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  3. Alkaline shear-thinning micro-nanocomposite hydrogels initiate endogenous TGFβ signaling for in situ bone regeneration

Alkaline shear-thinning micro-nanocomposite hydrogels initiate endogenous TGFβ signaling for in situ bone regeneration

  • NPJ Regen Med. 2023 Oct 13;8(1):56. doi: 10.1038/s41536-023-00333-z.
Yuting Niu # 1 2,  Zhen Yang # 3 4,  Yang Yang 3 4,  Xu Wang 3 4,  Ping Zhang 3 4,  Longwei Lv 3 4,  Sainan Wang 3 5,  Yan Liu 6 7 8,  Yunsong Liu 9 10,  Yongsheng Zhou 11 12
Affiliations

Affiliations

  • 1 Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, 100081, PR China. yuting.niu@bjmu.edu.cn.
  • 2 National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Translational Research Center for Orocraniofacial Stem Cells and Systemic Health, No. 22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, PR China. yuting.niu@bjmu.edu.cn.
  • 3 National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Translational Research Center for Orocraniofacial Stem Cells and Systemic Health, No. 22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, PR China.
  • 4 Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, 100081, PR China.
  • 5 Department of Cariology and Endodontology, Peking University School and Hospital of Stomatology, Beijing, 100081, PR China.
  • 6 Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, 100081, PR China. orthoyan@bjmu.edu.cn.
  • 7 National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Translational Research Center for Orocraniofacial Stem Cells and Systemic Health, No. 22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, PR China. orthoyan@bjmu.edu.cn.
  • 8 Laboratory of Biomimetic Nanomaterials, Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, 100081, PR China. orthoyan@bjmu.edu.cn.
  • 9 National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Translational Research Center for Orocraniofacial Stem Cells and Systemic Health, No. 22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, PR China. liuyunsong@hsc.pku.edu.cn.
  • 10 Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, 100081, PR China. liuyunsong@hsc.pku.edu.cn.
  • 11 National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Translational Research Center for Orocraniofacial Stem Cells and Systemic Health, No. 22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, PR China. kqzhouysh@hsc.pku.edu.cn.
  • 12 Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, 100081, PR China. kqzhouysh@hsc.pku.edu.cn.
  • # Contributed equally.
PMID: 37833374 DOI: 10.1038/s41536-023-00333-z
Abstract

Recruiting endogenous stem cells to bone defects without stem cell transplantation and exogenous factor delivery represents a promising strategy for bone regeneration. Herein, we develop an alkaline shear-thinning micro-nanocomposite hydrogel (10-MmN), aiming to alkaline-activate endogenous TGFβ1 and achieve in situ bone regeneration. It contains polyethyleneimine (PEI)-modified gelatin, laponite nanoplatelets (LAP), a bicarbonate buffer with a pH of 10, and gelatin microspheres (MSs). PEI-modified gelatin plays a pivotal role in hydrogel fabrication. It endows the system with sufficient positive charges, and forms a shear-thinning nanocomposite matrix in the pH 10 buffer (10-mN) with negatively charged LAP via electrostatic gelation. For biological functions, the pH 10 buffer dominates alkaline activation of endogenous serum TGFβ1 to recruit rat bone marrow stem cells through the Smad pathway, followed by improved osteogenic differentiation. In addition, MSs are incorporated into 10-mN to form 10-MmN, and function as substrates to provide good attachment sites for the recruited stem cells and facilitate further their osteogenic differentiation. In a rat critical-sized calvarial defect model, 10-MmN exhibits excellent biocompatibility, biodegradability, hydrogel infusion and retention in bone defects with flexible shapes and active bleeding. Importantly, it repairs ~95% of the defect areas in 3 months by recruiting TGFβR2+ and CD90+CD146+ stem cells, and promoting cell proliferation, osteogenic differentiation and bone formation. The present study provides a biomaterial-based strategy to regulate alkalinity in bone defects for the initiation of endogenous TGFβ signaling, which can be extended to treat Other Diseases.

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