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Chih-Sheng Chiang,1 Jian-Yi Chen,1 Min-Yu Chiang,1 Kai-Ting Hou,1 Wei-Ming Li,1 Shwu-Jen Chang,2 San-Yuan Chen11Department of Materials Science and Engineering, National Chiao Tung University, Hsinchu, Taiwan; 2Department of Biomedical Engineering, I-Shou University, Kaohsiung, TaiwanIntroduction: Stimulating the proliferation and differentiation of chondrocytes for the regeneration of articular cartilage is a promising strategy, but it is currently ineffective. Although both physical stimulation and growth factors play important roles in cartilage repair, their interplay remains unclear and requires further investigation. In this study, we aimed to clarify their contribution using a magnetic drug carrier that not only can deliver growth factors but also provide an external stimulation to cells in the two-dimensional environment.Materials and methods: We developed a nanocapsule (transforming growth factor-β1 [TGF-β1]-loaded magnetic amphiphilic gelatin nanocapsules [MAGNCs]; TGF-β1@MAGNCs) composed of hexanoic-anhydride-grafted gelatin and iron oxide nanoparticles to provide a combination treatment of TGF-β1 and magnetically induced physical stimuli. With the expression of Arg-Gly-Asp peptide in the gelatin, the TGF-β1@MAGNCs have an inherent affinity for chondrogenic ATDC5 cells.Results: In the absence of TGF-β1, ATDC5 cells treated with a magnetic field show significantly upregulated Col2a1 expression. Moreover, TGF-β1 slowly released from biodegradable TGF-β1@MAGNCs further improves the differentiation with increased expression of Col2a1 and Aggrecan.Conclusion: Our study shows the time-dependent interplay of physical stimuli and growth factors on chondrogenic regeneration, and demonstrates the promising use of TGF-β1@MAGNCs for articular cartilage repair.Keywords: physical stimuli, chondrogenic regeneration, TGF-β1, amphiphilic gelatin, combination stimuli