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1. Injectable mechanical pillows for attenuation of load-induced post-traumatic osteoarthritis

   https://doi.org/10.1093/rb/rbz013  

   Holyoak, Derek T; Wheeler, Tibra A; van der Meulen, Marjolein C; Singh, Ankur (April 2019, Regenerative Biomaterials)

   Abstract Osteoarthritis (OA) of the knee joint is a degenerative disease initiated by mechanical stress that affects millions of individuals. The disease manifests as joint damage and synovial inflammation. Post-traumatic osteoarthritis (PTOA) is a specific form of OA caused by mechanical trauma to the joint. The progression of PTOA is prevented by immediate post-injury therapeutic intervention. Intra-articular injection of anti-inflammatory therapeutics (e.g. corticosteroids) is a common treatment option for OA before end-stage surgical intervention. However, the efficacy of intra-articular injection is limited due to poor drug retention time in the joint space and the variable efficacy of corticosteroids. Here, we endeavored to characterize a four-arm maleimide-functionalized polyethylene glycol (PEG-4MAL) hydrogel system as a ‘mechanical pillow’ to cushion the load-bearing joint, withstand repetitive loading and improve the efficacy of intra-articular injections of nanoparticles containing dexamethasone, an anti-inflammatory agent. PEG-4MAL hydrogels maintained their mechanical properties after physiologically relevant cyclic compression and released therapeutic payload in an on-demand manner under in vitro inflammatory conditions. Importantly, the on-demand hydrogels did not release nanoparticles under repetitive mechanical loading as experienced by daily walking. Although dexamethasone had minimal protective effects on OA-like pathology in our studies, the PEG-4MAL hydrogel functioned as a mechanical pillow to protect the knee joint from cartilage degradation and inhibit osteophyte formation in an in vivo load-induced OA mouse model. 

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2. Non-Destructive Spatial Mapping of Glycosaminoglycan Loss in Native and Degraded Articular Cartilage Using Confocal Raman Microspectroscopy

   https://doi.org/10.3389/fbioe.2021.744197  

   Gao, Tianyu; Boys, Alexander J.; Zhao, Crystal; Chan, Kiara; Estroff, Lara A.; Bonassar, Lawrence J. (October 2021, Frontiers in Bioengineering and Biotechnology)

   Articular cartilage is a collagen-rich tissue that provides a smooth, lubricated surface for joints and is also responsible for load bearing during movements. The major components of cartilage are water, collagen, and proteoglycans. Osteoarthritis is a degenerative disease of articular cartilage, in which an early-stage indicator is the loss of proteoglycans from the collagen matrix. In this study, confocal Raman microspectroscopy was applied to study the degradation of articular cartilage, specifically focused on spatially mapping the loss of glycosaminoglycans (GAGs). Trypsin digestion was used as a model for cartilage degradation. Two different scanning geometries for confocal Raman mapping, cross-sectional and depth scans, were applied. The chondroitin sulfate coefficient maps derived from Raman spectra provide spatial distributions similar to histological staining for glycosaminoglycans. The depth scans, during which subsurface data were collected without sectioning the samples, can also generate spectra and GAG distributions consistent with Raman scans of the surface-to-bone cross sections. In native tissue, both scanning geometries demonstrated higher GAG content at the deeper zone beneath the articular surface and negligible GAG content after trypsin degradation. On partially digested samples, both scanning geometries detected an ∼100 μm layer of GAG depletion. Overall, this research provides a technique with high spatial resolution (25 μm pixel size) to measure cartilage degradation without tissue sections using confocal Raman microspectroscopy, laying a foundation for potential in vivo measurements and osteoarthritis diagnosis. 

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3. Reliability of a Novel Semiautomated Ultrasound Segmentation Technique for Assessing Average Regional Femoral Articular Cartilage Thickness

   https://doi.org/10.1123/jsr.2019-0476  

   Lisee, Caroline; McGrath, Melanie L.; Kuenze, Christopher; Zhang, Ming; Salzler, Matt; Driban, Jeffrey B.; Harkey, Matthew S. (September 2020, Journal of Sport Rehabilitation)

   Context : Ultrasound imaging is a clinically feasible tool to assess femoral articular cartilage and may have utility in tracking early knee osteoarthritis development. Traditional assessment techniques focus on measurements at a single location, which can be challenging to adopt for novice raters. Objective : To introduce a novel semiautomated ultrasound segmentation technique and determine the intrarater and interrater reliability of average regional femoral articular cartilage thickness and echo intensity of a novice and expert rater. Design : Descriptive observational study. Setting : Orthopedic clinic. Patients or Other Participants : Fifteen participants (mean [SD]; age 23.5 [4.6] y, height = 172.6 [9.3] cm, mass = 79.8 [15.7] kg) with a unilateral history of anterior cruciate ligament reconstruction participated. Intervention : None. Main Outcome Measures : One rater captured anterior femoral cartilage images of the participants’ contralateral knees using a transverse suprapatellar ultrasound assessment. The total femoral cartilage cross-sectional area of each image was segmented by a novice and expert rater. A novel custom program automatically separated the cartilage segmentations into medial, lateral, and intercondylar regions to determine the cross-sectional area and cartilage length. The average cartilage thickness in each region was calculated by dividing the cross-sectional area by the cartilage length. Echo intensity was calculated as the average gray-scale pixel value of each region. Two-way random effect intraclass correlations coefficient (ICC) for absolute agreement were used to determine the interrater reliability between a novice and expert rater, as well as the intrarater reliability of the novice rater. Results : The novice rater demonstrated excellent intrarater (ICC [ 2,k ] range = .993–.997) and interrater (ICC [ 2,k ] range = .944–.991) reliability with the expert rater of all femoral articular cartilage average thickness and echo intensity regions. Conclusions : The novel semiautomated average cartilage thickness and echo-intensity assessment is efficient, systematic, and reliable between an expert and novice rater with minimal training. 

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4. Chemically modified curcumin (CMC2.24) alleviates osteoarthritis progression by restoring cartilage homeostasis and inhibiting chondrocyte apoptosis via the NF-κB/HIF-2α axis

   https://doi.org/10.1007/s00109-020-01972-1  

   Zhou, Yan; Ming, Jianghua; Deng, Ming; Li, Yaming; Li, Bochun; Li, Jia; Ma, Yonggang; Chen, Zhonghui; Wang, Guirong; Liu, Shiqing (August 2020, Journal of Molecular Medicine)

   Disorders of cartilage homeostasis and chondrocyte apoptosis are major events in the pathogenesis of osteoarthritis (OA). Herein, we sought to assess the chondroprotective effect and underlying mechanisms of a novel chemically modified curcumin, CMC2.24, in modulating extracellular matrix (ECM) homeostasis and inhibiting chondrocyte apoptosis. Rats underwent the anterior cruciate ligament transection and medial menisci resection were treated by intra-articular injection with CMC2.24. In vitro study, rat chondrocytes were pretreated with CMC2.24 before stimulation with sodium nitroprusside (SNP). The effects of CMC2.24 on cartilage homeostasis and chondrocyte apoptosis were observed. The results from in vivo studies demonstrated that the intra-articular administration of CMC2.24 delayed cartilage degeneration and suppressed chondrocyte apoptosis. CMC2.24 ameliorated osteoarthritic cartilage destruction by promoting collagen 2a1 production and inhibited cartilage degradation and apoptosis by suppressing hypoxia-inducible factor-2a (Hif-2α), matrix metalloproteinase-3 (MMP-3), runt-related transcription factor 2 (RUNX2), cleaved caspase-3, vascular endothelial growth factor (VEGF), and the phosphorylation of IκBα and NF-κB p65. The in vitro results revealed that CMC2.24 exhibited a strong inhibitory effect on SNP-induced chondrocyte catabolism and apoptosis. The SNP-enhanced expression of Hif-2α, catabolic and apoptotic factor, decreased after CMC2.24 treatment in a dose-dependent manner. CMC2.24 pretreatment effectively inhibited SNP-induced IκBα and NF-κB p65 phosphorylation in rat chondrocytes, whereas the pretreatment with NF-κB antagonist BMS-345541 significantly enhanced the effects of CMC2.24. Taken together, these results demonstrated that CMC2.24 attenuates OA progression by modulating ECM homeostasis and chondrocyte apoptosis via suppression of the NF-κB/Hif-2α axis, thus providing a new perspective for the therapeutic strategy of OA. 

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5. Assessing Human Articular Cartilage Transcriptome Layers with RNA Sequencing

   Pondipornnont, P; Van_Wie, BJ; Driskell, R; Driskell, I; Bonassar, LJ; Gozen, A; Dong, W; Scalise, D; Wildung, M; Matan, S; et al (October 2024, American Institute of Chemical Engineering)

   Osteoarthritis, a chronic disease, remains an issue for adults that causes cartilage degradation within a joint . According to the Centers forDisease Control and Prevention (2023), over 32.5 million adults in the US are affected by osteoarthritis (OA). In this study we seek tounderstand the connection between tissue engineering and genetics to regenerate human articular cartilage (hAC). We purpose to validatea protocol for RNA isolation and characterize the transcriptome of hAC in a tri-layer fashion via bulk RNA sequencing (bulk-RNA-seq).Additionally, we aim to analyze the transcriptome of normal articular cartilage in comparison to the hAC chemical composition and physicalproperties. We are relating these properties to the tri-layers of hAC through histological staining with Safranin O—Fast green and imagingwith differential interference contrast (DIC) microscopy. We are relating these properties to superfic ial, middle, and deep zone with acryotome procedure, RNA extracted, and qualified by Bioanalyzer. Next, we generate bulk RNA sequencing of hAC layer-by-layer andcompare results to early passaging of Mesenchymal Stromal Cells (MSC) and tissues intended for Matrix-Induced Autologous ChondrocyteImplantation (MACI). We will use differential gene expression (DE) analysis by DESeq2 R package software for bulk-RNA-seq. The resultwill be interpreted in terms of differentiation from MSCs to gene expression patterns of tri-layer hAC. We will report on development andvalidation of protocols for isolating cells and their subsequent characterization with application in regenerating the tri-layered hACtranscriptome stimulatory bioreactors used in our laboratory and corresponding properties of the extracellular matrix (ECM) 

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