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Bone Morphogenetic Protein-9–Stimulated Adipocyte-Derived Mesenchymal Progenitors Entrapped in a Thermoresponsive Nanocomposite Scaffold Facilitate Cranial Defect Repair

Lee, Cody S. BS*,†,‡; Bishop, Elliot S. MD; Dumanian, Zari BA; Zhao, Chen MD, PhD; Song, Dongzhe DDS, PhD; Zhang, Fugui DDS, PhD; Zhu, Yunxiao PhD§,||; Ameer, Guillermo A. ScD§,||; He, Tong-Chuan MD, PhD; Reid, Russell R. MD, PhD

doi: 10.1097/SCS.0000000000005465
Scientific Foundation

Due to availability and ease of harvest, adipose tissue is a favorable source of progenitor cells in regenerative medicine, but has yet to be optimized for osteogenic differentiation. The purpose of this study was to test cranial bone healing in a surgical defect model utilizing bone morphogenetic protein-9 (BMP-9) transduced immortalized murine adipocyte (iMAD) progenitor cells in a citrate-based, phase-changing, poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN)-gelatin scaffold. Mesenchymal progenitor iMAD cells were transduced with adenovirus expressing either BMP-9 or green fluorescent protein control. Twelve mice underwent craniectomy to achieve a critical-sized cranial defect. The iMAD cells were mixed with the PPCN-gelatin scaffold and injected into the defects. MicroCT imaging was performed in 2-week intervals for 12 weeks to track defect healing. Histologic analysis was performed on skull sections harvested after the final imaging at 12 weeks to assess quality and maturity of newly formed bone. Both the BMP-9 group and control group had similar initial defect sizes (P = 0.21). At each time point, the BMP-9 group demonstrated smaller defect size, higher percentage defect healed, and larger percentage defect change over time. At the end of the 12-week period, the BMP-9 group demonstrated mean defect closure of 27.39%, while the control group showed only a 9.89% defect closure (P < 0.05). The BMP-9-transduced iMADs combined with a PPCN-gelatin scaffold promote in vivo osteogenesis and exhibited significantly greater osteogenesis compared to control. Adipose-derived iMADs are a promising source of mesenchymal stem cells for further studies in regenerative medicine, specifically bone engineering with the aim of potential craniofacial applications.

*The University of Chicago Pritzker School of Medicine

Laboratory of Craniofacial Biology and Development, Section of Plastic and Reconstructive Surgery, Department of Surgery

Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago

§Department of Biomedical Engineering, Northwestern University, Evanston

||Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL.

Address correspondence and reprint requests to Russell R. Reid, MD, PhD, Section of Plastic and Reconstructive Surgery, Department of Surgery, The University of Chicago Medicine, 5841 S Maryland Ave, Chicago, IL 60637; E-mail:

Received 8 January, 2019

Accepted 11 February, 2019

The reported work was supported in part by research grants from the National Institutes of Health (DE020140 to RRR) and the Chicago Biomedical Consortium with support from the Searle Funds at The Chicago Community Trust (RRR, T-CH, and GAA). CSL was a recipient of the Pritzker Summer Research Program scholarship partially funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grant #T35DK062719-29. The authors report no conflicts of interest.

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© 2019 by Mutaz B. Habal, MD.