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Mesenchymal Stem Cell Concentration and Bone Repair: Potential Pitfalls from Bench to Bedside

¹ David Geffen School of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, 16-155 CHS, Los Angeles, CA 90095
² New England Musculoskeletal Institute, Department of Orthopaedic Surgery, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030. E-mail address for J.R. Lieberman: JLieberman{at}uchc.edu
³ Department of Aerospace and Mechanical Engineering, Boston University, 110 Cummington Street, Boston, MA 02215

Investigation performed at the David Geffen School of Medicine, University of California, Los Angeles, California

Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from Medtronic, Inc. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.

Methods: The buffy coat was extracted from human bone marrow aspirate to obtain mesenchymal stem cell-enriched bone marrow aspirate. Fifty-nine athymic rats, each with a 6-mm femoral defect, were divided into six treatment groups: defect only (Group I), demineralized bone matrix and saline solution (Group II), demineralized bone matrix and bone marrow aspirate (Group III), demineralized bone matrix and mesenchymal stem cell-enriched bone marrow aspirate (Group IV), demineralized bone matrix and recombinant human bone morphogenetic protein-2 (rhBMP-2) (Group V [positive control]), and absorbable collagen sponge and rhBMP-2 (Group VI [positive control]). All animals were killed at twelve weeks for radiographic, micro-computed tomography, histomorphometric, and histologic analysis.

Results: There was wide variability in the mesenchymal stem cell concentrations obtained from the human donors. All ten defects healed in the positive control groups (Groups V and VI). Only one defect healed in each experimental group (Groups II, III, and IV) (i.e., three of forty-four defects healed). There was no significant difference among the radiographic scores of Groups II, III, and IV (p = 0.59), and the score for each of those groups was significantly higher than that for Group I (p 0.005) and significantly lower than those for Groups V and VI (p 0.001). The bone volume and mineral density did not differ among Groups III, IV, and V (p = 0.53). The percent total bone volume and percent normal bone volume in Group VI were significantly higher than those values in Groups I, III, and IV (p < 0.0001) and those in Group II (p = 0.048). In Groups II through V, the cortical bone was more dense than the lace-like bone in Group VI.

Conclusions: Neither bone marrow aspirate nor mesenchymal stem cell-enriched bone marrow aspirate mixed with demineralized bone matrix resulted in reliable healing of critical-sized bone defects. It is possible that a greater number of mesenchymal stem cells or an enhanced osteoinductive signal is required for adequate bone-healing. Mesenchymal stem cell and/or carrier variability may also contribute to differences in bone formation.

Clinical Relevance: This study identified potential problems when adapting the use of mesenchymal stem cells for consistent bone repair in a clinical setting.

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