joint, injection criteria (number of attempts, difficulty of injection, and successful injection) were assessed, scored, and statistically compared to the other joints.Results:The summation of IA injection criteria scores was significantly higher (p<0.05) in the femorotibial, femoropatellar, tibiotarsal, fetlock, pastern, and coffin joints in comparison to the hip joint.Conclusion:Anatomical and arthrographic-guided techniques offer considerable advantages for the characterization of anatomical landmarks and selection of the appropriate IA injection site in the hindlimb in dromedary camels. Furthermore, a reference approach for camels was established that is different from the approach for cattle and horses.

Comparison between Intra-Articular Injection of Infrapatellar Fat Pad (IPFP) Cell Concentrates and IPFP-Mesenchymal Stem Cells (MSCs) for Cartilage Defect Repair of the Knee Joint in Rabbits.

Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic method in regenerative medicine. Our previous research adopted a simple nonenzymatic strategy for the preparation of a new type of ready-to-use infrapatellar fat pad (IPFP) cell concentrates. The aim of this study was to compare the therapeutic efficacy of intra-articular (IA) injection of autologous IPFP cell concentrates and allogeneic IPFP-MSCs obtained from these concentrates in a rabbit articular cartilage defect model. IPFP-MSCs sprouting from the IPFP cell concentrates were characterized via flow cytometry as well as based on their potential for differentiation into adipocytes, osteoblasts, and chondrocytes. In the rabbit model, cartilage defects were created on the trochlear groove, followed by treatment with IPFP cell concentrates, IPFP-MSCs, or normal saline IA injection. Distal femur samples were evaluated at 6 and 12 weeks posttreatment via macroscopic observation and histological assessment based on the International Cartilage Repair Society (ICRS) macroscopic scoring system as well as the ICRS visual histological assessment scale. The macroscopic score and histological score were significantly higher in the IPFP-MSC group compared to the IPFP cell concentrate group at 12 weeks. Further, both treatment groups had higher scores compared to the normal saline group. In comparison to the latter, the groups treated with IPFP-MSCs and IPFP cell concentrates showed considerably better cartilage regeneration. Overall, IPFP-MSCs represent an effective therapeutic strategy for stimulating articular cartilage regeneration. Further, due to the simple, cost-effective, nonenzymatic, and safe preparation process, IPFP cell concentrates may represent an effective alternative to stem cell-based therapy in the clinic.

Mechanisms and Pharmaceutical Action of Lipid Nanoformulation of Natural Bioactive Compounds as Efficient Delivery Systems in the Therapy of Osteoarthritis.

Osteoarthritis (OA) is a degenerative joint disease. An objective of the nanomedicine and drug delivery systems field is to design suitable pharmaceutical nanocarriers with controllable properties for drug delivery and site-specific targeting, in order to achieve greater efficacy and minimal toxicity, compared to the conventional drugs. The aim of this review is to present recent data on natural bioactive compounds with anti-inflammatory properties and efficacy in the treatment of OA, their formulation in lipid nanostructured carriers, mainly liposomes, as controlled release systems and the possibility to be intra-articularly (IA) administered. The literature regarding glycosaminoglycans, proteins, polyphenols and their ability to modify the cell response and mechanisms of action in different models of inflammation are reviewed. The advantages and limits of using lipid nanoformulations as drug delivery systems in OA treatment and the suitable route of administration are also discussed. Liposomes containing glycosaminoglycans presented good biocompatibility, lack of immune system activation, targeted delivery of bioactive compounds to the site of action, protection and efficiency of the encapsulated material, and prolonged duration of action, being highly recommended as controlled delivery systems in OA therapy through IA administration. Lipid nanoformulations of polyphenols were tested both in vivo and in vitro models that mimic OA conditions after IA or other routes of administration, recommending their clinical application.

Treatment response in dogs with naturally occurring grade 3 elbow osteoarthritis following intra-articular injection of 117mSn (tin) colloid

The radionuclide 117mSn (tin-117m) embedded in a homogeneous colloid is a novel radiosynoviorthesis (RSO) device for intra-articular (IA) administration to treat synovial inflammation and mitigate osteoarthritis (OA) in dogs. A study to evaluate tin-117m colloid treatment response in dogs with OA was conducted at two centers, the School of Veterinary Medicine at Louisiana State University, and at a referral practice in Houston, Texas. The tin-117m colloid was administered per-protocol to 14 client-owned dogs with radiographically confirmed, grade 3 OA in one or both elbow joints. Dog owners and attending clinicians assessed the level of pain at baseline (BL) and the post-treatment pain response at 90-day intervals for one year. Owners assessed treatment response according to a pain severity score (PSS) and a pain interference score (PIS) as defined by the Canine Brief Pain Inventory. Clinicians reported a lameness score using a 0-5 scale, from no lameness to continuous non-weight bearing lameness, when observing dogs at a walk and a trot. The rate of treatment success as determined by improved mean PSS and PIS scores reported by dog owners was >70% at all time points. Clinicians reported an improved mean pain score from BL at post-treatment Days 90 (p<0.05), 180, and 270. The dog owner and clinician assessments of treatment success were significantly correlated (p>0.05) at Day 90 and Day 180 time points. Results indicated that a single IA dose of tin-117m colloid provided a significant reduction in pain and lameness and improved functionality for up to a full year, with no adverse treatment related effects, in a high percentage of dogs with advanced, clinical OA of the elbow joint.

Accuracy of the Fonseca Anamnestic Index for identifying pain-related and/or intra-articular Temporomandibular Disorders

ABSTRACT Objectives: This study established the diagnostic accuracy of the Fonseca Anamnestic Index (FAI) in relation to the Diagnostic Criteria for TMD (DC/TMD) standard.Methods: A total of 866 TMD patients and 57 TMD-free controls were instructed to answer the FAI and DC/TMD Symptom Questionnaire (SQ). Participants were subsequently categorized into no (NT), pain-related (PT), and/or intra-articular (IT) TMDs using the DC/TMD protocolized examination/algorithms. Receiver operating characteristics (ROC) curves, best cut-off points, and accuracy measures were determined.Results:The FAI demonstrated high accuracy for detecting all TMDs, PT, and IT (AUC = 0.96–0.98). The best cut-off points were 22.50 for all TMDs/IT and 27.50 for PT. Sensitivity of the FAI was high (94.23–98.21%), but specificity was moderate (87.72%) for all diagnostic categories.Discussion:The diagnostic accuracy of the FAI for identifying pain-related and intra-articular TMDs was high. FAI scores ≥25 points should be used to screen for TMDs.

Accuracy and Feasibility of Ultrasound-Guided Intra-articular Injection of the Rat Hip Joint

Intra-articular injection is frequently used as an effective diagnostic and treatment tool for hip joint diseases. However, the underlying treatment mechanism remains unclear because of a lack of experimental animal models. A challenge facing researchers is how to accurately and consistently perform injections involving animal hip joints. The purpose of this study, then, was to establish an ultrasound (US)-guided intra-articular (IA) injection technique using rat hip joints and to evaluate its accuracy and feasibility versus a fluoroscopy (FL)-guided technique. For this study, 20 US-guided and 20 FL-guided IA injections were administered to separate groups of Sprague-Dawley rats. For each procedure, 50 μL of iohexol was injected into the hip joint using a 25G needle. The US-guided injections were performed using a linear probe, and the FL-guided IA injections were performed using C-arm X-ray fluoroscopy. All injections were verified by computed tomography imaging. The number of successful injections and needle repositions per injection, as well as operating times, were recorded, and the rats were observed for complications for 10 d after the injections. Statistical analysis was used to compare US-guided and FL-guided techniques with significance set at p < 0.05. The success rate was markedly higher for the US-guided interventions (90%) than for the FL-guided interventions (75%) (p<0.05). The intervention time was shorter in the US-guided group (95.95 ± 8.376 s) than in the FL-guided group (110.70 ± 20.236 s) (p < 0.05), and the median number of needles repositioned per injection in the US-guided group (1.20 ± 0.41) was notably less than that in the FL-guided group (1.60 ± 0.68) (p < 0.05). A puncture site hematoma was noted in two rat hips (10%) the day after injection in the FL-guided group. Overall, the study indicated that ultrasound-guided intra-articular injection of the hip is a feasible, accurate and safe method for use in rats. This makes it a promising tool for diagnosing coxofemoral pain, producing hip osteoarthritis animal models and administering intra-articular medication.

Cartilage-targeting poly(ethylene glycol) (PEG)-formononetin (FMN) nanodrug for the treatment of osteoarthritis

Intra-articular (IA) injection is an efficient treatment for osteoarthritis, which will minimize systemic side effects. However, the joint experiences rapid clearance of therapeutics after intra-articular injection. Delivering system modified through active targeting strategies to facilitate localization within specific joint tissues such as cartilage is hopeful to increase the therapeutic effects. In this study, we designed a nanoscaled amphiphilic and cartilage-targeting polymer-drug delivery system by using formononetin (FMN)-poly(ethylene glycol) (PEG) (denoted as PCFMN), which was prepared by PEGylation of FMN followed by coupling with cartilage-targeting peptide (CollBP). Our results showed that PCFMN was approximately regular spherical with an average diameter about 218 nm. The in vitro test using IL-1β stimulated chondrocytes indicated that PCFMN was biocompatible and upregulated anabolic genes while simultaneously downregulated catabolic genes of the articular cartilage. The therapeutic effects in vivo indicated that PCFMN could effectively attenuate the progression of OA as evidenced by immunohistochemical staining and histological analysis. In addition, PCFMN showed higher intention time in joints and better anti-inflammatory effects than FMN, indicating the efficacy of cartilage targeting nanodrug on OA. This study may provide a reference for clinical OA therapy.