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ACS Biomater Sci Eng. 2018 Aug 13;4(8):2943-2955. doi: 10.1021/acsbiomaterials.8b00179. Epub 2018 Jun 7.

Thermoresponsive Citrate-Based Graphene Oxide Scaffold Enhances Bone Regeneration from BMP9-Stimulated Adipose-Derived Mesenchymal Stem Cells.

Zhao C1,2, Zeng Z2,3, Qazvini NT4, Yu X1,2, Zhang R2,3, Yan S2,3, Shu Y2,3, Zhu Y5,6, Duan C5, Bishop E7, Lei J1,2, Zhang W2,8, Yang C2,3, Wu K2,3, Wu Y2,9, An L2,10, Huang S1,2, Ji X2,3, Gong C11, Yuan C2,12, Zhang L2,3, Liu W1,2, Huang B2,3, Feng Y1,2, Zhang B2,10, Dai Z2,13, Shen Y2,14, Wang X2,3, Luo W2,3, Oliveira L2, Athiviraham A2, Lee MJ2, Wolf JM2, Ameer GA5,15,6, Reid RR2,7,6, He TC2,3,6, Huang W1.

Author information

1
Departments of Orthopedic Surgery, Nephrology, Cardiology, Clinical Laboratory Medicine, and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Chongqing 400016, China.
2
Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, 5841 South Maryland Avenue MC 3079, Chicago, Illinois 60637, United States.
3
Ministry of Education Key Laboratory of Diagnostic Medicine and School of Laboratory Medicine, The Affiliated Hospitals of Chongqing Medical University, 1 Medical College Road, Chongqing 400016, China.
4
Institute for Molecular Engineering, The University of Chicago, 5640 South Ellis Avenue, Chicago, Illinois 60637, United States.
5
Department of Biomedical Engineering, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States.
6
Center for Advanced Regenerative Engineering (CARE), 2145 Sheridan Road, Evanston, IL 60208, United States.
7
Department of Surgery, Laboratory of Craniofacial Biology and Development, Section of Plastic Surgery, The University of Chicago Medical Center, 5841 South Maryland Avenue MC6035, Chicago, Illinois 60637, United States.
8
Department of Laboratory Medicine and Clinical Diagnostics, The Affiliated University-Town Hospital of Chongqing Medical University, 55 Daxuecheng Zhonglu, Chongqing 401331, China.
9
Department of Immunology and Microbiology, Beijing University of Chinese Medicine, 11 N. Third Ring Road E., Beijing 100029, China.
10
Key Laboratory of Orthopaedic Surgery of Gansu Province and the Department of Orthopaedic Surgery, The Second Hospital of Lanzhou University, 82 Cuiyingmen, Lanzhou 730030, China.
11
Department of General Surgery, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan 430071, China.
12
Department of Biochemistry and Molecular Biology, China Three Gorges University School of Medicine, 8 Daxue Road, Yichang 443002, China.
13
Department of Orthopaedic Surgery, Chongqing Hospital of Traditional Chinese Medicine, 35 Jianxin East Road, Chongqing 400021, China.
14
Department of Orthopaedic Surgery, Xiangya Second Hospital of Central South University, 139 Renmin Road, Changsha 410011, China.
15
Department of Surgery, Feinberg School of Medicine, Northwestern University, 420 East Superior Street, Chicago, Illinois 60616, United States.

Abstract

Effective bone tissue engineering is important to overcome the unmet clinical challenges as more than 1.6 million bone grafts are done annually in the United States. Successful bone tissue engineering needs minimally three critical constituents: osteoprogenitor cells, osteogenic factors, and osteoinductive/osteoconductive scaffolds. Osteogenic progenitors are derived from multipotent mesenchymal stem cells (MSCs), which can be prepared from numerous tissue sources, including adipose tissue. We previously showed that BMP9 is the most osteogenic BMP and induces robust bone formation of immortalized mouse adipose-derived MSCs entrapped in a citrate-based thermoresponsive hydrogel referred to as PPCNg. As graphene and its derivatives emerge as promising biomaterials, here we develop a novel thermosensitive and injectable hybrid material by combining graphene oxide (GO) with PPCNg (designated as GO-P) and characterize its ability to promote bone formation. We demonstrate that the thermoresponsive behavior of the hybrid material is maintained while effectively supporting MSC survival and proliferation. Furthermore, GO-P induces early bone-forming marker alkaline phosphatase (ALP) and potentiates BMP9-induced expression of osteogenic regulators and bone markers as well as angiogenic factor VEGF in MSCs. In vivo studies show BMP9-transduced MSCs entrapped in the GO-P scaffold form well-mineralized and highly vascularized trabecular bone. Thus, these results indicate that GO-P hybrid material may function as a new biocompatible, injectable scaffold with osteoinductive and osteoconductive activities for bone regeneration.

KEYWORDS:

BMP9; PPCN; bone tissue engineering; graphene; graphene oxide; mesenchymal stem cells; scaffold; thermoresponsive

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