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Engineered Fibrin Gels for Parallel Stimulation of Mesenchymal Stem Cell Proangiogenic and Osteogenic Potential

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Abstract

Mesenchymal stem/stromal cells (MSCs) are under examination for use in cell therapies to repair bone defects resulting from trauma or disease. MSCs secrete proangiogenic cues and can be induced to differentiate into bone-forming osteoblasts, yet there is limited evidence that these events can be achieved in parallel. Manipulation of the cell delivery vehicle properties represents a candidate approach for directing MSC function in bone healing. We hypothesized that the biophysical properties of a fibrin gel could simultaneously regulate the proangiogenic and osteogenic potential of entrapped MSCs. Fibrin gels were formed by supplementation with NaCl (1.2, 2.3, and 3.9% w/v) to modulate gel biophysical properties without altering protein concentrations. MSCs entrapped in 1.2% w/v NaCl gels were the most proangiogenic in vitro, yet cells in 3.9% w/v gels exhibited the greatest osteogenic response. Compared to the other groups, MSCs entrapped in 2.3% w/v gels provided the best balance between proangiogenic potential, osteogenic potential, and gel contractility. The contribution of MSCs to bone repair was then examined when deployed in 2.3% w/v NaCl gels and implanted into an irradiated orthotopic bone defect. Compared to acellular gels after 3 weeks of implantation, defects treated with MSC-loaded fibrin gels exhibited significant increases in vessel density, early osteogenesis, superior morphology, and increased cellularity of repair tissue. Defects treated with MSC-loaded gels exhibited increased bone formation after 12 weeks compared to blank gels. These results confirm that fibrin gel properties can be modulated to simultaneously promote both the proangiogenic and osteogenic potential of MSCs, and fibrin gels modified by supplementation with NaCl are promising carriers for MSCs to stimulate bone repair in vivo.

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Acknowledgments

This work was supported by NIH Grants R03-DE021704 and R21-AG036963 and the AO Foundation (C10-39L) to JKL. This project was also supported by the California Institute for Regenerative Medicine UC Davis Stem Cell Training Program (CIRM T1-00006, CIRM TG2-01163) to BYB. We appreciate the assistance of Michael Kent, DVM, PhD, for his help in irradiating the animals and Mervin Yoder, M.D., for providing endothelial colony forming cells.

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The authors indicate no potential conflicts of interest.

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Authors and Affiliations

  1. Department of Biomedical Engineering, University of California, Davis, Davis, CA, 95616, USA

    Kaitlin C. Murphy, Marissa L. Hughbanks, Bernard Y. K. Binder, Caroline B. Vissers & J. Kent Leach

  2. Department of Orthopaedic Surgery, School of Medicine, University of California, Davis, Sacramento, CA, 95817, USA

    J. Kent Leach

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  1. Kaitlin C. Murphy
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  2. Marissa L. Hughbanks
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Correspondence to J. Kent Leach.

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Associate Editor Eric M. Darling oversaw the review of this article.

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Murphy, K.C., Hughbanks, M.L., Binder, B.Y.K. et al. Engineered Fibrin Gels for Parallel Stimulation of Mesenchymal Stem Cell Proangiogenic and Osteogenic Potential. Ann Biomed Eng 43, 2010–2021 (2015). https://doi.org/10.1007/s10439-014-1227-x

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