Terri A. Zachos, DVM, PhD; Thomas J. Smith, VetMB, MRCVS; and Eric Zellner
Although autologous tissues are commonly used in orthopaedic surgery, the need for alternatives to procedures that have the potential for morbidity has driven investigations targeting the development of cell-based therapies. Many of these therapies have shown great promise in in vitro settings, but these results often do not correlate with their utility in vivo, which is the best predictor of their potential for clinical applications in humans.
Adult stem cells
Adult stem cells are found in various tissues throughout the bodies of both juveniles and adults. By definition, these are undifferentiated cells that can be induced to become any of a number of cell types. Bone marrow-derived mesenchymal stem cells (BMDMSC) are of particular interest in orthopaedics, because cells in this lineage are involved in osteogenic differentiation.
BMDMSC, by virtue of their presence in bone marrow, have easy access to sites of fracture healing. However, only a small fraction (less than 0.01 percent) of the cells present in bone marrow are BMDMSC. A bone marrow aspirate may contain only a few thousand cells—not nearly enough to incite a significant osteogenic effect. For this reason, investigators are expanding these cells in culture to obtain the millions of cells necessary to induce bone healing.
BMDMSC can be obtained by harvesting bone marrow from a patient and growing the harvested cells ex vivo in cell culture media. The result is autogenous cells or cell autografts. However, this technique is not feasible in most clinical settings because a cell culture laboratory is not readily available for immediate transfer of the marrow sample.
A large body of experimental data demonstrates the safety and efficacy of using BMDMSC from another individual of the same species, referred to as cell allografts. This newer approach will make it easier for clinicians in various practice settings to use these cells, not only for bone healing but for regeneration of other tissues as well.
BMDMSC can be cultured and expanded in both commercial and academic laboratories. They can then be shipped on dry ice to physician and veterinarian researchers at distant locations for their use. Because these cells can be delivered to virtually any anatomic site via a percutaneous approach, they may be useful in numerous clinical scenarios in which a minimally invasive, biologic approach to tissue regeneration is desirable. For example, this type of cell-based therapy can be utilized in nonunion surgery, as well as in clinically delayed arthrodesis sites.
The clinical scenario
Because fracture repair in canines is similar to that routinely performed on humans, fracture repair and bone and soft tissue healing in dogs may be used as a naturally occurring animal model of injury, repair, and recovery in humans. In the clinical scenario, the recipient site should be surgically dèbrided (Fig. 1) to remove all fibrous tissue that may impede osteogenesis. Either a percutaneous approach using fluoroscopic guidance or a limited open approach may be used. The marrow cavity is accessed by drilling small holes in the sclerotic bone at the nonunion site.
This preparation provides access to the patient’s autologous stem cells, which can be directed to undergo osteogenic differentiation in response to a delivery of allograft BMDMSC. The allograft BMDMSC can be delivered through the same percutaneous or limited open approach (Fig. 2), reducing further compromise to the vascular supply of the recipient site.
The expanded, allogeneic cells can be delivered using any of several techniques designed to retain the cells at the site of interest, to make delivery through a percutaneous approach easy and safe, and to augment the osteogenic potential of the cells. The following carrier systems have been successfully used to deliver BMDMSC:
- absorbable collagen sponge
- absorbable gelatin sponge or powder
- autograft cancellous bone
- allograft cancellous bone
- autograft and/or allograft corticocancellous bone
- autologous bone marrow
- any combination of these carriers
These techniques are routinely being used in veterinary teaching hospitals and are beginning to be applied to humans. Thus, collaborations between orthopaedic surgeons and veterinary orthopaedic surgeons may be useful in investigating the efficacy of cell-based therapies.
Dr. Zachos, a diplomate of the American College of Veterinary Surgeons, is a second-year medical student in the College of Human Medicine at Michigan State University (MSU) . Dr. Smith, a member of the Royal College of Veterinary Surgeons, was an orthopaedic research fellow at MSU’s College of Veterinary Medicine, where Eric Zellner is a fourth-year veterinary medical student. Dr. Smith is currently an Assistant Professor of Surgery at the School of Veterinary and Biomedical Sciences, James Cook University, Townsville, New South Wales, Australia.
Bench to Bedside
“Bench to Bedside” is a quarterly column sponsored by the AAOS Research Development Committee (RDC) highlighting new translational research. The RDC—under the auspices of the Council on Research and Quality—serves as the primary liaison to the National Institutes of Health on issues in musculoskeletal research, and oversees research advocacy events, the clinician-scientist development programs, and the Kappa Delta Research Awards.
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