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    Functionalization of Novel Theranostic Hydrogels with Kartogenin-Grafted USPIO Nanoparticles To Enhance Cartilage Regeneration. Yang Wei,Zhu Ping,Huang Huanlei,Zheng Yuanyuan,Liu Jian,Feng Longbao,Guo Huiming,Tang Shuo,Guo Rui ACS applied materials & interfaces Here, kartogenin (KGN), an emerging stable nonprotein compound with the ability to promote differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) into chondrocytes, was grafted onto the surface of modified ultrasmall superparamagnetic iron-oxide (USPIO) and then integrated into cellulose nanocrystal/dextran hydrogels. The hydrogels served as a carrier for the USPIO-KGN and a matrix for cartilage repair. We carried out in vitro and in vivo studies, the results of which demonstrated that KGN undergoes long-term stable sustained release, recruits endogenous host cells, and induces BMSCs to differentiate into chondrocytes, thus enabling in situ cartilage regeneration. Meanwhile, the USPIO-incorporated theranostic hydrogels exhibited a distinct magnetic resonance contrast enhancement and maintained a stable relaxation rate, with almost no loss, both in vivo and in vitro. According to noninvasive in vivo observation results and immunohistochemistry analyses, the regenerated cartilage tissue was very similar to natural hyaline cartilage. This innovative diagnosis and treatment system increases the convenience and effectiveness of chondrogenesis. 10.1021/acsami.9b12288
    Mesenchymal Stromal/stem Cell-derived Extracellular Vesicles Promote Human Cartilage Regeneration . Vonk Lucienne A,van Dooremalen Sanne F J,Liv Nalan,Klumperman Judith,Coffer Paul J,Saris Daniël B F,Lorenowicz Magdalena J Theranostics Osteoarthritis (OA) is a rheumatic disease leading to chronic pain and disability with no effective treatment available. Recently, allogeneic human mesenchymal stromal/stem cells (MSC) entered clinical trials as a novel therapy for OA. Increasing evidence suggests that therapeutic efficacy of MSC depends on paracrine signalling. Here we investigated the role of extracellular vesicles (EVs) secreted by human bone marrow derived MSC (BMMSC) in human OA cartilage repair. METHODS:To test the effect of BMMSC-EVs on OA cartilage inflammation, TNF-alpha-stimulated OA chondrocyte monolayer cultures were treated with BMMSC-EVs and pro-inflammatory gene expression was measured by qRT-PCR after 48 h. To assess the impact of BMMSC-EVs on cartilage regeneration, BMMSC-EVs were added to the regeneration cultures of human OA chondrocytes, which were analyzed after 4 weeks for glycosaminoglycan content by 1,9-dimethylmethylene blue (DMMB) assay. Furthermore, paraffin sections of the regenerated tissue were stained for proteoglycans (safranin-O) and type II collagen (immunostaining). RESULTS:We show that BMMSC-EVs inhibit the adverse effects of inflammatory mediators on cartilage homeostasis. When co-cultured with OA chondrocytes, BMMSC-EVs abrogated the TNF-alpha-mediated upregulation of COX2 and pro-inflammatory interleukins and inhibited TNF-alpha-induced collagenase activity. BMMSC-EVs also promoted cartilage regeneration . Addition of BMMSC-EVs to cultures of chondrocytes isolated from OA patients stimulated production of proteoglycans and type II collagen by these cells. CONCLUSION:Our data demonstrate that BMMSC-EVs can be important mediators of cartilage repair and hold great promise as a novel therapeutic for cartilage regeneration and osteoarthritis. 10.7150/thno.20746
    Functionality of decellularized matrix in cartilage regeneration: A comparison of tissue versus cell sources. Sun Yu,Yan Lianqi,Chen Song,Pei Ming Acta biomaterialia Increasing evidence indicates that decellularized extracellular matrices (dECMs) derived from cartilage tissues (T-dECMs) or chondrocytes/stem cells (C-dECMs) can support proliferation and chondrogenic differentiation of cartilage-forming cells. However, few review papers compare the differences between these dECMs when they serve as substrates for cartilage regeneration. In this review, after an introduction of cartilage immunogenicity and decellularization methods to prepare T-dECMs and C-dECMs, a comprehensive comparison focuses on the effects of T-dECMs and C-dECMs on proliferation and chondrogenic differentiation of chondrocytes/stem cells in vitro and in vivo. Key factors within dECMs, consisting of microarchitecture characteristics and micromechanical properties as well as retained insoluble and soluble matrix components, are discussed in-depth for potential mechanisms underlying the functionality of these dECMs in regulating chondrogenesis. With this information, we hope to benefit dECM based cartilage engineering and tissue regeneration for future clinical application. STATEMENT OF SIGNIFICANCE:The use of decellularized extracellular matrix (dECM) is becoming a promising approach for tissue engineering and regeneration. Compared to dECM derived from cartilage tissue, recently reported dECM from cell sources exhibits a distinct role in cell based cartilage regeneration. In this review paper, for the first time, tissue and cell based dECMs are comprehensively compared for their functionality in cartilage regeneration. This information is expected to provide an update for dECM based cartilage regeneration. 10.1016/j.actbio.2018.04.048
    Lyophilized Scaffolds Fabricated from 3D-Printed Photocurable Natural Hydrogel for Cartilage Regeneration. Xia Huitang,Zhao Dandan,Zhu Hailin,Hua Yujie,Xiao Kaiyan,Xu Yong,Liu Yanqun,Chen Weiming,Liu Yu,Zhang Wenjie,Liu Wei,Tang Shengjian,Cao Yilin,Wang Xiaoyun,Chen Harry Huimin,Zhou Guangdong ACS applied materials & interfaces Repair of cartilage defects is highly challenging in clinical treatment. Tissue engineering provides a promising approach for cartilage regeneration and repair. As a core component of tissue engineering, scaffolds have a crucial influence on cartilage regeneration, especially in immunocompetent large animal and human. Native polymers, such as gelatin and hyaluronic acid, have known as ideal biomimetic scaffold sources for cartilage regeneration. However, how to precisely control their structure, degradation rate, and mechanical properties suitable for cartilage regeneration remains a great challenge. To address these issues, a series of strategies were introduced in the current study to optimize the scaffold fabrication. First, gelatin and hyaluronic acid were prepared into a hydrogel and 3D printing was adopted to ensure precise control in both the outer 3D shape and internal pore structure. Second, methacrylic anhydride and a photoinitiator were introduced into the hydrogel system to make the material photocurable during 3D printing. Finally, lyophilization was used to further enhance mechanical properties and prolong degradation time. According to the current results, by integrating photocuring 3D printing and lyophilization techniques, gelatin and hyaluronic acid were successfully fabricated into human ear- and nose-shaped scaffolds, and both scaffolds achieved shape similarity levels over 90% compared with the original digital models. The scaffolds with 50% infill density achieved proper internal pore structure suitable for cell distribution, adhesion, and proliferation. Besides, lyophilization further enhanced mechanical strength of the 3D-printed hydrogel and slowed its degradation rate matching to cartilage regeneration. Most importantly, the scaffolds combined with chondrocytes successfully regenerated mature cartilage with typical lacunae structure and cartilage-specific extracellular matrixes both in vitro and in the autologous goat model. The current study established novel scaffold-fabricated strategies for native polymers and provided a novel natural 3D scaffold with satisfactory outer shape, pore structure, mechanical strength, degradation rate, and weak immunogenicity for cartilage regeneration. 10.1021/acsami.8b10926