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Matrix elasticity of void-forming hydrogels controls transplanted-stem-cell-mediated bone formation

Nature Materials volume 14, pages 1269–1277 (2015)Cite this article

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Abstract

The effectiveness of stem cell therapies has been hampered by cell death and limited control over fate. These problems can be partially circumvented by using macroporous biomaterials that improve the survival of transplanted stem cells and provide molecular cues to direct cell phenotype. Stem cell behaviour can also be controlled in vitro by manipulating the elasticity of both porous and non-porous materials, yet translation to therapeutic processes in vivo remains elusive. Here, by developing injectable, void-forming hydrogels that decouple pore formation from elasticity, we show that mesenchymal stem cell (MSC) osteogenesis in vitro, and cell deployment in vitro and in vivo, can be controlled by modifying, respectively, the hydrogel’s elastic modulus or its chemistry. When the hydrogels were used to transplant MSCs, the hydrogel’s elasticity regulated bone regeneration, with optimal bone formation at 60 kPa. Our findings show that biophysical cues can be harnessed to direct therapeutic stem cell behaviours in situ.

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Figure 1: Fabrication and characterization of void-forming hydrogels.
Figure 2: Manipulating stem cell osteogenesis and proliferation by controlling the elasticity of the bulk phase of void-forming hydrogels.
Figure 3: Controlling cell deployment kinetics from void-forming hydrogels in vitro and in vivo.
Figure 4: Matrix elasticity regulates MSC-mediated bone regeneration.

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Acknowledgements

We thank S. Gunasekaran for assistance with sample cryosectioning, R. Choa for assistance with histologic analyses, and M. Brenner and V. Manoharan (Harvard University) for discussions on percolation. We thank K. Tomodo, P.-L. So and E. Hsiao (Gladstone Institute, San Francisco) for helpful discussions and editorial suggestions. We also acknowledge support from the Materials Research Science and Engineering Center (MRSEC, DMR-1420570) at Harvard University (D.J.M., X.Z., N.H.), funding from NIH (R37 DE013033), the Belgian American Educational Foundation (E.L.), an NSF Graduate Research Fellowship (N.H.), an Einstein Visiting Fellowship (D.J.M.) and funding of the Einstein Foundation Berlin through the Charité—Universitätsmedizin Berlin, Berlin-Brandenburg School for Regenerative Therapies GSC 203, the Harvard College Research Program (C.M.M., M.X.) and Harvard College PRISE, Herchel-Smith and Pechet Family Fund Fellowships (M.X.).

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Author notes

  1. Nathaniel Huebsch & Kangwon Lee

    Present address: Present address: Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA (N.H.); Graduate School of Convergence Science and Technology, Seoul National University, Seoul 16229, Korea (K.L.).,

Authors and Affiliations

  1. Harvard University School of Engineering and Applied Sciences, Cambridge, Massachusetts 02138, USA

    Nathaniel Huebsch, Evi Lippens, Kangwon Lee, Manav Mehta, Sandeep T. Koshy, Max C. Darnell, Rajiv M. Desai, Christopher M. Madl, Maria Xu, Xuanhe Zhao, Ovijit Chaudhuri, Catia Verbeke, Woo Seob Kim, Karen Alim, Donald E. Ingber & David J. Mooney

  2. Wyss Institute for Biologically Inspired Engineering, Cambridge, Massachusetts 02138, USA

    Nathaniel Huebsch, Evi Lippens, Kangwon Lee, Manav Mehta, Sandeep T. Koshy, Max C. Darnell, Rajiv M. Desai, Ovijit Chaudhuri, Catia Verbeke, Woo Seob Kim, Donald E. Ingber & David J. Mooney

  3. Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts 02139, USA

    Nathaniel Huebsch & Sandeep T. Koshy

  4. Julius Wolff Institute, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany

    Manav Mehta & Georg N. Duda

  5. Berlin-Brandenburg Center for Regenerative Therapies, 13353 Berlin, Germany

    Manav Mehta & Georg N. Duda

  6. Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    Xuanhe Zhao

  7. Stanford University Department of Mechanical Engineering, Stanford, California 94305, USA

    Ovijit Chaudhuri

  8. Department of Plastic Surgery, College of Medicine, Chung-Ang University, Heuk Seok-Dong, Dong Jak-Gu, Seoul 156-755, Korea

    Woo Seob Kim

  9. Departments of Pathology & Surgery, Vascular Biology Program, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA

    Akiko Mammoto & Donald E. Ingber

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Contributions

The experiments were designed by N.H., E.L. and D.J.M. and carried out by N.H., K.L., M.M., A.M., M.C.D., R.D., S.T.K., C.V., E.L., C.M.M., M.X., O.C., W.S.K. and X.Z. New reagents and analytical tools were provided by M.M., G.N.D., K.A., A.M. and D.E.I. The manuscript was written by N.H. and D.J.M. The principal investigator is D.J.M.

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Correspondence to David J. Mooney.

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Huebsch, N., Lippens, E., Lee, K. et al. Matrix elasticity of void-forming hydrogels controls transplanted-stem-cell-mediated bone formation. Nature Mater 14, 1269–1277 (2015). https://doi.org/10.1038/nmat4407

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