The Journal of Bone and Joint Surgery

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Commentary & Perspective

Commentary & Perspective on
"Percutaneous Autologous Bone-Marrow Grafting for Nonunions"
by Ph. Hernigou, MD, et al.

Commentary & Perspective by
Jay R. Lieberman, MD*,
UCLA Medical Center, Los Angeles, California

Over the past five years, there has been tremendous interest in the appropriate selection of bone-graft materials to treat fractures, nonunions, and other bone-repair problems. Concerns about donor-site morbidity and the necessarily limited supply associated with harvesting autologous bone-marrow graft have created interest in the use of recombinant bone morphogenetic proteins and other bone-marrow graft substitutes. In this study, Hernigou et al. report on the use of percutaneous bone-marrow aspiration and the influence of concentrated progenitor cells on the treatment of atrophic tibial nonunions. This technique was first reported in the 1980s, but the number of progenitor cells transplanted^1-3 and the number of progenitor cells necessary to obtain healing were not assessed.

Hernigou et al. report on sixty atrophic tibial nonunions treated with a percutaneous bone-marrow grafting technique. In this technique, bone marrow was aspirated from both anterior iliac crests, concentrated via centrifugation, and then injected percutaneously into the fibrous tissue of the nonunion. Patients were treated with either internal fixation or a cast postoperatively. Healing was obtained in fifty-three of the sixty patients in an average of twelve weeks (range, four to sixteen weeks) after cell injection. Healing was significantly slower in patients with a type-II or III open fracture, a fracture located in the distal one-third of the tibia, or in patients with one or more comorbidities. There were seven fractures that did not heal.

The critical element in determining success of this percutaneous bone-grafting technique was the number of transplanted progenitor cells. All seven tibiae that did not heal had been treated with an aspirate that contained <1000 progenitor cells/cm³and <30,000 progenitor cells in total. However, this was not determined until after the procedure was done.

The results of the study are quite exciting since they demonstrate a minimally invasive bone-grafting alternative for the treatment of nonunions. Bone-marrow aspiration is a well-accepted technique, and the use of concentrated progenitor cells allows for a minimally invasive bone-graft option. It is relatively simple to harvest the bone marrow, but certain guidelines must be followed to maximize the yield of progenitor cells⁴. However, there are several issues that require further study.

First, this treatment was most successful in patients with closed or type-I tibial fractures. Of the sixty fractures treated, only twelve were type II or type III. Patients also had minimal angular deformity and small bone defects. Second, the issue of variability in cellular yield clearly influenced the results of this treatment. The number of progenitor cells was noted to decrease with age in women. Since these data were not obtained until after cell implantation, this is a problem for which there is no solution at the present time. This does not mean that this therapy should not be used in postmenopausal females, but the biologic potential of the nonunion site must be evaluated. Third, the ability to prepare and centrifuge cells in a timely fashion and in all types of hospital environments requires further study. The details of the centrifugation process, the time that it took to prepare the cells, and the specific equipment needed were not fully discussed in the manuscript. However, it seems that this type of strategy could be universally adapted for use in operating rooms. Fourth, the tibial fractures treated in this study all had been initially managed in either a closed fashion or with external fixation. Patients that had a prior intramedullary rod were not included in this study. In addition, the bone defects treated were small; thus, an obvious question that arises is whether this therapy can be adapted for use in larger bone defects and with an open technique.

It would seem that some type of matrix would be necessary to serve as a carrier for the bone-marrow aspirate in these types of cases. This technique would have to be compared to standard autologous bone grafting in a randomized trial. Finally, the success of this percutaneous technique suggests that further study is needed in other areas, including studying the mechanism of action of implanted cells. Do these cells actually become incorporated in the fracture callus or do they just stimulate the migration of responding cells? Another area for investigation would be to combine this type of cell-based therapy with recombinant bone morphogenic proteins in patients that have limited biologic potential, such as elderly patients or patients with systemic disease. In theory, this type of treatment would combine a bioactive factor with responding cells. The cell-based technique examined in this study is attractive because the approach is minimally invasive and because minimal morbidity is associated with this type of harvest. The selection of a particular bone graft strategy will be influenced by the biology at the host site and the biomechanical environment. Cost-effective strategies need to be implemented on the basis of these factors.

*The author did not receive grants or outside funding in support of his research or preparation of this manuscript. The author received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity (National Institutes of Health, Musculoskeletal Transplant Foundation, DePuy Inc.). No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the author is affiliated or associated.

References

1. Connolly J, Guse R, Lippiello L, Dehne R. Development of an osteogenic bone-marrow preparation. J Bone Joint Surg Am. 1989;71:684-91.
2. Connolly JF, Guse R, Tiedeman J, Dehne R. Autologous marrow injection as a substitute for operative grafting of tibial nonunions. Clin Orthop Relat Res. 1991;266:259-70.
3. Healey JH, Zimmerman PA, McDonnell JM, Lane JM. Percutaneous bone marrow grafting of delayed union and nonunion in cancer patients. Clin Orthop Relat Res. 1990;256:280-5.
4. Muschler GF, Boehm C, Easley K. Aspiration to obtain osteoblast progenitor cells from human bone marrow: the influence of aspiration volume. J Bone Joint Surg Am. 1997;79:1699-1709. Erratum in: J Bone Joint Surg Am. 1998;80:302.