Pathogenesis-Guided Engineering of Multi-Bioactive Hydrogel Co-Delivering Inflammation-Resolving Nanotherapy and Pro-Osteogenic Protein for Bone Regeneration

作者全名："Liu, Shan; Wang, Wenle; Wu, Peng; Chen, Zhiyu; Pu, Wendan; Li, Lanlan; Li, Gang; Zhang, Jianxiang; Song, Jinlin"

作者地址："[Liu, Shan; Wang, Wenle; Song, Jinlin] Chongqing Med Univ, Chongqing Key Lab Oral Dis & Biomed Sci, Chongqing Municipal Key Lab Oral Biomed Engn Highe, Stomatol Hosp, Chongqing 401147, Peoples R China; [Liu, Shan; Wang, Wenle; Wu, Peng; Chen, Zhiyu; Pu, Wendan; Li, Lanlan; Li, Gang; Zhang, Jianxiang] Army Med Univ, Mil Med Univ 3, Coll Pharm, Dept Pharmaceut, Chongqing 400038, Peoples R China; [Wu, Peng] Vocat & Tech Coll, Coll Pharm & Med Technol, Hanzhong 723000, Shaanxi, Peoples R China; [Chen, Zhiyu] Chongqing Med Univ, Dept Orthoped, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Li, Gang] Army Med Univ, Mil Med Univ 3, Southwest Hosp, Dept Stomatol, Chongqing 400038, Peoples R China; [Zhang, Jianxiang] Army Med Univ, Mil Med Univ 3, Inst Combined Injury, State Key Lab Trauma Burn & Combined Injury, Chongqing 400038, Peoples R China"

通信作者："Song, JL (通讯作者)，Chongqing Med Univ, Chongqing Key Lab Oral Dis & Biomed Sci, Chongqing Municipal Key Lab Oral Biomed Engn Highe, Stomatol Hosp, Chongqing 401147, Peoples R China.; Li, G; Zhang, JX (通讯作者)，Army Med Univ, Mil Med Univ 3, Coll Pharm, Dept Pharmaceut, Chongqing 400038, Peoples R China.; Li, G (通讯作者)，Army Med Univ, Mil Med Univ 3, Southwest Hosp, Dept Stomatol, Chongqing 400038, Peoples R China.; Zhang, JX (通讯作者)，Army Med Univ, Mil Med Univ 3, Inst Combined Injury, State Key Lab Trauma Burn & Combined Injury, Chongqing 400038, Peoples R China."

来源：ADVANCED FUNCTIONAL MATERIALS

ESI学科分类：MATERIALS SCIENCE

WOS号：WOS:000976372000001

JCR分区：Q1

影响因子：18.5

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：bone defect; hydrogels; inflammation; nanotherapy; osteogenesis; osteoimmune environment

摘要："There are still great challenges in promoting bone defect repair via regeneration strategies. In view of delayed bone healing due to local inflammation, herein, pathogenesis-guided engineering of multi-bioactive hydrogel therapy is proposed for bone regeneration, by simultaneously improving the osteoimmune environment and enhancing osteogenic differentiation of stem cells. After discovering the pivotal role of persistent inflammation and bone loss in the pathogenesis of periodontitis by transcriptomics, a multi-bioactive nanotherapy based on self-assembled nanomicelles (PP5 NMs) is first developed. PP5 NMs effectively rescue osteogenesis of human periodontal ligament cells under pathological conditions and promote bone formation in rats with mandibular or cranial bone defects. By integrating PP5 NMs, a pro-osteogenic protein rhBMP9, and a hydrogel-forming temperature-responsive material, a multifunctional hydrogel therapy is further engineered, which can regulate the pro-inflammatory/oxidative microenvironment and accelerate bone regeneration. The obtained multi-bioactive hydrogel capable of co-delivering and sustainedly releasing PP5 NMs and rhBMP9 displays excellent bone regeneration capability, by synergistic effects of inflammation-resolving and pro-osteogenic differentiation of stem cells. Mechanistically, this hydrogel therapy improves the osteoimmune environment by attenuating pathogenesis and enhancing stem cell differentiation via the TLR4/NF-kappa B/HO-1 axis and activating the Smad1/5/8 protein complex. The hydrogel is promising for treating different inflammatory bone diseases."

基金机构："National Natural Science Foundation of China [82100986, U22A20314, 81971727]; Program for Scientific and Technological Innovation Leader of Chongqing [CQYC20210302362]; National Key R&D of Program of China [2022YFC2504200]; Natural Science Foundation of Chongqing [cstc2021jcyj-msxmX0414]"

基金资助正文："S.L. and W.L.W. contributed equally to this work. This study was supported by the National Natural Science Foundation of China (Nos. 82100986, U22A20314, and 81971727), the Program for Scientific and Technological Innovation Leader of Chongqing (No. CQYC20210302362), National Key R & D of Program of China (No. 2022YFC2504200), and the Natural Science Foundation of Chongqing (No. cstc2021jcyj-msxmX0414). All experiments regarding human periodontal ligament cells were approved by the Human Ethics Committee of Chongqing Medical University (Chongqing, China), approval No. CQHS-REC-2022 (LSNo.167). All animal experiments were performed in line with the Guide for the Care and Use of Laboratory Animals proposed by National Institutes of Health. All procedures and protocols were approved by the Animal Ethics Committee at Third Military Medical University (Chongqing, China), approval No. AMUWEC20211294."