Three-dimensional bioprinting of multicell-laden scaffolds containing bone morphogenic protein-4 for promoting M2 macrophage polarization and accelerating bone defect repair in diabetes mellitus

Xin Sun; Zhenjiang Ma; Xue Zhao; Wenjie Jin; Chenyu Zhang; Jie Ma; Lei Qiang; Wenhao Wang; Qian Deng; Han Yang; Jinzhong Zhao; Qianqian Liang; Xiaojun Zhou; Tao Li; Jinwu Wang

Bioactive Materials (Mar 2021)

Three-dimensional bioprinting of multicell-laden scaffolds containing bone morphogenic protein-4 for promoting M2 macrophage polarization and accelerating bone defect repair in diabetes mellitus

Xin Sun,
Zhenjiang Ma,
Xue Zhao,
Wenjie Jin,
Chenyu Zhang,
Jie Ma,
Lei Qiang,
Wenhao Wang,
Qian Deng,
Han Yang,
Jinzhong Zhao,
Qianqian Liang,
Xiaojun Zhou,
Tao Li,
Jinwu Wang

Affiliations

Xin Sun: Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China
Zhenjiang Ma: Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China
Xue Zhao: Department of Radiology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China; Department of Radiology, Minhang Hospital of Fudan University, Minhang Central Hospital, No. 170 Xinsong Road, Shanghai 201100, China
Wenjie Jin: Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China
Chenyu Zhang: Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China
Jie Ma: Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China
Lei Qiang: Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China; Southwest JiaoTong University College of Medicine, No. 111 North 1st Section of Second Ring Road, Chengdu, 610031, China
Wenhao Wang: Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China; Southwest JiaoTong University College of Medicine, No. 111 North 1st Section of Second Ring Road, Chengdu, 610031, China
Qian Deng: Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China; Southwest JiaoTong University College of Medicine, No. 111 North 1st Section of Second Ring Road, Chengdu, 610031, China
Han Yang: School of Biomedical Engineering, Shanghai JiaoTong University, No. 1956 Huashan Road, Shanghai, 200030, China
Jinzhong Zhao: Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600, Yishan Road, Shanghai 200233, China
Qianqian Liang: Spine Institute, Shanghai University of Traditional Chinese Medicine, No.1200 Cailun Road, Shanghai 200032, China
Xiaojun Zhou: College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, No. 2999, North Renmin Road, Shanghai 201620, China; Corresponding author.
Tao Li: Department of Orthopaedics, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine, No.1665 Kongjiang Road, Shanghai, 200092, China; Corresponding author.
Jinwu Wang: Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China; Corresponding author.

Journal volume & issue: Vol. 6, no. 3
pp. 757 – 769

Abstract

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Critical-sized bone defect repair in patients with diabetes mellitus remains a challenge in clinical treatment because of dysfunction of macrophage polarization and the inflammatory microenvironment in the bone defect region. Three-dimensional (3D) bioprinted scaffolds loaded with live cells and bioactive factors can improve cell viability and the inflammatory microenvironment and further accelerating bone repair. Here, we used modified bioinks comprising gelatin, gelatin methacryloyl (GelMA), and 4-arm poly (ethylene glycol) acrylate (PEG) to fabricate 3D bioprinted scaffolds containing BMSCs, RAW264.7 macrophages, and BMP-4-loaded mesoporous silica nanoparticles (MSNs). Addition of MSNs effectively improved the mechanical strength of GelMA/gelatin/PEG scaffolds. Moreover, MSNs sustainably released BMP-4 for long-term effectiveness. In 3D bioprinted scaffolds, BMP-4 promoted the polarization of RAW264.7 to M2 macrophages, which secrete anti-inflammatory factors and thereby reduce the levels of pro-inflammatory factors. BMP-4 released from MSNs and BMP-2 secreted from M2 macrophages collectively stimulated the osteogenic differentiation of BMSCs in the 3D bioprinted scaffolds. Furthermore, in calvarial critical-size defect models of diabetic rats, 3D bioprinted scaffolds loaded with MSNs/BMP-4 induced M2 macrophage polarization and improved the inflammatory microenvironment. And 3D bioprinted scaffolds with MSNs/BMP-4, BMSCs, and RAW264.7 cells significantly accelerated bone repair. In conclusion, our results indicated that implanting 3D bioprinted scaffolds containing MSNs/BMP-4, BMSCs, and RAW264.7 cells in bone defects may be an effective method for improving diabetic bone repair, owing to the direct effects of BMP-4 on promoting osteogenesis of BMSCs and regulating M2 type macrophage polarization to improve the inflammatory microenvironment and secrete BMP-2.

Published in Bioactive Materials

ISSN: 2452-199X (Online)
Publisher: KeAi Communications Co., Ltd.
Country of publisher: China
LCC subjects: Technology: Electrical engineering. Electronics. Nuclear engineering: Materials of engineering and construction. Mechanics of materials; Science: Biology (General)
Website: https://www.keaipublishing.com/en/journals/bioactive-materials/

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