Search Results (82)

Degenerative joint disease is a major cause of disability, and although glucocorticosteroids and hyaluronic acid are widely used to reduce inflammation and improve joint mobility, the development of effective delivery systems remains a challenge. This study describes injectable sodium hyaluronate (HA)-based hydrogels modified with synthetic polymers, including polyacrylic acid (PA), ammonium acryloyldimethyltaurate/VP copolymer (AX), a polyvinyl acetate–polyvinylpyrrolidone mixture (PVA–PVP), and polyethylene glycol 4000 (PEG), loaded with prednisolone disodium phosphate (PSP). The aim was to investigate molecular interactions between PSP and HA-based polymer networks and to determine how these interactions influence hydrogel structure, viscosity, and drug release. Viscosity was measured using a Brookfield rotational viscometer, while intermolecular interactions were analyzed by ATR–FTIR and DSC. Drug release was evaluated using a paddle-over-disc apparatus and quantified spectrophotometrically. Release kinetics were analyzed using zero-, first-, and second-order models as well as the Higuchi, Korsmeyer–Peppas, and Peppas–Sahlin equations. PSP incorporation affected the dynamic viscosity of all formulations, and excipient type also significantly influenced hydrogel viscosity. ATR–FTIR and DSC analyses indicated hydrogen bond formation between PSP and the macromolecules of HA, PA, AX, and PEG. The PA-containing formulation formed the most extensive polymer network structure and exhibited the highest viscosity. Drug release followed mainly first-order, Higuchi, and Korsmeyer–Peppas models, while the release exponent n (0.58 ± 0.01–0.60 ± 0.01) indicated anomalous transport. These findings provide molecular insight into drug–polymer interactions in HA-based hydrogels and highlight their potential as injectable systems for intra-articular delivery of PSP. Full article

Background/Objectives: Goupi plaster (GP) is a traditional black plaster composed of a biphasic fibrous–oil matrix containing multiple bioactive compounds, and it has been widely used for the treatment of musculoskeletal disorders. Representative active compounds include sinomenine, osthole, cinnamaldehyde, and imperatorin, which exhibit anti-inflammatory and analgesic effects. However, due to its heterogeneous matrix structure and multi-component nature, the pharmaceutical delivery behavior of GP remains difficult to evaluate using conventional methods. Therefore, this study aimed to establish an integrated structure–release–permeation–pharmacokinetic evaluation framework to systematically characterize the transdermal delivery behavior of GP. Methods: GP was evaluated using multi-level analysis, including microstructural imaging (FESEM), in vitro release, ex vivo skin permeation, and in vivo dual-site microdialysis. Four representative bioactive compounds (sinomenine, osthole, cinnamaldehyde, and imperatorin) were selected as marker compounds. Release data were fitted to kinetic models, and structure–release relationships were examined using the Higuchi release constant (k_h). Skin-barrier alterations were assessed by attenuated total reflectance–Fourier transform infrared spectroscopy (ATR–FTIR) and differential scanning calorimetry (DSC). Local concentrations in subcutaneous (SC) and intra-articular (IA) compartments were measured by ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) to explore potential in vitro–in vivo correlation (IVIVC). Results: FESEM revealed a fibrous–oil network structure. GP exhibited sustained, diffusion-dominated release, with k_h = 0.9908–0.9977 and Korsmeyer–Peppas (K–P) release exponents (n) = 0.61–0.66, differing from active pharmaceutical ingredient (API) controls. Fiber area fraction and fiber length density showed negative correlations with k_h (r = −0.91 to −0.99); ex vivo permeation profiles varied among compounds, and ATR–FTIR and DSC analyses showed moderate changes in skin-barrier properties. Dual-site microdialysis demonstrated sustained local exposure, and a positive relationship was observed between in vitro release and in vivo concentrations. Conclusions: This study establishes an integrated structure–release–permeation–pharmacokinetic evaluation framework for traditional black plaster systems. The observed IVIVC is descriptive rather than predictive, reflecting a trend-level association under the current experimental conditions. These findings highlight the importance of integrating in vitro release, skin permeation, and local pharmacokinetics for understanding drug delivery behavior in complex transdermal matrix systems, and provide a methodological basis for quality consistency evaluation of traditional black plaster formulations. Full article

Temporomandibular joint osteoarthritis (TMJOA) is a degenerative maxillofacial disorder marked by progressive cartilage degradation and subchondral bone resorption, severely compromising patients’ quality of life. Intra-articular injection (IA), a standard route for conservative therapy, offers clinical advantages in safety and efficacy; however, outcomes remain limited due to short drug retention, poor tissue penetration, and variable agent efficacy, necessitating repeated administration. To overcome these limitations, fisetin-loaded poly (lactic-co-glycolic acid) nanoparticles (FST-PNP) were developed as a localized drug delivery system (DDS) for TMJOA treatment. Physicochemical analyses showed FST-PNP had uniform spherical morphology, excellent dispersibility, stability, high encapsulation efficiency, and substantial drug loading capacity. An in vitro study demonstrated more sustained and stable release from FST-PNP than free fisetin. The in vivo IA administration of FST-PNP preserved mandibular condylar osteochondral structures in TMJOA models. Notably, FST-PNP suppressed the expression of metalloproteinase-13 and a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS5) as catabolic enzymes and downregulated p16 and p21 as senescence markers, indicating synergistic anti-inflammatory and anti-senescent effects. These findings highlight FST-PNP as a DDS integrating controlled-release with multifaceted therapeutic actions, providing a promising strategy for IA therapy of TMJOA. Full article

The anterior labral–ligamentous complex (ALLC), formed by the integration of the anterior inferior glenohumeral ligament and anterior glenoid labrum, plays a critical role in shoulder stability and represents a potential target for regenerative injection therapy. However, precise ultrasound-guided targeting of this capsular–labral interface has not been anatomically validated. This feasibility cadaveric study evaluated the accuracy of ultrasound-guided in-plane injection directed at the ALLC at its glenoid attachment. A fresh-frozen human cadaver specimen was examined in the supine position with the shoulder in external rotation. Stepwise lateral-to-medial and cranial-to-caudal ultrasound scanning was performed to localize the ALLC. A 23-gauge needle was advanced in a cranial-to-caudal in-plane trajectory, and 1–2 mL of red filler was injected into the capsular–labral interface. Subsequent layer-by-layer dissection was conducted to assess injectate localization. In both shoulders (2/2), red filler was confined within the ALLC without extra-capsular leakage, diffuse intra-articular pooling, or neurovascular staining. These findings demonstrate the anatomical feasibility of ultrasound-guided targeted delivery to the anterior capsular–labral complex. This proof-of-concept study provides foundational anatomical validation for the development of regenerative injection protocols directed at the shoulder capsular–labral enthesis. Full article

Knee osteoarthritis (KOA) is a degenerative joint disorder characterized by chronic inflammation and progressive cartilage degradation. Mesenchymal stem cell (MSC)-based therapies have demonstrated therapeutic potential; however, increasing evidence suggests that their efficacy primarily arises from paracrine factors, highlighting the potential of cell free approaches. In this study, we developed an injectable, thermosensitive composite hydrogel incorporating adipose-derived MSC (AD-MSC) supernatant within a Pluronic F-127 (PF-127)/sodium hyaluronate (HA) matrix. The hydrogel exhibited a solution state at a low temperature and rapidly transitioned into a stable gel at a physiological temperature without chemical crosslinkers. Microstructural analysis revealed a porous, interconnected three-dimensional network favorable for the sustained release of bioactive factors. In a rat model of KOA, intra-articular administration of the AD-MSC supernatant-loaded hydrogel significantly improved joint architecture and locomotor performance, alleviated synovial inflammation, and preserved cartilage integrity. Radiographic and histological assessments demonstrated reduced cartilage degeneration and subchondral bone alterations. Moreover, the treatment markedly decreased intra-articular levels of proinflammatory cytokines (IL-1β and TNF-α) and the cartilage degradation marker CTX-II in a time-dependent manner. These findings indicated that the sustained local delivery of AD-MSC-derived supernatant effectively modulated joint inflammation and attenuated cartilage degeneration, with the hydrogel serving primarily as a delivery vehicle for these bioactive factors. This cell-free injectable biomaterial platform could offer a promising therapeutic strategy for the treatment of knee osteoarthritis. Full article

Stem cell therapy represents an intrinsic part of regenerative medicine, with expanding applications in orthopedic and musculoskeletal research. Although studies span from small-animal models to early-phase clinical trials, the field remains fragmented, with wide variation in stem cell types, delivery methods, and target tissues. A consolidated overview is needed to inform future directions and bridge the gap between preclinical promise and clinical application. This scoping review synthesized evidence from 500 preclinical and clinical studies, identified through systematic searches and screened in accordance with PRISMA-ScR guidelines. Data were extracted on stem cell type and source, delivery approach, targeted tissue and organ, and disease indication. We found that autologous bone marrow-derived mesenchymal stem cells were the most used, with adipose- and perinatal-derived cells gaining prominence in recent years. Small-animal models such as rats and rabbits predominated, while large-animal and human studies focused mainly on knee osteoarthritis. Intra-articular injection was the principal delivery method across both preclinical and clinical settings. By mapping prevailing practices and emerging trends, this review provides a comprehensive reference for researchers, clinicians, and regulatory stakeholders. It highlights translational pathways, identifies critical gaps, and offers evidence to guide the design of safe, effective, and scalable regenerative therapies in orthopedics. Full article

Background/Objectives: Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by α-L-iduronidase (IDUA) deficiency, leading to progressive glycosaminoglycan (GAG) accumulation and severe joint involvement. Gene editing represents a promising alternative to restore localized enzyme production. Therefore, this study aimed to evaluate the feasibility, efficacy, and safety of in situ genome editing through intra-articular administration of a nonviral CRISPR/Cas9 system to increase localized IDUA expression in an MPS I mouse model. Methods: Cationic liposomes were formulated to deliver plasmids encoding the CRISPR/Cas9 system targeted to the ROSA26 locus along with an IDUA donor sequence. In vitro assays were performed in fibroblast-like synoviocytes (FLSs) isolated from MPS I mice to assess cytotoxicity, gene editing efficiency, and IDUA activity. In vivo, MPS I mice received intra-articular injections in the knee joints, either as a single dose (short-term study) or monthly for three months (long-term study). IDUA activity, GAG levels, and genome editing efficiency were evaluated in joint tissues, synovial fluid, serum, and major organs. Results: Gene-edited FLS showed sustained IDUA activity for up to 30 days with low cytotoxicity. In vivo, intra-articular administration resulted in a significant increase in IDUA activity in joint tissue and synovial fluid without detectable systemic IDUA. Long-term treatment led to persistent joint-localized IDUA activity, significant reductions (>50%) in GAG levels, and detectable genome editing in joint DNA. Conclusions: Intra-articular delivery of CRISPR/Cas9 via cationic liposomes enables safe and effective localized genome editing, representing a promising strategy for treating joint manifestations of MPS I. Full article

Background/Objectives: Poly(lactic-co-glycolic acid) (PLGA) microspheres offer sustained drug delivery but often suffer from broad particle size distribution (PSD), leading to inconsistent release profiles. This study investigates wet sieving as a post-processing strategy to precisely control PSD, quantified by the Span value, and evaluates its impact on the performance of triamcinolone acetonide (TA)-loaded PLGA microspheres. Methods: Triamcinolone acetonide-loaded PLGA microspheres were prepared via emulsification-solvent evaporation. Wet sieving was employed as a post-processing strategy to obtain distinct particle size fractions and groups with defined polydispersity (Span values). The microspheres were characterized for particle size distribution, drug loading, surface morphology, and in vitro release kinetics. To establish the in vivo relevance of polydispersity control, the pharmacokinetic profiles of different Span groups were first determined using LC-MS/MS following intra-articular injection in rats. Subsequently, their therapeutic efficacy was evaluated in a rat model of knee osteoarthritis, with outcomes assessed by joint swelling measurement and histopathological analysis. Results: Microspheres were prepared, fractionated into distinct size groups (0–20, 20–28, 28–40, 40–50, >50 μm) and polydispersity groups (Span = 1.4, 0.8, 0.5). We identified Span as a dominant factor independent of mean particle size. Reducing the Span from 1.4 to 0.5 significantly decreased burst release (24.15% to 14.51%), prolonged mean residence time (MRT 88.52 to 123.53 h), and enhanced anti-inflammatory and cartilage-protective effects in a rat model of knee osteoarthritis. Conclusions: This work establishes Span ≤ 0.5 as a critical quality attribute and presents wet sieving as a simple, effective method to ensure batch-to-batch consistency and predictable in vivo performance for PLGA microsphere products. Full article

Background/Objectives: Osteoarthritis (OA) is a multifactorial degenerative joint disease characterized by synovial inflammation, oxidative stress, and progressive cartilage degeneration. This study investigated whether intra-articular N-acetylcysteine (NAC) attenuates synovial inflammation and oxidative stress and whether these effects translate into structural cartilage protection. Methods: OA was induced in rats by anterior cruciate ligament transection (ACLT). NAC (5 mg/50 µL) was administered intra-articularly once weekly for three weeks post-ACLT. Inflammatory cytokines (IL-1β, IL-6, TNF-α), oxidative stress markers (iNOS, TAS, TOS, OSI), and cartilage degradation markers (MMP-13, COMP, CTX-II) were quantified in synovial fluid and cartilage homogenates using ELISA. Cartilage integrity was evaluated histologically using the modified Mankin scoring system. Results: Compared with controls, NAC significantly reduced synovial IL-1β, IL-6, TNF-α, MMP-13, and iNOS levels and improved the synovial redox profile by increasing TAS and reducing TOS and OSI (all p < 0.05). In contrast, NAC did not significantly alter cartilage homogenate levels of inflammatory cytokines, oxidative stress indices, or degradation markers (COMP, CTX-II, MMP-13). Histological analysis demonstrated persistent cartilage fissuring, hypocellularity, and proteoglycan loss in both groups (p > 0.05). Conclusions: Intra-articular NAC exerts potent anti-inflammatory and antioxidative effects within the synovial compartment but fails to prevent cartilage degeneration in the ACLT model. These findings indicate a compartment-specific therapeutic profile, suggesting that NAC may function as a symptom-modifying agent in synovitis-dominant OA rather than a structure-modifying therapy. Future studies should focus on optimized delivery systems or combination strategies targeting cartilage and subchondral bone to achieve disease modification. Full article

Gel-based depots are increasingly recognized as platforms to extend the intratissue residence of local anesthetics (LAs) while reducing systemic exposure. Hydrogels, organogels, and emerging bigels represent three distinct architectures defined by their continuous phases and drug–matrix interactions. Hydrogels provide hydrated polymer networks with predictable injectability, tunable degradation, and diffusion- or stimulus-responsive release, enabling sustained analgesia in perineural, peri-incisional, intra-articular, and implant-adjacent settings. Organogels, formed by supramolecular assembly of low-molecular-weight gelators in lipids or semi-polar solvents, strongly solubilize lipophilic LA bases and enhance barrier partitioning, making them suitable for dermal, transdermal, and mucosal applications in outpatient or chronic pain care. Bigels integrate aqueous and lipid domains within biphasic matrices, improving rheology, spreadability, and dual-solubilization capacity, although their use in LA delivery remains at the formulation stage, with no validated in vivo pharmacology. This narrative review synthesizes the design principles, release mechanisms, and translational evidence across these platforms, highlighting domain-specific advantages and barriers related to mechanical robustness, sterilization, reproducibility, and regulatory feasibility. We propose a platform-level framework in which depot selection is aligned with LA chemistry, anatomical context, and clinical objectives to guide the development of workflow-compatible next-generation LA depots. Full article

Osteoarthritis (OA) is a debilitating joint disease affecting over 500 million people globally, characterized by cartilage degradation, chronic pain, and failed tissue repair. Neurogenic inflammation, driven by neuropeptides including Substance P (SP) and calcitonin gene-related peptide (CGRP), plays a key role in the pathogenesis of OA. This study explores the therapeutic potential of extracellular vesicles (EVs) derived from infrapatellar fat pad mesenchymal stem/stromal cells (IFP-MSCs) transduced with CGRP antagonist CGRP_8-37 (aCGRP IFP-MSC EVs). These EVs are enriched in anti-inflammatory miRNAs and proteins, and they express neprilysin (CD10), enabling SP degradation. Herein, several LncRNAs were identified, which have been known to interact with miRNAs that affect the knee joint homeostasis. Specifically, 11 LncRNAs (ZFAS1, EMX2OS, HOTAIRM1, RPS6KA2-AS1, DANCR, LINC-ROR, GACAT1, GNAS-AS1, HAR1A, OIP5-AS1, TERC) interact with miRNAs that promote cell proliferation, prevent apoptosis, and preserve homeostasis. In vitro, aCGRP IFP-MSC EVs downregulated pro-inflammatory markers (TNF, TLR4, MAPK8) in dorsal root ganglia and promoted chondrocyte gene expression consistent with anabolism and matrix remodeling. In vivo, intra-articular EV delivery attenuated pain behaviors, preserved the cartilage structure, restored PRG4+ stem/progenitor cell localization, and trended toward reduced SP levels. Histological analysis confirmed improved collagen organization and reduced matrix degradation. These findings suggest that aCGRP IFP-MSC EVs exert multimodal effects on neuroinflammation, cartilage regeneration, and joint homeostasis. This cell-free, gene-enhanced EV therapy offers a promising disease-modifying strategy for the treatment of OA, with the potential to address both structural changes and chronic pain associated with this disease. Full article

Osteoarticular infections (OAIs), including osteomyelitis, septic arthritis, prosthetic joint infections, and facture-related infections, remain a major challenge due to biofilm formation and the prevalence of multidrug-resistant (MDR) pathogens. Although OAIs are predominantly caused by Staphylococcus aureus and coagulase-negative staphylococci, the increasing incidence of MDR Gram-negative infections adds further complexity to their management. Standard approaches, combining surgery and prolonged antibiotic therapy, frequently result in recurrence and poor outcomes. Bacteriophage (phage) therapy has emerged as a promising adjunct or alternative approach, offering high host specificity, replication at the infection site, and activity against biofilm-embedded bacteria. This review highlights recent advances in phage therapy for OAIs, focusing on administration routes (intravenous, intra-articular, topical, and oral) and on novel pharmaceutical delivery systems such as hydrogels, bone cements, microparticles, nanoparticles, and implant coatings. Preclinical and early clinical studies have analyzed phage stability, controlled release, and the synergistic effects of combined phage/antibiotic therapy. However, challenges remain regarding standardization, immunogenicity, and regulatory approval. Nonetheless, phage therapy shows promise for clinical translation as an adjunct or alternative to conventional treatments for OAIs. Well-designed clinical trials are urgently needed to confirm the efficacy of phage therapy, optimize delivery strategies, and integrate the treatments in routine practice. Despite encouraging outcomes for a successful clinical implementation, regulation and standardization of GMP production are required. Full article

The pathogenesis of knee osteoarthritis (OA) is multifaceted and involves the complete joint microenvironment. Despite beneficial evidence of curcumin, the mechanistic insights of nanoemulsified curcumin (n-Cur) delivery to the knee-OA microenvironment are limited. The study aimed to establish localized delivery of curcumin nanoemulsion in the knee joint of OA rats and to examine detailed histopathological changes. n-Cur was prepared using a neutral dietary oil and a surfactant. Adult (5 mo) male SD rats were intra-articularly delivered 40 mg/mL of monoiodoacetate (MIA) to induce OA in the left knee and further treated with n-Cur (30 mg/mL). The effect of n-Cur on macrophage recruitment was evaluated using a co-culture model of CHON 001 and RAW 264.7 cells. In the MIA model, localized delivery of n-Cur significantly reduced knee joint edema and joint space narrowing in the target site. Curcumin ameliorated cartilage degeneration by reducing fibrillation, hypocellularity, and restoring matrix proteoglycan, as evidenced by histology. Reduced synovial inflammation displays the effect of curcumin on the synovium, possibly by lowering the recruitment of macrophages in chemoattractant-stimulated chondrocytes. Thus, curcumin nanoemulsion can act as a chondroprotective agent, modulating the OA microenvironment by reducing joint edema, synovial inflammation, and oxidative stress in the OA model. Full article

Cartilage regeneration has long been a major challenge in the treatment of osteoarthritis (OA). Aiming to develop a simple outpatient treatment for knee OA, we have demonstrated the potential of combining Nomura’s jellyfish mucin (JM) and hyaluronic acid (HA) to contribute to cartilage repair and regeneration in chondrocytes. In this study, we examined the effects of moon jellyfish JM and jellyfish collagen (JC) on chondrocytes. Polydactyly-derived chondrocytes (PDs), obtained from polydactyly surgery, were used. PDs were cultured in media supplemented with JM or JC, harvested, and evaluated by RT-qPCR. The effects of simultaneous addition of the inflammatory cytokine IL-1β were also examined. Furthermore, the effects on rat articular cartilage were investigated. A mono-iodoacetate (MIA) model was created by intra-articular injection in 6-week-old rats, followed by four intra-articular injections. Evaluations were performed using macroscopic observation and histological assessment with the OARSI scoring system. In vitro, the addition of JM or JC significantly affected the expression of ACAN, MMP3, and ADAMTS5. However, in vivo, intra-articular injection of JM alone did not significantly suppress cartilage degeneration in MIA-induced OA model rats. Both JM and JC may contribute to the suppression of cartilage degeneration as well as to cartilage repair and regeneration, even in the absence of HA. However, further studies are needed to clarify the optimal conditions, such as dosage, timing, and delivery method, that are required to achieve these effects in articular cartilage. Full article

Injectable hydrogels are adaptable drug delivery systems capable of forming localized depots that align with the anatomical and physiological constraints of administration sites. Their performance depends on both the injection environment and the properties of the therapeutic cargo. Applications span ocular, intra-articular, subcutaneous, intramuscular, tumoral, central nervous system, and mucosal delivery, where hydrogels address challenges of clearance, retention, and compatibility. Beyond bulk depots, particulate hydrogel formats such as microgels and nanogels improve syringeability, modularity, and integration with nanoparticle carriers. Functional versatility arises from stimuli responsiveness, including pH, enzymatic, thermal, redox, and light triggers, and from hybrid designs that integrate multiple cues for precision control. Loading strategies range from passive encapsulation to affinity binding and covalent conjugation, with release governed by diffusion, degradation, and stimuli-modulated kinetics. Translational progress depends on reproducible fabrication, scalable manufacturing, and device integration, while site-dependent constraints and regulatory hurdles remain significant challenges. Full article