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Engineering anatomically shaped human bone grafts

Warren L. Grayson, Mirjam Fröhlich, Keith Yeager, Sarindr Bhumiratana, M. Ete Chan, Christopher Cannizzaro, Leo Q. Wan, X. Sherry Liu, X. Edward Guo, and Gordana Vunjak-Novakovic
PNAS February 23, 2010 107 (8) 3299-3304; https://doi.org/10.1073/pnas.0905439106
Warren L. Grayson
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Mirjam Fröhlich
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Keith Yeager
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Sarindr Bhumiratana
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M. Ete Chan
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Christopher Cannizzaro
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Leo Q. Wan
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X. Sherry Liu
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X. Edward Guo
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Gordana Vunjak-Novakovic
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  • For correspondence: gv2131@columbia.edu
  1. Edited by Stephen F. Badylak, University of Pittsburgh Medical Center, Pittsburgh, PA, and accepted by the Editorial Board September 1, 2009 (received for review May 20, 2009)

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Abstract

The ability to engineer anatomically correct pieces of viable and functional human bone would have tremendous potential for bone reconstructions after congenital defects, cancer resections, and trauma. We report that clinically sized, anatomically shaped, viable human bone grafts can be engineered by using human mesenchymal stem cells (hMSCs) and a “biomimetic” scaffold-bioreactor system. We selected the temporomandibular joint (TMJ) condylar bone as our tissue model, because of its clinical importance and the challenges associated with its complex shape. Anatomically shaped scaffolds were generated from fully decellularized trabecular bone by using digitized clinical images, seeded with hMSCs, and cultured with interstitial flow of culture medium. A bioreactor with a chamber in the exact shape of a human TMJ was designed for controllable perfusion throughout the engineered construct. By 5 weeks of cultivation, tissue growth was evidenced by the formation of confluent layers of lamellar bone (by scanning electron microscopy), markedly increased volume of mineralized matrix (by quantitative microcomputer tomography), and the formation of osteoids (histologically). Within bone grafts of this size and complexity cells were fully viable at a physiologic density, likely an important factor of graft function. Moreover, the density and architecture of bone matrix correlated with the intensity and pattern of the interstitial flow, as determined in experimental and modeling studies. This approach has potential to overcome a critical hurdle—in vitro cultivation of viable bone grafts of complex geometries—to provide patient-specific bone grafts for craniofacial and orthopedic reconstructions.

  • biomimetic
  • bioreactor
  • craniofacial regeneration
  • mesenchymal stem cells
  • temporomandibular joint
  • tissue engineering

Footnotes

  • 1To whom correspondence should be addressed. E-mail: gv2131{at}columbia.edu.
  • Author contributions: W.L.G. and G.V.-N. designed research; W.L.G., M.F., K.Y., S.B., M.E.C., C.C., L.Q.W., and X.S.L. performed research; W.L.G., M.F., S.B., L.Q.W., X.E.G., and G.V.-N. analyzed data; and W.L.G., K.Y., and G.V.-N. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission. S.F.B. is a guest editor invited by the Editorial Board.

  • This article contains supporting information online at www.pnas.org/cgi/content/full/0905439106/DCSupplemental.

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    Engineering anatomically shaped human bone grafts
    Warren L. Grayson, Mirjam Fröhlich, Keith Yeager, Sarindr Bhumiratana, M. Ete Chan, Christopher Cannizzaro, Leo Q. Wan, X. Sherry Liu, X. Edward Guo, Gordana Vunjak-Novakovic
    Proceedings of the National Academy of Sciences Feb 2010, 107 (8) 3299-3304; DOI: 10.1073/pnas.0905439106

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    Engineering anatomically shaped human bone grafts
    Warren L. Grayson, Mirjam Fröhlich, Keith Yeager, Sarindr Bhumiratana, M. Ete Chan, Christopher Cannizzaro, Leo Q. Wan, X. Sherry Liu, X. Edward Guo, Gordana Vunjak-Novakovic
    Proceedings of the National Academy of Sciences Feb 2010, 107 (8) 3299-3304; DOI: 10.1073/pnas.0905439106
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