Liposome-based nanocolloids for restoring lubrication and targeted therapy in osteoarthritis.

Hyaluronans in the treatment of osteoarthritis of the knee: evidence for disease-modifying activity

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.

Objective: Osteoarthritis (OA) is a chronic degenerative musculoskeletal disease and one of the leading causes of chronic musculoskeletal pain, often affecting the knee. Despite intra-articular (IA) injectable hyaluronan (HA) preparations are widely used in the treatment of this debilitating condition, only a few data about their efficacy have been reported so far. Therefore, the use of HA in OA management is not universally recommend in clinical practice. Oxygen-ozone (O2O3) therapy can be employed in several pain-related conditions and diseases. However, both its efficacy and safety for IA therapy in knee OA have never been explored. Here, we evaluated the reliability of knee IA therapy with O2O3 compared to IA HA in chronic knee OA. Methods: A total of 42 consecutive chronic OA patients with radiological diagnosis of knee OA were prospectively enrolled in this single-blind, controlled study. After randomization, all patients underwent IA therapy with O2O3 or HA (q1wk) for 4 weeks, with additional 4 weeks of follow-up. Examination of the adverse events occurred during the whole study was performed. To measure knee function and pain, visual analogue scale (VAS), Oxford knee questionnaire (OKQ), and 12-item short form survey (SF-12) were administered. EuroQol five dimensions questionnaire (EQ-5D) was used to assess patients’ quality of life. Results: No significant difference in adverse events occurrence was observed. Knee IA treatment with O2O3 showed shorter reduction of pain compared to IA HA. VAS score decreased in both groups during the treatment period (p<0.001), while OKQ score significantly increased (p<0.001). SF-12 and EQ-5D scores were comparable between the two groups of patients. Conclusions: Despite IA administration of O2O3 and hyaluronan are comparable treatments in knee OA both in terms of safety and quality of life improvement, the latter shows longer times of pain reduction.

Viscosupplementation in the treatment of osteoarthritis

ConspectusIn the course of evolution, nature has achieved remarkably lubricated surfaces, with healthy articular cartilage in the major (synovial) joints being the prime example, that can last a lifetime as they slide past each other with ultralow friction (friction coefficient μ = the force to slide surfaces past each other/load compressing the surfaces < 0.01) under physiological pressures (up to 10 MPa or more)). Such properties are unmatched by any man-made materials. The precise mechanism of low friction between such sliding cartilage tissues, which is closely related to osteoarthritis (OA), the most widespread joint disease, affecting hundreds of millions worldwide, has been studied for nearly a century, but is still not fully understood. Traditionally, the roles of load bearing by interstitial fluid within the cartilage bulk and that of thin exuded fluid films at the interface between the sliding cartilage surfaces have been proposed as the main lubrication mechanism. More recent work, however, suggests that molecular boundary layers at the surfaces of articular cartilage and other tissues play a major role in their lubrication. In particular, in recent years hydration lubrication has emerged as a new paradigm for boundary lubrication in aqueous media based on subnanometer hydration shells which massively reduce frictional dissipation. The vectors of hydration lubrication include trapped hydrated ions, hydrated surfactants, biological macromolecules, biomimetic polymers, polyelectrolytes and polyzwitterionic brushes, and close-packed layers of phosphatidylcholine (PC) vesicles, all having in common the exposure of highly hydrated groups at the slip plane. Among them, vesicles (or bilayers) of PC lipids, which are the most widespread lipid class in mammals, are exceptionally efficient lubricating elements as a result of the high hydration of the phosphocholine headgroups they expose. Such lipids are ubiquitous in joints, leading to the proposal that macromolecular surface complexes exposing PC bilayers are responsible for the remarkable lubrication of cartilage. Cartilage, comprising ∼70% water, may be considered to be a complex biological hydrogel, and studying the frictional properties of hydrogels may thus provide new insights into its lubrication mechanisms, leading in turn to novel, highly lubricious hydrogels that may be used in a variety of biomedical and other applications. A better understanding of cartilage lubrication could moreover lead to better treatments for OA, for example, through intra-articular injections of appropriate lubricants or through the creation of low-friction hydrogels that may be used as tissue engineering scaffolds for diseased cartilage.In this Account, we begin by introducing the concept and origin of hydration lubrication, extending from the seminal study of lubrication by hydrated simple ions to more complex systems. We then briefly review different modes of lubrication in synovial joints, focusing primarily on boundary lubrication. We consider modes of hydrogel lubrication and different kinds of such low-friction synthetic gels and then focus on cartilage-inspired, boundary-lubricated hydrogels. We conclude by discussing challenges and opportunities.

Intra-articular (IA) glucocorticoid injection is widely used in patients with knee osteoarthritis (OA), but the safety of this technique is in question among physicians. Intramuscular (IM) glucocorticoid injection could be an alternative approach. To investigate whether an IM glucocorticoid injection is noninferior to an IA glucocorticoid injection in reducing knee pain for patients with knee OA in primary care. The KIS trial, a multicenter, open-label, randomized clinical noninferiority trial including patients with symptomatic knee OA, was conducted in 80 primary care general practices in the southwest of the Netherlands. The study was conducted from March 1, 2018, to July 28, 2020. Patients were randomly allocated to receive an injection of triamcinolone acetonide, 40 mg, either IM in the ipsilateral ventrogluteal region or IA in the knee joint. All patients were followed up for 24 weeks. The pain score at 4 weeks measured with Knee Injury and Osteoarthritis Outcome Score (range, 0-100; 0 indicates extreme pain), with a noninferiority margin of -7 (IM minus IA). A per-protocol analysis was prespecified as the primary analysis. A total of 145 patients (94 women [65%]; mean [SD] age, 67 [10] years) were included; of these, 138 patients (IM, 72; IA, 66) were included in the per-protocol analysis. Clinically relevant improvements in knee pain were reached up to 12 weeks after the injection in both groups. At 4 weeks, the estimated mean difference in the Knee Injury and Osteoarthritis Outcome Score between the 2 groups was -3.4 (95% CI, -10.1 to 3.3). Noninferiority could not be declared because the lower limit exceeded the noninferiority margin. Intramuscular injection was noninferior to IA injection at 8 (mean difference, 0.7; 95% CI, -6.5 to 7.8) and 24 (mean difference, 1.6; 95% CI, -5.7 to 9.0) weeks. No significant difference was found among all the secondary outcomes. These results were similar for the sensitivity analysis in an intention-to-treat population. The most frequently reported adverse events were hot flush (IM, 7 [10%] vs IA, 14 [21%]) and headache (IM, 10 [14%] vs IA, 12 [18%]), and all events were classified as nonserious. Based on the findings of this trial, among patients with knee OA in primary care, IM glucocorticoid injection could present an inferior effect in reducing pain at 4 weeks compared with IA injection. Noninferiority of an IM injection was observed at 8 and 24 weeks after injection. This trial provides data for shared decision-making, taking into account the advantages and disadvantages of both types of injections. Dutch Trial Registry: NTR6968.

Autologous Interleukin 1 Receptor Antagonist Blood-Derived Products for Knee Osteoarthritis: A Systematic Review

ABSTRACTIntroduction: The lack of a complete understanding of the complex processes involved in the etiopathogenesis and subsequent appropriate phenotyping makes it difficult to find therapies that may be efficacious in most patients with osteoarthritis (OA). Consensus recommendations involve mainly non-pharmacological approaches. Analgesics and NSAIDs are considered second choice options due to their poor efficacy/safety ratios. To some extent, OA may be considered an orphan disease. Therefore, there is an urgent need to identify effective and safe new pharmacologic modalities for treating OA.Areas covered: This review is based on a Medline comprehensive literature search for published articles evaluating new formulations of current drugs and promising emerging therapies in OA. We discuss the current status of novel systemic agents in development including potent analgesic options, inhibitors of innate immunity, inducible nitric oxide synthase (iNOS), pro-inflammatory cytokines and cartilage proteases as well as bone agents. Furthermore, we also revise the potential benefit of intraarticular (IA) therapy with hyaluronic acid (HA), pro-inflammatory mediator blockers, cartilage anabolic agents, mesenchymal stem cell and gene transfer.Expert opinion: Despite the renewed interest in the search of new compounds for treatment of OA, results have been limited. Novel systemic and IA administered agents are in active development. IA drug administration is particularly an attractive approach because can diminish some of the severe side effects associated with systemic drugs. Indeed, one of the most promising fields for pharmacology innovation in OA is joint injected therapy, as suggested by preliminary data from recent studies using IA sprifermin (rhFGF-18), mesenchymal stem cells or TGF-B1 transduced allogenic chondrocytes. Last, the effort to develop new drugs must be accompanied by the interest for establishing well-defined phenotypes, and only then, a more tailored therapy should be practiced in OA.

Role of intra-articular hyaluronic acid preparations in medical management of osteoarthritis of the knee

High drug loading hydrophobic cross-linked dextran microspheres as novel drug delivery systems for the treatment of osteoarthritis

THU0462 Intra-Articular Delivery of Kartogenin-Conjugated Chitosan Nano/Microparticles for Cartilage Regeneration

PMS75 PATIENT- AND PHYSICIAN-IDENTIFIED FACTORS GUIDING TREATMENT CHOICE IN KNEE OSTEOARTHRITIS AND PATIENT PREFERENCE FOR INTRA-ARTICULAR THERAPY

Medical ozone is a molecule composed of three oxygen atoms with anti-inflammatory, analgesic, and antioxidant functions. Ozone therapy (O 3 or O 2 - O 3 ) for knee osteoarthritis has gradually received increasing attention from researchers in recent years. Here, we discuss the research hotspots and development trends of ozone therapy for knee osteoarthritis through literature visualization and analysis. (1) From 2012 to the present, the overall trend of publications on ozone treatment for knee osteoarthritis has been increasing annually, and it has received widespread attention, especially in Iran and China. (2) Keyword analysis revealed that the keywords with the greatest number of citations for ozone treatment of knee osteoarthritis are "osteoarthritis," "ozone," "knee osteoarthritis," "ozone therapy," and "hyaluronic acid." (3) The results of the cocitation analysis revealed that the themes of the cocited literature are concentrated in 11 directions: intra-articular injections, intra-articular oxygen ozone, treatment of knee osteoarthritis, rehabilitation studies, time effects, pain function, comprehensive review, growth factors, rheumatic diseases, ultrasound-guided corticosteroid injections, and placebo. (4) The hotspots of the available highly cited literature have focused mainly on the efficacy and safety of ozone or growth factors alone in the treatment of knee osteoarthritis. Most of the literature suggests that intra-articular injections are the most common form of ozone therapy, and the accuracy and safety of ozone injections can be ensured using ultrasound-guided techniques. Ozone therapy has a positive short-term effect on pain control and functional recovery within 6 months after injection, but how to maintain the long-term efficacy of ozone therapy has rarely been described. It is hypothesized that the combination of ozone and growth factors may be beneficial for prolonging the efficacy of ozone therapy. (5) Ozone therapy has no advantages over other therapies in terms of therapeutic efficacy. Compared with ozone therapy, platelet-rich plasma and growth factor-rich plasma have better long-term outcomes in the treatment of knee osteoarthritis, whereas stromal vascular components have the best effects on pain relief and functional improvement. Few studies address the combination of ozone and growth factors for the treatment of knee osteoarthritis, and a few clinical studies registered have explored other treatments (e.g., corticosteroids). (6) Future studies could further explore the specific mechanisms and optimal dosing regimens of ozone combined with different growth factors in the treatment of knee osteoarthritis to compensate for the short-term efficacy of ozone therapy and to validate the long-term efficacy and safety of this combination therapy. It is also imperative to develop international guidelines for ozone therapy for osteoarthritis of the knee as soon as possible.

Surface-attached layers of phosphatidylcholine (PC) lipid vesicles (liposomes) may reduce the friction coefficient μ (= force-to-slide/load) between the sliding surfaces down to μ ≈ 10−3–10−4 up to tens of atm contact pressures, as high as those in the major joints (hips or knees). Such friction reduction is attributed to hydration lubrication by the highly-hydrated phosphocholine head-groups exposed at the outer vesicle surfaces. It has been suggested therefore that intra-articular (IA) administration of liposomes as potential boundary lubricants may alleviate degenerative, friction-associated joint conditions such as osteoarthritis (OA), which is associated with insufficient lubrication at the articular cartilage surface. To overcome the problem, common to all nanoparticles, of rapid removal by the mononuclear phagocyte system, as well as to ensure long-term colloidal stability during storage, functionalizing liposomes with poly(ethylene glycol) moieties, PEGylation, is often used. Here we describe a different liposome functionalization approach, using poly(2-methacryloyloxyethyl phosphorylcholine), PMPC, moieties (strictly, lipid–PMPC conjugates), and compare the retention time in mice joints of such PMPCylated liposomes with otherwise-identical but PEGylated vesicles following IA administration. We find, using fluorescence labeling and in vivo optical imaging, that when PMPC-stabilized liposomes are injected into mice knee joints, there is a massive increase of the vesicles’ retention half-life in the joints of about (4–5)-fold (ca. 300–400% increase in retention time) compared with the PEGylated liposomes (and some 100-fold longer than the retention time of intra-articularly injected hyaluronan or HA). Such PMPCylated liposomes are therefore promising candidates as potential long-lived boundary lubricants at the articular cartilage surface, with implication for friction-associated pathologies. Moreover, as lipid vesicles are well known to be efficient drug carriers, such long retention in the joints may enable analgesic or anti-inflammatory agents for joint pathologies to be more efficiently delivered via IA administration using PMPCylated liposomal vehicles relative to PEGylated ones.

Intra-articular oxygen-ozone therapy in knee osteoarthritis: Results of a 31-week randomized, single-blind study versus intra-articular hyaluronic acid