Hypoxia-mimicking scaffolds with controlled release of DMOG and PTHrP to promote cartilage regeneration via the HIF-1 alpha/YAP signaling pathway

作者全名："Chen, Li; Huang, Xiao; Chen, Hong; Bao, Dingsu; Su, Xudong; Wei, Li; Hu, Ning; Huang, Wei; Xiang, Zhou"

作者地址："[Chen, Li; Huang, Xiao; Chen, Hong; Su, Xudong; Wei, Li; Hu, Ning; Huang, Wei] Chongqing Med Univ, Dept Orthoped, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Chen, Li; Xiang, Zhou] Sichuan Univ, West China Hosp, Dept Orthoped, Chengdu 610041, Sichuan, Peoples R China; [Bao, Dingsu] Southwest Med Univ, Dept Orthoped, Affiliated Tradit Chinese Med Hosp, Luzhou 646000, Sichuan, Peoples R China"

通信作者："Hu, N; Huang, W (通讯作者)，Chongqing Med Univ, Dept Orthoped, Affiliated Hosp 1, Chongqing 400016, Peoples R China.; Xiang, Z (通讯作者)，Sichuan Univ, West China Hosp, Dept Orthoped, Chengdu 610041, Sichuan, Peoples R China."

来源：INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:000906643800001

JCR分区：Q1

影响因子：8.2

年份：2023

卷号：226

期号：　

开始页：716

结束页：729

文献类型：Article

关键词：Dimethyloxalylglycine; Parathyroid hormone-related protein; Scaffold; Controlled release; Hypoxia; Chondrogenesis

摘要："Efficiently driving chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) while avoiding undesired hypertrophy remains a challenge in the field of cartilage tissue engineering. Here, we report the sequential combined application of dimethyloxalylglycine (DMOG) and parathyroid hormone-related protein (PTHrP) to facilitate chondrogenesis and prevent hypertrophy. To support their delivery, poly(lactic-co-glycolic acid) (PLGA) microspheres were fabricated using a double emulsion method. Subsequently, these microspheres were incorporated onto a poly(l-lactic acid) (PLLA) scaffold with a highly porous structure, high inter -connectivity and collagen-like nanofiber architecture to construct a microsphere-based scaffold delivery system. These functional constructs demonstrated that the spatiotemporally controlled release of DMOG and PTHrP effectively mimicked the hypoxic microenvironment to promote chondrogenic differentiation with phenotypic stability in a 3D culture system, which had a certain correlation with the interaction between hypoxia-inducible Factor 1 alpha (HIF-1 alpha) and yes-associated protein (YAP). Subcutaneous implantation in nude mice revealed that the constructs were able to maintain cartilage formation in vivo at 4 and 8 weeks. Overall, this study indicated that DMOG and PTHrP controlled-release PLGA microspheres incorporated with PLLA nanofibrous scaffolds provided an advantageous 3D hypoxic microenvironment for efficacious and clinically relevant cartilage regeneration and is a promising treatment for cartilage injury."

基金机构：National Natural Science Foundation of China; China Postdoctoral Science Foun-dation; Joint Project of Chongqing Health Commission and Science and Technology Bureau; [82072443]; [2022M710557]; [2019ZDXM014]

基金资助正文："Acknowledgments This work was supported by the National Natural Science Foundation of China (Grant No. 82072443) , the China Postdoctoral Science Foun-dation (Grant No. 2022M710557) , and Joint Project of Chongqing Health Commission and Science and Technology Bureau (Grant No. 2019ZDXM014) . We thank American Journal Experts (AJE) for English language editing."