Tissue engineering of bone and cartilage has progressed from simple to sophisticated materials with defined porosity, surface features, and the ability to deliver biological factors. To avoid eliciting a foreign body response due to inclusion of allogeneic cells, advances in functional scaffold design harness the endogenous ability of the body to regenerate. We review advancements in the surface and structural properties of typical polymeric, ceramic, and metallic scaffolds for orthopedic use. First, we provide an overview of methods and materials, with a focus on additive manufacturing and electrospinning. Multidimensional physical properties of scaffolds, including three-dimensional macrostructure, pore design, and two-dimensional hierarchical surface roughness, allow tissue regeneration at different spatial and temporal scales. Enhanced biological response can be achieved through surface functionalization and the use of exogenous factors. Finally, different in vitro and in vivo models are discussed for translation of these technologies for clinical use. Impact Statement: Challenges in musculoskeletal tissue regeneration affect millions of patients globally. Scaffolds for tissue engineering bone and cartilage provide promising solutions that increase healing and decrease need for complicated surgical procedures. Porous scaffolds have emerged as an attractive alternative to traditional scaffolds. However, the success of advanced materials, use of biological factors, and manufacturing techniques can vary depending on use case. This review provides perspective on porous scaffold manufacturing, characterization and application, and can be used to inform future scaffold design.

Circular RNAs (circRNAs) are involved in the development of various diseases, but there is little knowledge of circRNAs in osteoarthritis (OA). The aim of study was to identify circRNA expression in articular cartilage and to explore the function of chondrocyte extracellular matrix (ECM)-related circRNAs (circRNA-CER) in cartilage. To identify circRNAs that are specifically expressed in cartilage, we compared the expression of circRNAs in OA cartilage with that in normal cartilage. Bioinformatics was employed to predict the interaction of circRNAs and mRNAs in cartilage. Loss-of-function and rescue experiments for circRNA-CER were performed in vitro. A total of 71 circRNAs were differentially expressed in OA and normal cartilage. CircRNA-CER expression increased with interleukin-1 and tumor necrosis factor levels in chondrocytes. Silencing of circRNA-CER using small interfering RNA suppressed MMP13 expression and increased ECM formation. CircRNA-CER could compete for miR-136 with MMP13. Our results demonstrated that circRNA-CER regulated MMP13 expression by functioning as a competing endogenous RNA (ceRNA) and participated in the process of chondrocyte ECM degradation. We propose that circRNA-CER could be used as a potential target in OA therapy.

Degradation of extracellular matrix (ECM) underlies loss of cartilage tissue in osteoarthritis, a common disease for which no effective disease-modifying therapy currently exists. Here we describe BNTA, a small molecule with ECM modulatory properties. BNTA promotes generation of ECM components in cultured chondrocytes isolated from individuals with osteoarthritis. In human osteoarthritic cartilage explants, BNTA treatment stimulates expression of ECM components while suppressing inflammatory mediators. Intra-articular injection of BNTA delays the disease progression in a trauma-induced rat model of osteoarthritis. Furthermore, we identify superoxide dismutase 3 (SOD3) as a mediator of BNTA activity. BNTA induces SOD3 expression and superoxide anion elimination in osteoarthritic chondrocyte culture, and ectopic SOD3 expression recapitulates the effect of BNTA on ECM biosynthesis. These observations identify SOD3 as a relevant drug target, and BNTA as a potential therapeutic agent in osteoarthritis.

Objective: Long noncoding RNAs (lncRNAs) play crucial regulatory roles in diverse biologic processes, but knowledge of lncRNAs in osteoarthritis (OA) is limited. The aim of this study was to identify lncRNA expression in articular cartilage and to explore the function of cartilage injury–related lncRNAs (lncRNA‐CIR) in OA.Methods: To identify lncRNAs specifically expressed in OA cartilage, we compared the expression of lncRNAs in OA cartilage with that in normal cartilage using microarray and quantitative polymerase chain reaction (qPCR) analyses. In OA cartilage, lncRNA‐CIR was specifically, differentially, and highly expressed. The function of lncRNA‐CIR was determined by silencing and overexpression in vitro. Extracellular matrix (ECM)–related molecules were detected by qPCR, Western blot, and immunofluorescence analyses.Results: Up to 152 lncRNAs were found to be differentially expressed (>8‐fold) in OA and normal cartilage (82 lncRNAs more highly expressed and 70 less highly expressed in OA cartilage than in normal cartilage). A specific differentially expressed lncRNA‐CIR was selected according to the results of the higher expression in OA cartilage and OA chondrocytes. The expression of lncRNA‐CIR increased in chondrocytes with in vitro treatment with interleukin‐1β and tumor necrosis factor α. Silencing of lncRNA‐CIR by small interfering RNA promoted the formation of collagen and aggrecan and reduced the expression of matrix‐degrading enzymes, such as MMP13 and ADAMTS5. The expression of collagen and aggrecan was reduced, whereas the expression of matrix‐degrading enzymes was increased, after overexpression of lncRNA‐CIR.Conclusion: The results indicate that lncRNA‐CIR contributes to ECM degradation and plays a key role in the pathogenesis of OA. We propose that lncRNA‐CIR could be used as a potential target in OA therapy.