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Published online on July 29, 2005, 10.1073/pnas.0504705102
PNAS | August 9, 2005 | vol. 102 | no. 32 | 11450-11455


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MEDICAL SCIENCES
In vivo engineering of organs: The bone bioreactor

Molly M. Stevens *, {dagger}, Robert P. Marini {ddagger}, Dirk Schaefer §, ¶, Joshua Aronson *, Robert Langer *, and V. Prasad Shastri ||, **

*Department of Chemical Engineering, Massachusetts Institute of Technology, 45 Carleton Street, E25-342, Cambridge, MA 02139; {dagger}Department of Materials, Imperial College London, Prince Consort Road, London SW7 2AZ, United Kingdom; {ddagger}Division of Comparative Medicine, Massachusetts Institute of Technology, 45 Carleton Street, E25-021, Cambridge, MA 02139; Department of Surgery, University of Basel, Spitalstrasse 21, 4031 Basel, Switzerland; and ||Department of Biomedical Engineering, Vanderbilt University, 5824 Stevenson Center, Nashville, TN 37232

Contributed by Robert Langer, June 8, 2005

Treatment of large defects requires the harvest of fresh living bone from the iliac crest. Harvest of this limited supply of bone is accompanied by extreme pain and morbidity. This has prompted the exploration of other alternatives to generate new bone using traditional principles of tissue engineering, wherein harvested cells are combined with porous scaffolds and stimulated with exogenous mitogens and morphogens in vitro and/or in vivo. We now show that large volumes of bone can be engineered in a predictable manner, without the need for cell transplantation and growth factor administration. The crux of the approach lies in the deliberate creation and manipulation of an artificial space (bioreactor) between the tibia and the periosteum, a mesenchymal layer rich in pluripotent cells, in such a way that the body's healing mechanism is leveraged in the engineering of neotissue. Using the "in vivo bioreactor" in New Zealand White rabbits, we have engineered bone that is biomechanically identical to native bone. The neobone formation followed predominantly an intramembraneous path, with woven bone matrix subsequently maturing into fully mineralized compact bone exhibiting all of the histological markers and mechanical properties of native bone. We harvested the bone after 6 weeks and transplanted it into contralateral tibial defects, resulting in complete integration after 6 weeks with no apparent morbidity at the donor site. Furthermore, in a proof-of-principle study, we have shown that by inhibiting angiogenesis and promoting a more hypoxic environment within the "in vivo bioreactor space," cartilage formation can be exclusively promoted.

cartilage | tissue engineering | hard tissue | vascularized organs

Author contributions: M.M.S., R.L., and V.P.S. designed research; M.M.S., R.P.M., D.S., J.A., and V.P.S. performed research; M.M.S. and J.A. analyzed data; and M.M.S., D.S., R.L., and V.P.S. wrote the paper.

Abbreviations: HA, hyaluronic acid; H&E, hematoxylin/eosin.

§ Deceased October 8, 2004.

** To whom correspondence should be addressed. E-mail: prasad.shastri{at}vanderbilt.edu.

© 2005 by The National Academy of Sciences of the USA


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