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Nanomedicine (London, England) Jul 2024This study focused on developing a topical gel incorporating lornoxicam-loaded poly(lactic-co-glycolic acid) and polyethylene glycol (PLGA-PEG) blend nanoparticles to...
This study focused on developing a topical gel incorporating lornoxicam-loaded poly(lactic-co-glycolic acid) and polyethylene glycol (PLGA-PEG) blend nanoparticles to mitigate gastrointestinal (GIT) side effects and enhance therapeutic efficacy. Synthesized nanoparticles were subjected to characterization, permeation studies, and acute oral toxicity analysis post-incorporation into the gel using a S/O/W double emulsion solvent. The nanoparticles displayed a smooth, spherical morphology (170-321 nm) with increased entrapment efficiency (96.2%). LOX exhibited a permeation rate of 70-94% from the nanoparticle-infused gel, demonstrating favorable biocompatibility at the cellular level. The formulated gel, enriched with nanoparticles, holds promising prospects for drug-delivery systems and promising improved therapeutic outcomes for LOX.
PubMed: 38953843
DOI: 10.1080/17435889.2024.2359356 -
European Journal of Pain (London,... Jul 2024
PubMed: 38953582
DOI: 10.1002/ejp.2312 -
Magnetic Resonance in Medicine Jul 2024To assess the potential for accelerating continuous-wave (CW) T dispersion measurement with compressed sensing approach via studying the effect that the data reduction...
PURPOSE
To assess the potential for accelerating continuous-wave (CW) T dispersion measurement with compressed sensing approach via studying the effect that the data reduction has on the ability to detect differences between intact and degenerated articular cartilage with different spin-lock amplitudes and to assess quantitative bias due to acceleration.
METHODS
Osteochondral plugs (n = 27, 4 mm diameter) from femur (n = 14) and tibia (n = 13) regions from human cadaver knee joints were obtained from commercial biobank (Science Care, USA) under Ethical permission 134/2015. MRI of specimens was performed at 9.4T with magnetization prepared radial balanced SSFP (bSSFP) readout sequence, and the CWT relaxation time maps were computed from the measured data. The relaxation time maps were evaluated in the cartilage zones for different acceleration factors. For reference, Osteoarthritis Research Society International (OARSI) grading and biomechanical measurements were performed and correlated with the MRI findings.
RESULTS
Four-fold acceleration of CWT dispersion measurement by compressed sensing approach was feasible without meaningful loss in the sensitivity to osteoarthritic (OA) changes within the articular cartilage. Differences were significant between intact and OA groups in the superficial and transitional zones, and CWT correlated moderately with the reference measurements (0.3 < r < 0.7).
CONCLUSION
CWT was able to differentiate between intact and OA cartilage even with four-fold acceleration. This indicates that acceleration of CWT dispersion measurement by compressed sensing approach is feasible with negligible loss in the sensitivity to osteoarthritic changes in articular cartilage.
PubMed: 38953429
DOI: 10.1002/mrm.30206 -
Knee Surgery, Sports Traumatology,... Jul 2024This study addresses the gap in the current literature by evaluating the combined treatment of autologous bone grafting and autologous chondrocyte implantation (ABCI)...
Autologous bone grafting in combination with autologous chondrocyte implantation yields favourable outcomes in the treatment of osteochondral defects of the knee: A systematic literature review.
PURPOSE
This study addresses the gap in the current literature by evaluating the combined treatment of autologous bone grafting and autologous chondrocyte implantation (ABCI) for osteochondral defects of the knee. It aims to evaluate clinical outcomes against methodological quality and to summarize histological results and surgical techniques.
METHODS
A thorough search was conducted across Pubmed, Cochrane and Embase databases. Studies reporting clinical outcomes of ABCI for osteochondral defects of the knee were included. Patient-reported outcome measures (PROMs), failure rates, methodological quality and potential conflicts of interest were evaluated. Histological results and surgical techniques were summarized.
RESULTS
Eighteen studies with 344 analyzed patients met the eligibility criteria for inclusion. All studies showed a significant improvement (p < 0.05) across different PROMs (subjective International Knee Documentation Committee score, Cincinnati Knee Rating System, Visual Analogue Scale, Lysholm Score, Tegner Activity Scale, Knee injury and Osteoarthritis Outcome Score and Knee Society Score) compared to the preoperative status. Failure rates ranged from 0% to 17.6%, with a mean follow-up of 73.2 months (range: 9.0-143.6 months). Methodological quality was low to medium, including only one comparative study. Six studies reviewed reported a potential conflict of interest. The histological assessment showed effective bonding between autologous chondrocytes and bone graft. A large degree of variability was observed in the operative technique used.
CONCLUSION
The current literature suggests that ABCI yields good clinical outcomes at mid- to long-term follow-up with favourable histological results for osteochondral defects of the knee. However, future research should focus on high-quality comparative studies to better guide treatment choices. Introducing ABCI as the standard abbreviation may enhance clarity in future research.
LEVEL OF EVIDENCE
Level IV.
PubMed: 38953161
DOI: 10.1002/ksa.12342 -
Journal of Pain Research 2024Joint pain is one of the most commonly reported pain types in the United States. In the case of patients suffering from inflammatory diseases such as osteoarthritis (OA)...
PURPOSE
Joint pain is one of the most commonly reported pain types in the United States. In the case of patients suffering from inflammatory diseases such as osteoarthritis (OA) and gout, persistent inflammation due to long-term overexpression of several key cytokines has been linked to neuronal hypersensitivity and damage within the joints. Ultimately, a subset of patients develop chronic pain. Pharmacologic treatment of joint pain involves the use of analgesics such as acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), opioids, antidepressants, as well as intra-articular injections of corticosteroids and hyaluronic acid. However, NSAIDs are short-acting and fail to alleviate severe pain, opioids are generally ineffective at managing chronic pain, and all therapeutic options involve increased risks of serious side effects.
METHODS
We explored the therapeutic and analgesic effects of transforming growth factor-β-activated kinase 1 (TAK1) inhibition in both the monoiodoacetate (MIA) and monosodium urate (MSU) models of joint pain as an innovative strategy for alleviating chronic inflammatory pain. Mechanical allodynia (Von Frey), weight-bearing and histological changes were measured in separate groups of rats receiving either the selective TAK1 inhibitor, HS-276, gabapentin or vehicle.
RESULTS
Our data support that TAK1 inhibition effectively prevented the development of mechanical allodynia and differential weight-bearing in the MIA model. In the MSU model of gouty arthritis, treatment with HS-276 significantly reduced mechanical allodynia and knee edema in female rats, but not male rats. Histological evaluation of effected joints in both models showed that HS-276 treatment significantly reduced disease-induced degradation of the joint.
CONCLUSION
Our results support that TAK1 is a critical signaling node in inflammatory joint diseases such as OA and gouty arthritis. Selective pharmacological inhibition significantly attenuated several aspects of the disease, including joint degeneration and mechanical pain. Thus, TAK1 is a novel therapeutic target for the treatment of painful inflammatory joint diseases.
PERSPECTIVE
This article reports on the therapeutic potential of TAK1 in the treatment of chronic inflammatory joint diseases such as OA and gout. Using the selective TAK1 inhibitor, HS-276, we show the therapeutic and analgesic effects of TAK1 inhibition in two preclinical murine models of inflammatory joint pain.
PubMed: 38952995
DOI: 10.2147/JPR.S451409 -
BioRxiv : the Preprint Server For... May 2024Osteoarthritis (OA) poses a significant healthcare burden with limited treatment options. While genome-wide association studies (GWAS) have identified over 100...
UNLABELLED
Osteoarthritis (OA) poses a significant healthcare burden with limited treatment options. While genome-wide association studies (GWAS) have identified over 100 OA-associated loci, translating these findings into therapeutic targets remains challenging. Integrating expression quantitative trait loci (eQTL), 3D chromatin structure, and other genomic approaches with OA GWAS data offers a promising approach to elucidate disease mechanisms; however, comprehensive eQTL maps in OA-relevant tissues and conditions remain scarce. We mapped gene expression, chromatin accessibility, and 3D chromatin structure in primary human articular chondrocytes in both resting and OA-mimicking conditions. We identified thousands of differentially expressed genes, including those associated with differences in sex and age. RNA-seq in chondrocytes from 101 donors across two conditions uncovered 3782 unique eGenes, including 420 that exhibited strong and significant condition-specific effects. Colocalization with OA GWAS signals revealed 13 putative OA risk genes, 10 of which have not been previously identified. Chromatin accessibility and 3D chromatin structure provided insights into the mechanisms and conditional specificity of these variants. Our findings shed light on OA pathogenesis and highlight potential targets for therapeutic development.
HIGHLIGHTS
∘ Comprehensive analysis of sex- and age-related global gene expression in human chondrocytes revealed differences that correlate with osteoarthritis ∘ First response eQTLs in chondrocytes treated with an OA-related stimulus ∘ Deeply sequenced Hi-C in resting and activated chondrocytes helps connect OA risk variants to their putative causal genes ∘ Colocalization analysis reveals 13 (including 10 novel) putative OA risk genes.
PubMed: 38952796
DOI: 10.1101/2024.05.05.592567 -
IScience Jun 2024The development of osteoarthritis (OA) involves subchondral bone lesions, but the role of osteoblastic autophagy-related genes (ARGs) in osteoarthritis is unclear....
The development of osteoarthritis (OA) involves subchondral bone lesions, but the role of osteoblastic autophagy-related genes (ARGs) in osteoarthritis is unclear. Through integrated analysis of single-cell dataset, Bulk RNA dataset, and 367 ARGs extracted from GeneCards, 40 ARGs were found. By employing multiple machine learning algorithms and PPI networks, three key genes (DDIT3, JUN, and VEGFA) were identified. Then the RF model constructed from these genes indicated great potential as a diagnostic tool. Furthermore, the model's effectiveness in predicting OA has been confirmed through external validation datasets. Moreover, the expression of ARGs was examined in osteoblasts subject to excessive mechanical stress, human and mouse tissues. Finally, the role of ARGs in OA was confirmed through co-culturing explants and osteoblasts. Thus, osteoblastic ARGs could be crucial in OA development, providing potential diagnostic and treatment strategies.
PubMed: 38952687
DOI: 10.1016/j.isci.2024.110130 -
Journal of Orthopaedic Surgery and... Jul 2024In recent years, the use of tapered-wedge short stems has increased due to their ability to preserve bones and tendons. Surgical techniques occasionally result in a...
BACKGROUND
In recent years, the use of tapered-wedge short stems has increased due to their ability to preserve bones and tendons. Surgical techniques occasionally result in a varus position of the stem, which is particularly pronounced in short stems. Although the varus position is not clinically problematic, there are reports of an increased incidence of stress shielding and cortical hypertrophy. Thus, we evaluated and examined the acceptable range of varus angles using finite element analysis.
METHODS
Patients diagnosed with osteoarthritis of the hip joint who had undergone arthroplasty were selected and classified into three types [champagne-flute (type A), intermediate (type B), and stovepipe (type C)]. Finite element analysis was performed using Mechanical Finder. The model was created using a Taperloc microplasty stem with the varus angle increased by 1° from 0° to 5° from the bone axis and classified into seven zones based on Gruen's zone classification under loading conditions in a one-leg standing position. The volume of interest was set, the mean equivalent stress for each zone was calculated.
RESULTS
A significant decrease in stress was observed in zone 2, and increased stress was observed in zones 3 and 4, suggesting the emergence of a distal periosteal reaction, similar to the results of previous studies. In zone 2, there was a significant decrease in stress in all groups at a varus angle ≥ 3°. In zone 3, stress increased from ≥ 3° in type B and ≥ 4° in type C. In zone 4, there was a significant increase in stress at varus angles of ≥ 2° in types A and B and at ≥ 3° in type C.
CONCLUSION
In zone 2, the varus angle at which stress shielding above Engh classification grade 3 may appear is expected to be ≥ 3°. Distal cortical hypertrophy may appear in zones 3 and 4; the narrower the medullary cavity shape, the smaller the allowable angle of internal recession, and the wider the medullary cavity shape, the wider the allowable range. Long-term follow-up is required in patients with varus angles > 3°.
Topics: Humans; Finite Element Analysis; Stress, Mechanical; Hip Prosthesis; Arthroplasty, Replacement, Hip; Male; Female; Prosthesis Design; Aged; Osteoarthritis, Hip; Middle Aged
PubMed: 38951850
DOI: 10.1186/s13018-024-04856-z -
Scientific Reports Jul 2024Cartilage tissue engineering aims to develop functional substitutes for treating cartilage defects and osteoarthritis. Traditional two-dimensional (2D) cell culture...
Cartilage tissue engineering aims to develop functional substitutes for treating cartilage defects and osteoarthritis. Traditional two-dimensional (2D) cell culture systems lack the complexity of native cartilage, leading to the development of 3D regenerative cartilage models. In this study, we developed a 3D model using Gelatin Methacryloyl (GelMA)-based hydrogels seeded with Y201 cells, a bone marrow mesenchymal stem cell line. The model investigated chondrogenic differentiation potential in response to Wnt3a stimulation within the GelMA scaffold and validated using known chondrogenic agonists. Y201 cells demonstrated suitability for the model, with increased proteoglycan content and upregulated chondrogenic marker expression under chondrogenic conditions. Wnt3a enhanced cell proliferation, indicating activation of the Wnt/β-catenin pathway, which plays a role in cartilage development. GelMA hydrogels provided an optimal scaffold, supporting cell viability and proliferation. The 3D model exhibited consistent responses to chondrogenic agonists, with TGF-β3 enhancing cartilage-specific extracellular matrix (ECM) production and chondrogenic differentiation. The combination of Wnt3a and TGF-β3 showed synergistic effects, promoting chondrogenic differentiation and ECM production. This study presents a 3D regenerative cartilage model with potential for investigating cartilage biology, disease mechanisms, and drug screening. The model provides insights into complex cartilage regeneration mechanisms and offers a platform for developing therapeutic approaches for cartilage repair and osteoarthritis treatment.
Topics: Wnt3A Protein; Chondrogenesis; Cell Differentiation; Tissue Engineering; Cell Proliferation; Hydrogels; Mesenchymal Stem Cells; Humans; Cartilage; Gelatin; Tissue Scaffolds; Transforming Growth Factor beta3; Cell Line; Extracellular Matrix; Wnt Signaling Pathway; Chondrocytes; Animals
PubMed: 38951570
DOI: 10.1038/s41598-024-65970-w -
CNS Drugs Jul 2024Synthetic cannabinoids are compounds made in the laboratory to structurally and functionally mimic phytocannabinoids from the Cannabis sativa L. plant, including...
Synthetic cannabinoids are compounds made in the laboratory to structurally and functionally mimic phytocannabinoids from the Cannabis sativa L. plant, including delta-9-tetrahydrocannabinol (THC). Synthetic cannabinoids (SCs) can signal via the classical endogenous cannabinoid system (ECS) and the greater endocannabidiome network, highlighting their signalling complexity and far-reaching effects. Dronabinol and nabilone, which mimic THC signalling, have been approved by the Food and Drug Administration (FDA) for treating nausea associated with cancer chemotherapy and/or acquired immunodeficiency syndrome (AIDS). However, there is ongoing interest in these two drugs as potential analgesics for a variety of other clinical conditions, including neuropathic pain, spasticity-related pain, and nociplastic pain syndromes including fibromyalgia, osteoarthritis, and postoperative pain, among others. In this review, we highlight the signalling mechanisms of FDA-approved synthetic cannabinoids, discuss key clinical trials that investigate their analgesic potential, and illustrate challenges faced when bringing synthetic cannabinoids to the clinic.
PubMed: 38951463
DOI: 10.1007/s40263-024-01098-9