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The demand of favorable scaffolds has increased for the emerging cartilage tissue engineering. Chondroitin sulfate (CS) and silk fibroin have been investigated and reported with ...safety and excellent biocompatibility as tissue engineering scaffolds. However, the rapid degradation rate of pure CS scaffolds presents a challenge to effectively recreate neo-tissue similar to natural articular cartilage. Meanwhile the silk fibroin is well used as a structural constituent material because its remarkable mechanical properties, long-lasting in vivo stability and hypoimmunity. The application of composite silk fibroin and CS scaffolds for joint cartilage repair has not been well studied. Here we report that the combination of silk fibroin and CS could synergistically promote articular cartilage defect repair. The silk fibroin (silk) and silk fibroin/CS (silk-CS) scaffolds were fabricated with salt-leaching, freeze-drying and crosslinking methodologies. The biocompatibility of the scaffolds was investigated in vitro by cell adhesion, proliferation and migration with human articular chondrocytes. We found that silk-CS scaffold maintained better chondrocyte phenotype than silk scaffold; moreover, the silk-CS scaffolds reduced chondrocyte inflammatory response that was induced by interleukin (IL)-1β, which is in consistent with the well-documented anti-inflammatory activities of CS. The in vivo cartilage repair was evaluated with a rabbit osteochondral defect model. Silk-CS scaffold induced more neo-tissue formation and better structural restoration than silk scaffold after 6 and 12weeks of implantation in ICRS histological evaluations. In conclusion, we have developed a silk fibroin/ chondroitin sulfate scaffold for cartilage tissue engineering that exhibits immuno-inhibition property and can improve the self-repair capacity of cartilage.
Severe cartilage defect such as osteoarthritis (OA) is difficult to self-repair because of its avascular, aneural and alymphatic nature. Current scaffolds often focus on providing sufficient mechanical support or bio-mimetic structure to promote cartilage repair. Thus, silk has been adopted and investigated broadly. However, inflammation is one of the most important factors in OA. But few scaffolds for cartilage repair reported anti-inflammation property. Meanwhile, chondroitin sulfate (CS) is a glycosaminoglycan present in the natural cartilage ECM, and has exhibited a number of useful biological properties including anti-inflammatory activity. Thus, we designed this silk-CS scaffold and proved that this scaffold exhibited good anti-inflammatory effects both in vitro and in vivo, promoted the repair of articular cartilage defect in animal model.
The most challenging aspects in treating articular cartilage injury include identifying the cellular and molecular mechanism(s) that lead to matrix changes and the differentiation and ...dedifferentiation behavior of chondrocytes, and understanding how they affect the structural integrity of the articular cartilage and tissue remodeling. Several treatment strategies have been proposed. A better understanding of the signaling pathways and growth and transcription factors for genes responsible for chondrogenesis is an important component in the development of new therapies to prevent cartilage degeneration or promote repair to replicate the physiologic and functional properties of the original cartilage.
Chondral and osteochondral lesions due to injury or other pathology commonly result in the development of osteoarthritis, eventually leading to progressive total joint destruction. Although current ...progress suggests that biologic agents can delay the advancement of deterioration, such drugs are incapable of promoting tissue restoration. The limited ability of articular cartilage to regenerate renders joint arthroplasty an unavoidable surgical intervention. This Review describes current, widely used clinical repair techniques for resurfacing articular cartilage defects; short-term and long-term clinical outcomes of these techniques are discussed. Also reviewed is a developmental pipeline of acellular and cellular regenerative products and techniques that could revolutionize joint care over the next decade by promoting the development of functional articular cartilage. Acellular products typically consist of collagen or hyaluronic-acid-based materials, whereas cellular techniques use either primary cells or stem cells, with or without scaffolds. Central to these efforts is the prominent role that tissue engineering has in translating biological technology into clinical products; therefore, concomitant regulatory processes are also discussed.
Osteoarthritis is one of the leading causes of pain and disability in the aged population due to articular cartilage damage. This warrants investigation of signaling mechanisms that could protect ...cartilage from degeneration and degradation. Here we show in a murine model of experimental osteoarthritis that YAP activation by transgenic overexpression or by deletion of its upstream inhibitory kinases Mst1/2 preserves articular cartilage integrity, whereas deletion of YAP in chondrocytes promotes cartilage disruption. Our work shows that YAP is both necessary and sufficient for the maintenance of cartilage homeostasis in osteoarthritis. Mechanistically, inflammatory cytokines, such as TNFα or IL-1β, trigger YAP/TAZ degradation through TAK1-mediated phosphorylation. Furthermore, YAP directly interacts with TAK1 and attenuates NF-κB signaling by inhibiting substrate accessibility of TAK1. Our study establishes a reciprocal antagonism between Hippo-YAP/TAZ and NF-κB signaling in regulating the induction of matrix-degrading enzyme expression and cartilage degradation during osteoarthritis pathogenesis.
Articular cartilage defects, caused by trauma, osteoarthritis, or other diseases, always lead to severe joint pain and joint dysfunction. Without access to progenitor cells and the supply of blood ...and nutrients, the impaired articular cartilage would be short of the capability to self-repair. Although the present clinical treatments, including autogenous and allograft osteochondral transplantation, microfracture technique, and so forth, have shown some efficacies, their drawbacks, such as donor insufficiency and poor-integration with adjacent tissue, limit the satisfactory repair of articular cartilage defects and cause unsatisfied prognosis. Cartilage tissue engineering, involving the combination of progenitor cells with scaffolds, which serve as artificial extracellular matrices (ECMs), provides a promising strategy for cartilage regeneration. Recently, thermosensitive hydrogels have attracted much attention as scaffolds for cartilage tissue engineering owing to their unique physical properties analogous to the native ECM. In this review, we summarize the fabrication, characterization of newly reported thermosensitive hydrogels as cartilage tissue engineering scaffolds. The potential challenges and future perspectives are proposed.
Articular cartilage is a connective tissue consisting of a specialized extracellular matrix （ECM） that dominates the bulk of its wet and dry weight. Type Ⅱ collagen and aggrecan are the main ECM ...proteins in cartilage. However, little attention has been paid to less abundant molecular components, especially minor collagens, including type Ⅳ, Ⅵ, Ⅸ, Ⅹ, Ⅺ, Ⅻ, ⅩⅢ, and ⅩⅣ, etc. Although accounting for only a small fraction of the mature matrix, these minor collagens not only play essential structural roles in the mechanical properties, organization, and shape of articular cartilage, but also fulfil specific biological functions. Genetic studies of these minor collagens have revealed that they are associated with multiple connective tissue diseases, especially degenerative joint disease. The progressive destruction of cartilage involves the degradation of matrix constituents including these minor collagens. The generation and release of fragmented molecules could generate novel biochemical markers with the capacity to monitor disease progression, facilitate drug development and add to the existing toolbox for in vitro studies, preclinical research and clinical trials.
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Articular cartilage is a remarkable tissue whose sophisticated composition and architecture allow it to withstand complex stresses within the joint. Once injured, cartilage lacks the ...capacity to self-repair, and injuries often progress to joint wide osteoarthritis (OA) resulting in debilitating pain and loss of mobility. Current palliative and surgical management provides short-term symptom relief, but almost always progresses to further deterioration in the long term. A number of bioactive factors, including drugs, corticosteroids, and growth factors, have been utilized in the clinic, in clinical trials, or in emerging research studies to alleviate the inflamed joint environment or to promote new cartilage tissue formation. However, these therapies remain limited in their duration and effectiveness. For this reason, current efforts are focused on improving the localization, retention, and activity of these bioactive factors. The purpose of this review is to highlight recent advances in drug delivery for the treatment of damaged or degenerated cartilage. First, we summarize material and modification techniques to improve the delivery of these factors to damaged tissue and enhance their retention and action within the joint environment. Second, we discuss recent studies using novel methods to promote new cartilage formation via biofactor delivery, that have potential for improving future long-term clinical outcomes. Lastly, we review the emerging field of orthobiologics, using delivered and endogenous cells as drug-delivering “factories” to preserve and restore joint health. Enhancing drug delivery systems can improve both restorative and regenerative treatments for damaged cartilage.
Articular cartilage is a remarkable and sophisticated tissue that tolerates complex stresses within the joint. When injured, cartilage cannot self-repair, and these injuries often progress to joint-wide osteoarthritis, causing patients debilitating pain and loss of mobility. Current palliative and surgical treatments only provide short-term symptomatic relief and are limited with regards to efficiency and efficacy. Bioactive factors, such as drugs and growth factors, can improve outcomes to either stabilize the degenerated environment or regenerate replacement tissue. This review highlights recent advances and novel techniques to enhance the delivery, localization, retention, and activity of these factors, providing an overview of the cartilage drug delivery field that can guide future research in restorative and regenerative treatments for damaged cartilage.
Modern concepts of osteoarthritis (OA) have been forever changed by modern imaging phenotypes demonstrating complex and multi-tissue pathologies involving cartilage, subchondral bone and ...(increasingly recognized) inflammation of the synovium. The synovium may show significant changes, even before visible cartilage degeneration has occurred, with infiltration of mononuclear cells, thickening of the synovial lining layer and production of inflammatory cytokines. The combination of sensitive imaging modalities and tissue examination has confirmed a high prevalence of synovial inflammation in all stages of OA, with a number of studies demonstrating that synovitis is related to pain, poor function and may even be an independent driver of radiographic OA onset and structural progression. Treating key aspects of synovial inflammation therefore holds great promise for analgesia and also for structure modification. This article will review current knowledge on the prevalence of synovitis in OA and its role in symptoms and structural progression, and explore lessons learnt from targeting synovitis therapeutically.
Osteoarthritis (OA) is the most common form of arthritis. It is characterized by progressive destruction of articular cartilage and the development of chronic pain and constitutes a considerable ...socioeconomic burden. Currently, pharmacological treatments mostly aim to relieve the OA symptoms associated with inflammation and pain. However, with increasing understanding of OA pathology, several potential therapeutic targets have been identified, enabling the development of disease-modifying OA drugs (DMOADs). By targeting inflammatory cytokines, matrix-degrading enzymes, the Wnt pathway, and OA-associated pain, DMOADs successfully modulate the degenerative changes in osteoarthritic cartilage. Moreover, regenerative approaches aim to counterbalance the loss of cartilage matrix by stimulating chondrogenesis in endogenous stem cells and matrix anabolism in chondrocytes. Emerging strategies include the development of senolytic drugs or RNA therapeutics to eliminate the cellular or molecular sources of factors driving OA. This review describes the current developmental status of DMOADs and the corresponding results from preclinical and clinical trials and discusses the potential of emerging therapeutic approaches to treat OA.
Circular RNAs (circRNAs) have emerged as significant biological regulators. Herein, we aimed to elucidate the role of an unidentified circRNA (circPDE4B) that is reportedly downregulated in ...osteoarthritis (OA) tissues.
The effects of circPDE4B were explored in human and mouse chondrocytes in vitro. Specifically, RNA pull-down (RPD)-mass spectrometry analysis (MS), immunoprecipitation, glutathione-S-transferase (GST) pull-down, RNA immunoprecipitation and RPD assays were performed to verify the interactions between circPDE4B and the RIC8 guanine nucleotide exchange factor A (RIC8A)/midline 1 (MID1) complex. A mouse model of OA was also employed to confirm the role of circPDE4B in OA pathogenesis in vivo.
circPDE4B regulates chondrocyte cell viability and extracellular matrix metabolism. Mechanistically, FUS RNA binding protein (FUS) was found to promote the splicing of circPDE4B, while downregulation of circPDE4B in OA is partially caused by upstream inhibition of FUS. Moreover, circPDE4B facilitates the association between RIC8A and MID1 by acting as a scaffold to promote RIC8A degradation through proteasomal degradation. Furthermore, ubiquitination of RIC8A at K415 abrogates RIC8A degradation. The circPDE4B-RIC8A axis was observed to play an important role in regulating downstream p38 mitogen-activated protein kinase (MAPK) signalling. Furthermore, delivery of a circPDE4B adeno-associated virus (AAV) abrogates the breakdown of cartilage matrix by medial meniscus destabilisation in mice, whereas a RIC8A AAV induces the opposite effect.
This work highlights the function of the circPDE4B-RIC8A axis in OA joints, as well as its regulation of MAPK-p38, suggesting this axis as a potential therapeutic target for OA.
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