Mesenchymal Stem Cells for Bone Repair: Preclinical Studies and Potential Orthopedic Applications
Section snippets
Mesenchymal stem cell isolation and expansion
MSCs are typically isolated from a small bone marrow aspirate obtained from the iliac crest in humans and large animals [11], [19], [20]. In small animals, marrow is typically isolated from the mid-diaphysis of the femur or tibia. Although MSCs are found at a frequency of approximately 1/100,000 nucleated cells in bone marrow [8], MSCs can be isolated and expanded with high efficiency, typically by using standard cell culture techniques, which results in multiple therapeutic doses from one
Characterization of adult mesenchymal stem cells
MSCs have a characteristic immunophenotype and have specific cell surface markers: SH-2, 3, and 4 [8], [14], [21]. The SH-2 antibody reacts with an epitope present on transforming growth factor-beta receptor endoglin (CD105) [22]. SH-3 and SH-4 antibodies recognize distinct epitopes on the membrane bound ecto-5′-nucleotidase (CD73) [14], [23], [24]. Antibodies for SH-2, SH-3, and SH-4 do not react with hematopoietic cells or with osteocytes. SB-10 antigen was also identified as being present on
Critically sized femoral defects
The rat femoral gap model was established and optimized by Stevenson, Einhorn and others [3], [32], [33]. This model is a critically sized segmental defect, typically 8 mm long, that makes it possible to investigate bone repair of cell-loaded implants in an orthotopic site, by using either immunocompromised or immunocompetent animals.
In the first experiment, bone marrow from Fischer 344 rats was used to isolate and expand mesenchymal stem cells for syngeneic implantation [15]. At the end of the
Allogeneic mesenchymal stem cells without the use of immunosuppressive therapy
Providing an autologous MSC construct clinically requires acquisition of a diagnostic bone marrow aspirate from the patient, several weeks for cell expansion and quality control testing, and then implantation back into the patient. The utility of such an approach is limited since there would be a delay of perhaps 1-2 months in providing treatment to the patient. Culture preparation per patient upon request also increases costs and in turn, cost to the patient. An alternative approach would be
Other approaches using mesenchymal stem cells for bone repair
We have discussed animal models that use a ceramic scaffold, namely HA/TCP, as a substrate for MSC induced bone formation for long bone repair. However, for clinical situations requiring bone grafting, such as in the long bone, these ceramics may have unsuitable mechanical properties, exhibiting brittle behavior, and slow resorption rates. The combination of the fracturing of the implant during repair, which results in micromotion, and the ceramic remaining in the defect may impede bone
Summary
Mesenchymal stem cell-based bone regeneration has been demonstrated in various animal models. Preclinical models described in this review primarily focused on the repair of segmental defects. Other orthopedic applications, such as spine fusion and craniotomy defects, are also of interest for the delivery of MSCs. Although preclinical and clinical data for other applications demonstrate safety and efficacy of MSCs, many issues still surround the mechanism of action. Concerns exist regarding the
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