Intra-articular Drug Delivery Research Articles

Resveratrol nanocrystals based dissolving microneedles with highly efficient for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a common immune disease characterized mainly by erosive arthritis with extensive clinical sequelae. Resveratrol (Res) has pharmacological effects in the treatment of RA, but it has not been widely used in the clinic due to its poor water solubility and low bioavailability. In this study, a drug delivery system (Res-NC MNs) of dissolved microneedles (MNs) loaded with Res nanocrystals (NC) was designed for the treatment of RA. Res-NC MNs can improve the drawbacks of long-term oral drug delivery with toxic side effects and low compliance associated with intra-articular drug delivery. In this study, Res-NC was prepared by media milling and loaded into soluble microneedles prepared from hyaluronic acid (HA) by vacuum casting for the treatment of RA. HA has high mechanical strength and can penetrate the cuticle layer of the skin for effective drug delivery. In in vivo pharmacodynamic experiments, Res-NC MNs achieved better therapeutic efficacy in the treatment of RA compared with oral Res. These findings suggest that Res-NC MNs may be an effective and promising drug delivery strategy for the treatment of RA.

Recent advances in polymeric microparticle-based drug delivery systems for knee osteoarthritis treatment.

Due to the poor bioavailability and high joint clearance of drugs, sustained delivery of therapeutic agents has proven difficult in the treatment of osteoarthritis (OA). Intra-articular (IA) drug delivery strategy is an attractive option for enhancing OA patients' prognosis, for which various polymer materials have been used as drug carriers due to their attractive delivery properties, to slow or even reverse the progress of OA by prolonging the duration of therapeutic agent residence in the joint. This article focuses on the recent developments in natural and synthetic polymer-based microsphere drug delivery systems for treating knee osteoarthritis. It evaluates the translational potential of some novel formulations for clinical application.

Surface modified cationic PLGA microparticles as long-acting injectable carriers for intra-articular small molecule drug delivery

Controlled local delivery of therapeutics (small molecule drug crystals or biologics) for knee-associated diseases such as osteoarthritis necessitates patient compliance, ensuring that the injected depot does not trigger local tissue inflammation and immune responses. A local drug delivery strategy that releases drug at a controlled rate while ensuring minimal tolerability issues at the injection site would be an appealing paradigm in intra-articular (IA) therapies. Herein, we report the formulation development and characterization of surface modified PLGA microparticles (MPs) through the surface integration of a cationic lipid, DOTAP (1,2-Dioleoyl-3-trimethylammonium propane). Following IA administration, these particles are able to interact with anionic synovial fluid glycosaminoglycans (GAGs) to form an in-situ surface coating in the knee joint, thereby reducing the depot-associated local inflammatory response. The formulated microparticles were about 10–40 µm in size range, with a +19 to +33 mV overall surface charge after DOTAP lipid surface integration. These particles showed preferential surface adhesion with endogenous anionic GAGs (e.g., hyaluronic acid) due to electrostatic interactions in vitro, and approximately 65 % of the model drug triamcinolone acetonide (TCA) was released after 10 weeks in simulated synovial fluid. The uncoated and DOTAP-coated PLGA microparticles had no effect on mouse osteoblast MC3T3 cell viability and human macrophage inflammatory response. Further, DOTAP-coated particles showed a marginal decrease in pro-inflammatory cytokines in naïve rats following knee injection. Together, the results suggest that surface-modified PLGA particles may have promising potential as delivery carriers for long-acting injectables.

Advancing drug delivery to articular cartilage: From single to multiple strategies.

Articular cartilage (AC) injuries often lead to cartilage degeneration and may ultimately result in osteoarthritis (OA) due to the limited self-repair ability. To date, numerous intra-articular delivery systems carrying various therapeutic agents have been developed to improve therapeutic localization and retention, optimize controlled drug release profiles and target different pathological processes. Due to the complex and multifactorial characteristics of cartilage injury pathology and heterogeneity of the cartilage structure deposited within a dense matrix, delivery systems loaded with a single therapeutic agent are hindered from reaching multiple targets in a spatiotemporal matched manner and thus fail to mimic the natural processes of biosynthesis, compromising the goal of full cartilage regeneration. Emerging evidence highlights the importance of sequential delivery strategies targeting multiple pathological processes. In this review, we first summarize the current status and progress achieved in single-drug delivery strategies for the treatment of AC diseases. Subsequently, we focus mainly on advances in multiple drug delivery applications, including sequential release formulations targeting various pathological processes, synergistic targeting of the same pathological process, the spatial distribution in multiple tissues, and heterogeneous regeneration. We hope that this review will inspire the rational design of intra-articular drug delivery systems (DDSs) in the future.

Hydrogel for the Treatment of Osteoarthritis

Worldwide, the prevalence of osteoarthritis has grown significantly in recent years, and the rate of growth is accelerating. In recent years, the number of people with osteoarthritis has increased rapidly worldwide, and the rate of increase is on the rise. The development of osteoarthritis at an advanced stage can cause significant physical and psychological damage to patients. This article will introduce the application of natural and synthetic hydrogels in the field of osteoarthritis treatment. Natural hydrogels such as gelatin, alginate and polysaccharide have good biocompatibility and biodegradability and can be used for intra-articular drug delivery after modification. Synthetic hydrogels such as polyvinyl alcohol, polyethylene glycol and poly (lactic acid-hydroxyacetic acid) copolymer have good mechanical properties and can be used for intra-articular drug delivery and joint lubricants. In this article describes the application of hydrogels to carry a range of drugs and cell growth factors for the treatment of osteoarthritis, to act as scaffolds for cell growth, to lubricate joint cavities, and to reduce loads on joints, as well as several hydrogel modification methods to give them better biological or mechanical properties.

Near-Infrared Light-Activated Mesoporous Polydopamine for Temporomandibular Joint Osteoarthritis Combined Photothermal-Chemo Therapy.

The treatments generally employed for temporomandibular joint osteoarthritis (TMJOA) involve physical therapy and chemotherapy, etc., whose therapeutic efficacies are impaired by the side effects and suboptimal stimulus responsiveness. Although the intra-articular drug delivery system (DDS) has shown effectiveness in addressing osteoarthritis, there is currently little reported research regarding the use of stimuli-responsive DDS in managing TMJOA. Herein, we prepared a novel near-infrared (NIR) light-sensitive DDS (DS-TD/MPDA) by using mesoporous polydopamine nanospheres (MPDA) as NIR responders and drug carriers; diclofenac sodium (DS) as the anti-inflammatory medication; and 1-tetradecanol (TD) with a phase-inversion temperature of 39 °C as the drug administrator. Upon exposure to 808 nm NIR laser, DS-TD/MPDA could raise the temperature up to the melting point of TD through photothermal conversion, and intelligently trigger DS release. The resultant nanospheres exhibited an excellent photothermal effect and effectively controlled the release of DS through laser irradiation to accommodate the multifunctional therapeutic effect. More importantly, the biological evaluation of DS-TD/MPDA for TMJOA treatment was also performed for the first time. The experiments' results demonstrated that DS-TD/MPDA displayed a good biocompatibility in vitro and in vivo during metabolism. After injection into the TMJ of rats afflicted with TMJOA induced by unilateral anterior crossbite for 14 days, DS-TD/MPDA could alleviate the deterioration of TMJ cartilage, thus ameliorating osteoarthritis. Therefore, DS-TD/MPDA could be a promising candidate for photothermal-chemotherapy for TMJOA.

Application of magnetic particle imaging to evaluate nanoparticle fate in rodent joints.

Nanoparticles are a promising approach for improving intra-articular drug delivery and tissue targeting. However, techniques to non-invasively track and quantify their concentration in vivo are limited, resulting in an inadequate understanding of their retention, clearance, and biodistribution in the joint. Currently, fluorescence imaging is often used to track nanoparticle fate in animal models; however, this approach has limitations that impede long-term quantitative assessment of nanoparticles over time. The goal of this work was to evaluate an emerging imaging modality, magnetic particle imaging (MPI), for intra-articular tracking of nanoparticles. MPI provides 3D visualization and depth-independent quantification of superparamagnetic iron oxide nanoparticle (SPION) tracers. Here, we developed and characterized a polymer-based magnetic nanoparticle system incorporated with SPION tracers and cartilage targeting properties. MPI was then used to longitudinally assess nanoparticle fate after intra-articular injection. Magnetic nanoparticles were injected into the joints of healthy mice, and evaluated for nanoparticle retention, biodistribution, and clearance over 6weeks using MPI. In parallel, the fate of fluorescently tagged nanoparticles was tracked using in vivo fluorescence imaging. The study was concluded at day 42, and MPI and fluorescence imaging demonstrated different profiles in nanoparticle retention and clearance from the joint. MPI signal was persistent over the study duration, suggesting NP retention of at least 42days, much longer than the 14days observed based on fluorescence signal. These data suggest that the type of tracer - SPIONs or fluorophores - and modality of imaging can affect interpretation of nanoparticle fate in the joint. Given that understanding particle fate over time is paramount for attaining insights about therapeutic profiles in vivo, our data suggest MPI may yield a quantitative and robust method to non-invasively track nanoparticles following intra-articular injection on an extended timeline.

An intra‐articular injectable phospholipids‐based gel for the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory and destructive arthropathy with a high deformity rate. Despite numerous studies and clinical trials, no curative treatment is available for large weight-bearing joints. Intra-articular (IA) injections could deliver high concentrations of drug to the afflicted joint and improve the drug efficacy while reducing systemic toxicity. However, free drugs are rapidly cleared from synovial fluid and do not significantly halt the progression of joint disease. Herein, a phospholipids-based controlled-release gel was prepared for sustained IA delivery of celastrol (CEL) and the therapeutic efficiency was evaluated in a rheumatoid arthritis rabbit model. The CEL-loaded gel (CEL-gel) contained up to 70% phospholipids yet was easy to inject. After injecting into the joint cavity, CEL-gel achieved sol to gel phase transition without special stimuli and gelling agent. In vitro release and in vivo pharmacokinetic studies evidenced the stable and sustained release action of CEL-gel. A single IA injection of CEL-gel could maintain therapeutic efficiency for about 25 d and showed much better anti-arthritic efficacy compared to repeated injections of free drug solution (CEL-sol). Furthermore, the IA injection of CEL-gel greatly reduced the systemic toxicity of CEL. With good biocompatibility and biodegradability, CEL-gel might be a promising IA drug delivery system.

Applications and prospects of intra-articular drug delivery system in arthritis therapeutics.

Arthritis is a kind of chronic disease that affects joints and muscles with the symptoms of joint pain, inflammation and limited movement of joints. Among various clinical therapies, drug therapy has been extensively applied because of its accessibility, safety and effectiveness. In recent years, the intra-articular injection has dramatic therapeutic effects in treating arthritis with high patient compliance and low side effects. In this review, we will introduce pathology of arthritis, along with the accessible treatment and diagnosis methods, then we will summarize major advances of current hopeful intra-articular delivery systems such as microspheres, hydrogels, nanoparticles and liposomes. At last, some safety assessments in the preclinical work and the main challenges for the further development of intra-articular treatment were also discussed.

Intra-articular delivery of antioxidative polymer-based nanospheres reduces intracellular reactive oxygen species in macrophages and alleviates cartilage damage in a rat model.

Cartilage damage is frequent in various joint diseases, mainly manifested by the loss of type II collagen and the degradation of proteoglycans. Diclofenac sodium is a commonly used drug for the treatment of joint diseases, but simple administration is often affected by drug clearance and rapid metabolism. Intra-articular drug delivery is an effective method for local enrichment of high concentration of drugs. However, due to the short half-life of diclofenac sodium, prolonging the stability and duration of the drug can alleviate the disadvantages of direct intra-articular application. Nanospheres for delivering drugs to treat joint diseases could be a remedy for cartilage damage. In addition, excessive production of reactive oxygen species (ROS) by macrophages activated in damaged cartilage would aggravate cartilage damage. Therefore, this study intends to use poly lactic-co-glycolic acid nanospheres to load and deliver diclofenac sodium to inhibit chondrocyte death while regulating the generation of ROS, thereby promoting the treatment of cartilage damage.

Recent Advances in Animal Models, Diagnosis, and Treatment of Temporomandibular Joint Osteoarthritis.

Temporomandibular joint osteoarthritis (TMJOA) is a gradual degenerative jaw joint condition. Until recent years, TMJOA is still relatively unrecognized and ineffective to be treated. Appropriate animal models with reliable detection methods can help researchers understand the pathophysiology of TMJOA and find therapeutic options. In this study, we summarized common animal models of TMJOA created by chemical, surgical, mechanical, and genetical approaches. The relevant pathological symptoms and induction mechanisms were outlined. In addition, different pathological indicators, furthermore, emerging therapeutic regimens, such as intra-articular drug delivery and tissue engineering-based approaches to treat TMJOA based on these animal models, were summarized and updated. Understanding the physiology and pathogenesis of the TMJOA, together using various ways to diagnose the TMJOA, were elaborated, including imaging techniques, molecular techniques for detecting inflammatory cytokines, histochemical staining, and histomorphometry measures. A more reliable diagnosis will enable the development of new prevention and more effective treatment strategies and thereby improve the quality of life of TMJOA patients. Impact statement Temporomandibular joint osteoarthritis (TMJOA) affects 8 to 16 percent of the population worldwide. However, TMJOA is still relatively unrecognized and ineffective to be treated in the clinic. Appropriate animal models with reliable diagnostic methods can help researchers understand the pathophysiology of TMJOA and find therapeutic options. We herein summarized common animal models of TMJOA and various ways to diagnose the TMJOA. More importantly, emerging therapeutic regimens to treat TMJOA based on these animal models were summarized. With the aid of strategies listed, more effective treatment strategies will be developed and thereby improve the life quality of TMJOA patients.

MRI-guided sacroiliac joint injections in children and adults: current practice and future developments.

Common etiologies of low back pain include degenerative arthrosis and inflammatory arthropathy of the sacroiliac joints. The diagnostic workup revolves around identifying and confirming the sacroiliac joints as a pain generator. Diagnostic sacroiliac joint injections often serve as functional additions to the diagnostic workup through eliciting a pain response that tests the hypothesis that the sacroiliac joints do or do not contribute to the patient's pain syndrome. Therapeutic sacroiliac joint injections aim to provide medium- to long-term relief of symptoms and reduce inflammatory activity and, ultimately, irreversible structural damage. Ultrasonography, fluoroscopy, computed tomography, and magnetic resonance imaging (MRI) may be used to guide sacroiliac joint injections. The populations that may benefit most from MRI-guided sacroiliac joint procedures include children, adolescents, adults of childbearing age, and patients receiving serial injections due to the ability of interventional MRI to avoid radiation exposure. Most clinical wide-bore MRI systems can be used for MRI-guided sacroiliac joint injections. Turbo spin echo pulse sequences optimized for interventional needle display visualize the needle tip with an error margin of < 1mm or less. Published success rates of intra-articular sacroiliac joint drug delivery with MRI guidance range between 87 and 100%. The time required for MR-guided sacroiliac joint injections in adults range between 23-35min and 40min in children. In this article, we describe techniques for MRI-guided sacroiliac joint injections, share our practice of incorporating interventional MRI in the care of patients with sacroiliac joint mediated pain, discuss the rationales, benefits, and limitations of interventional MRI, and conclude with future developments.

Knee Osteoarthritis Therapy: Recent Advances in Intra-Articular Drug Delivery Systems.

Drug delivery for osteoarthritis (OA) treatment is a continuous challenge because of their poor bioavailability and rapid clearance in joints. Intra-articular (IA) drug delivery is a common strategy and its therapeutic effects depend mainly on the efficacy of the drug-delivery system used for OA therapy. Different types of IA drug-delivery systems, such as microspheres, nanoparticles, and hydrogels, have been rapidly developed over the past decade to improve their therapeutic effects. With the continuous advancement in OA mechanism research, new drugs targeting specific cell/signaling pathways in OA are rapidly evolving and effective drug delivery is critical for treating OA. In this review, recent advances in various IA drug-delivery systems for OA treatment, OA targeted strategies, and related signaling pathways in OA treatment are summarized and analyzed based on current publications.

APPLICATION OF MAGNETIC PARTICLE TECHNOLOGY TO ASSESS NANOPARTICLE LOCALIZATION TO CARTILAGE

Purpose: Osteoarthritis (OA) is a highly prevalent, musculoskeletal disease, affecting an estimated 30 million individuals. To combat OA, intra-articular drug delivery systems such as nanoparticles (NPs) are used to improve drug bioavailability, retention, and localization. To monitor NP retention and biodistribution, NPs are often conjugated or loaded with near-infrared fluorophores and imaged using in vivo optical imaging systems. However, this current standard for in vivo particle tracking is associated with limitations such as signal attenuation and photobleaching that impede long-term tracking and understanding of how particles are localized, distributed, and cleared from diseased joints.

Intra-articular drug delivery systems for osteoarthritis therapy: shifting from sustained release to enhancing penetration into cartilage

Osteoarthritis (OA) is a progressive chronic inflammation that leads to cartilage degeneration. OA Patients are commonly given pharmacological treatment, but the available treatments are not sufficiently effective. The development of sustained-release drug delivery systems (DDSs) for OA may be an attractive strategy to prevent rapid drug clearance and improve the half-life of a drug at the joint cavity. Such delivery systems will improve the therapeutic effects of anti-inflammatory effects in the joint cavity. Whereas, for disease-modifying OA drugs (DMOADs) which target chondrocytes or act on mesenchymal stem cells (MSCs), the cartilage-permeable DDSs are required to maximize their efficacy. This review provides an overview of joint structure in healthy and pathological conditions, introduces the advances of the sustained-release DDSs and the permeable DDSs, and discusses the rational design of the permeable DDSs for OA treatment. We hope that the ideas generated in this review will promote the development of effective OA drugs in the future.

Intra-Articular Drug Delivery for Osteoarthritis Treatment

Osteoarthritis (OA) is the most prevalent degenerative joint disease affecting millions of people worldwide. Currently, clinical nonsurgical treatments of OA are only limited to pain relief, anti-inflammation, and viscosupplementation. Developing disease-modifying OA drugs (DMOADs) is highly demanded for the efficient treatment of OA. As OA is a local disease, intra-articular (IA) injection directly delivers drugs to synovial joints, resulting in high-concentration drugs in the joint and reduced side effects, accompanied with traditional oral or topical administrations. However, the injected drugs are rapidly cleaved. By properly designing the drug delivery systems, prolonged retention time and targeting could be obtained. In this review, we summarize the drugs investigated for OA treatment and recent advances in the IA drug delivery systems, including micro- and nano-particles, liposomes, and hydrogels, hoping to provide some information for designing the IA injected formulations.

Injectable hyaluronic acid hydrogels encapsulating drug nanocrystals for long-term treatment of inflammatory arthritis.

Antiproliferative chemotherapeutic agents offer a potential effective treatment for inflammatory arthritis. However, their clinical application is limited by high systemic toxicity, low joint bioavailability as well as formulation challenges. Here, we report an intra‐articular drug delivery system combining hyaluronic acid hydrogels and drug nanocrystals to achieve localized and sustained delivery of an antiproliferative chemotherapeutic agent camptothecin for long‐term treatment of inflammatory arthritis. We synthesized a biocompatible, in situ‐forming injectable hyaluronic acid hydrogel using a naturally occurring click chemistry: cyanobenzothiazole/cysteine reaction, which is the last step reaction in synthesizing D‐luciferin in fireflies. This hydrogel was used to encapsulate camptothecin nanocrystals (size of 160–560 nm) which released free camptothecin in a sustained manner for 4 weeks. In vivo studies confirmed that the hydrogel remained in the joint over 4 weeks. By using the collagen‐induced arthritis rat model, we demonstrate that the hydrogel‐camptothecin formulation could alleviate arthritis severity as indicated by the joint size and interleukin‐1β level in the harvested joints, as well as from histological and microcomputed tomography evaluation of joints. The hydrogel‐nanocrystal formulation strategy described here offers a potential solution for intra‐articular therapy for inflammatory arthritis.

Spatially and time-resolved SAXS for monitoring dynamic structural transitions during in situ generation of non-lamellar liquid crystalline phases in biologically relevant media

Formation of high viscous inverse lyotropic liquid crystalline phases in situ upon exposure of low viscous drug-loaded lipid preformulations to synovial fluid provides a promising approach for design of depot formulations for intra-articular drug delivery. Rational formulation design relies on a fundamental understanding of the synovial fluid-mediated dynamic structural transitions occurring at the administration site. At conditions mimicking the in vivo situation, we investigated in real-time such transitions at multiple positions by synchrotron small-angle X-ray scattering (SAXS) combined with an injection-cell. An injectable diclofenac-loaded quaternary preformulation consisting of 72/8/10/10% (w/w) glycerol monooleate/1,2-dioleoyl-glycero-3-phospho-rac-(1-glycerol)/ethanol/water was injected into hyaluronic acid solution or synovial fluid. A fast generation of a coherent drug depot of inverse bicontinuous Im3m and Pn3m cubic phases was observed. Through construction of 2D spatial maps from measurements performed 60 min after injection of the preformulation, it was possible to differentiate liquid crystalline rich- and excess hyaluronic acid solution- or synovial fluid-rich regimes. Synchrotron SAXS findings confirmed that the exposure of the preformulation to the media leads to alterations in structural features in position- and time-dependent manners. Effects of biologically relevant medium composition on the structural features, and implications for development of formulations with sustained drug release properties are highlighted.

Synergistic and receptor-mediated targeting of arthritic joints via intra-articular injectable smart hydrogels containing leflunomide-loaded lipid nanocarriers.

Intra-articular drug delivery represents a tempting strategy for local treatment of rheumatoid arthritis. Targeting drugs to inflamed joints bypasses systemic-related side effects. Albeit, rapid drug clearance and short joint residence limit intra-articular administration. Herein, injectable smart hydrogels comprising free/nanoencapsulated leflunomide (LEF) were developed. Nanostructured lipid carriers (NLCs), 200-300nm, were coated with either chondroitin sulfate (CHS), hyaluronic acid (HA), or chitosan (CS) to provide joint targetability. Coated NLCs were incorporated in either hyaluronic/pluronic (HP) or chitosan/β-glycerophosphate (CS/βGP) hydrogels. Optimized systems ensured convenient gelation time (14-100s), injectability (5-15s), formulation-dependent mechanical strength, and extended LEF release up to 51days. In vivo intra-articular injection in induced arthritis rat model revealed that rats treated with HA-coated NLCs showed the fastest recovery. Histopathological examination demonstrated perfect joint healing in case of HA-coated LEF-NLCs in CS/βGP thermogel manifested as minor erosion of subchondral bone, improved intensity of extracellular matrix, cartilage thickness, and chondrocyte number. Both HA- and CHS-coated NLCs reduced TNF-α level 4-5-fold relative to positive control. The feat would be achieved via active targeting to CD44 receptors overexpressed in the articular tissue, limiting chondrocyte apoptosis together with innate synergistic targetability by promoting chondrocyte proliferation and neovascularization, inhibiting the production of pro-inflammatory cytokines, thus enhancing cartilaginous tissue repair.

EtoGel for Intra-Articular Drug Delivery: A New Challenge for Joint Diseases Treatment.

Ethosomes® have been proposed as potential intra-articular drug delivery devices, in order to obtain a longer residence time of the delivered drug in the knee joint. To this aim, the conventional composition and preparation method were modified. Ethosomes® were prepared by using a low ethanol concentration and carrying out a vesicle extrusion during the preparation. The modified composition did not affect the deformability of ethosomes®, a typical feature of this colloidal vesicular topical carrier. The maintenance of sufficient deformability bodes well for an effective ethosome® application in the treatment of joint pathologies because they should be able to go beyond the pores of the dense collagen II network. The investigated ethosomes® were inserted in a three-dimensional network of thermo-sensitive poloxamer gel (EtoGel) to improve the residence time in the joint. Rheological experiments evidenced that EtoGel could allow an easy intra-articular injection at room temperature and hence transform itself in gel form at body temperature into the joint. Furthermore, EtoGel seemed to be able to support the knee joint during walking and running. In vitro studies demonstrated that the amount of used ethanol did not affect the viability of human chondrocytes and nanocarriers were also able to suitably interact with cells.