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A New Porcine In Vivo Animal Model of Disc Degeneration: Response of Anulus Fibrosus Cells, Chondrocyte-Like Nucleus Pulposus Cells, and Notochordal Nucleus Pulposus Cells to Partial Nucleotomy

Omlor, Georg W., MD*; Nerlich, Andreas G., MD; Wilke, Hans-Joachim, PhD; Pfeiffer, Michael, MD§; Lorenz, Helga, DVM; Schaaf-Keim, Markus, MD*; Bertram, Helge, PhD; Richter, Wiltrud, PhD; Carstens, Claus, MD*; Guehring, Thorsten, MD

doi: 10.1097/BRS.0b013e3181b723c9
Basic Science
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Study Design. In vivo animal study.

Objectives. To describe a new porcine disc degeneration model, and to analyze disc remodeling and degeneration after nucleotomy with special view to the different nucleus pulposus (NP) cell types.

Summary of Background Data. Thus far, predominantly smaller animals were used for disc degeneration models; however, such small discs were inappropriate to investigate cell implementation therapies. Though notochordal cells (NCs) are important for disc formation and maintenance, differences in the amount of NCs between human and animal discs have often been neglected.

Methods. Twenty-four Goettingen minipigs underwent partial nucleotomy with a 16G biopsy cannula, to remove ∼10% of total NP volume. Animals were followed up for 3, or 24 weeks and analyzed by radiographs, MRIs, (immuno)histology, gene expression analysis, and biomechanical testing.

Results. Three weeks after nucleotomy disc height was reduced by 26%, and magnetic resonance imaging signal intensity by 40%. At 24 weeks disc height was decreased by 32%. Increased degenerative changes were found in a histodegeneration score 3 and 24 weeks after nucleotomy, as well as considerable NP scarification after 3 weeks. In controls, cytokeratin-8 immunohistochemistry identified NCs in proximity to chondrocyte-like NP cells at approximately equal ratio. After nucleotomy, NCs were considerably reduced to <10% of total NP cells. Matrix genes were upregulated, except for aggrecan that decreased to 35% of initial values 3 weeks after nucleotomy. Matrix degrading factors (matrix metalloproteinases 13 and 3) were continuously upregulated, whereas transcripts of their inhibitors (tissue inhibitors of matrix metalloproteinase 2 and 3) were downregulated. No significant changes in segmental spinal flexibility or bone density were found after nucleotomy.

Conclusion. We introduced a new disc degeneration model with relatively large discs that could be used for cell therapeutic approaches. The study gives further information about disc remodeling after nucleotomy and indicates the relevance of an altered cellular composition for the development of disc degeneration.

Partial disc nucleotomy was performed on Goettingen minipigs to establish a new disc degeneration model, that offers large scaled discs, and thus could be used for the development of cell therapeutic approaches. Three and 24 weeks after nucleotomy, degenerative changes were found on a histologic, radiologic, biomechanical, and biomolecular basis.

From the *Department of Orthopaedic Surgery, University of Heidelberg, Germany; †Institute of Pathology, Academic Hospital München-Bogenhausen, Germany; ‡Institute of Orthopaedic Research and Biomechanics, University of Ulm, Germany; §Department of Orthopaedic Surgery, HELIOS Rosmann Klinik Breisach a. Rhein, Germany; ¶Department of Experimental Orthopaedics, University of Heidelberg, Germany; and ∥Department of Trauma Surgery, BG-Hospital Ludwigshafen, University of Heidelberg, Germany.

Acknowledgment date: August 5, 2008. Revision date: February 24, 2009. Acceptance date: April 24, 2009.

The manuscript submitted does not contain information about medical device(s)/drug(s).

Institutional funds were received in support of this work. No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript.

Supported by a research fund of the Orthopedic University Hospital, Heidelberg, Germany.

Address correspondence and reprint requests to Thorsten Guehring, MD, Department of Trauma Surgery, BG-Hospital Ludwigshafen, Germany; E-mail: tguehrin@ix.urz.uni-heidelberg.de

© 2009 Lippincott Williams & Wilkins, Inc.