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Optimizing Collagen Scaffolds for Bone Engineering

Effects of Cross-linking and Mineral Content on Structural Contraction and Osteogenesis

Lee, Justine C. MD, PhD*,†; Pereira, Clifford T. MBBS*,†; Ren, Xiaoyan MD, PhD*,†; Huang, Weibiao PhD*,†; Bischoff, David PhD; Weisgerber, Daniel W. BA§; Yamaguchi, Dean T. MD, PhD; Harley, Brendan A. ScD§; Miller, Timothy A. MD*,†

doi: 10.1097/SCS.0000000000001918
Scientific Foundations

Introduction: Osseous defects of the craniofacial skeleton occur frequently in congenital, posttraumatic, and postoncologic deformities. The field of scaffold-based bone engineering emerged to address the limitations of using autologous bone for reconstruction of such circumstances. In this work, the authors evaluate 2 modifications of three-dimensional collagen-glycosaminoglycan scaffolds in an effort to optimize structural integrity and osteogenic induction.

Methods: Human mesenchymal stem cells (hMSCs) were cultured in osteogenic media on nonmineralized collagen-glycosaminoglycan (C-GAG) and nanoparticulate mineralized collagen-glycosaminoglycan (MC-GAG) type I scaffolds, in the absence and presence of cross-linking. At 1, 7, and 14 days, mRNA expression was analyzed using quantitative real-time -reverse-transcriptase polymerase chain reaction for osteocalcin (OCN) and bone sialoprotein (BSP). Structural contraction was measured by the ability of the scaffolds to maintain their original dimensions. Mineralization was detected by microcomputed tomographic (micro-CT) imaging at 8 weeks. Statistical analyses were performed with Student t-test.

Results: Nanoparticulate mineralization of collagen-glycosaminoglycan scaffolds increased expression of both OCN and BSP. Cross-linking of both C-GAG and MC-GAG resulted in decreased osteogenic gene expression; however, structural contraction was significantly decreased after cross-linking. Human mesenchymal stem cells-directed mineralization, detected by micro-CT, was increased in nanoparticulate mineralized scaffolds, although the density of mineralization was decreased in the presence of cross-linking.

Conclusions: Optimization of scaffold material is an essential component of moving toward clinically translatable engineered bone. Our current study demonstrates that the combination of nanoparticulate mineralization and chemical cross-linking of C-GAG scaffolds generates a highly osteogenic and structurally stable scaffold.

*Division of Plastic and Reconstructive Surgery, UCLA David Geffen School of Medicine

Division of Plastic and Reconstructive Surgery

Research Service, Greater Los Angeles VA Healthcare System, Los Angeles, CA

§Department of Chemical and Biomolecular Engineering, Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL.

Address correspondence and reprint requests to Justine C. Lee, MD, PhD, UCLA Division of Plastic and Reconstructive Surgery, 200 UCLA Medical Plaza, Suite 465, Los Angeles, CA 90095;. E-mail:

Received 27 June, 2014

Accepted 29 March, 2015

This work was supported by a Merit Review Grant (1I01BX001367-01A2) awarded by the U.S. Department of Veteran's Affairs (TAM), the Aramont Foundation, and the Jean Perkins Foundation (JCL). DWW was funded at UIUC from National Science Foundation (NSF) Grant 0965918 IGERT: Training the Next Generation of Researchers in Cellular and Molecular Mechanics and BioNanotechnologyThe authors report no conflicts of interest.

© 2015 by Mutaz B. Habal, MD.