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Healing Critical Defects in the Femur

Christopher Evans, PhD, is the Maurice Mueller Professor of Orthopaedic Surgery and Director of the Center for Advanced Orthopaedic Studies in the Department of Orthopaedic Surgery at Beth Israel Deaconess Medical Center.

Vaida Glatt, PhD, is a Senior Research Fellow with the Trauma Research Group of the Institute of Health and Biomedical Innovation at Queensland University of Technology Brisbane, Queensland.


Introduction
Large segmental defects heal poorly and often present clinical challenges. Approaches used to improve healing include autograft and allograft bone, distraction osteogenesis, vascularized bone grafts and the application of BMP-2 and BMP-7. We wanted to determine whether modulation of the mechanical environment could improve bone healing in a rat femoral segmental defect model.

The responsiveness of bone to mechanical stimulation has been known for well over a century, and there is a considerable body of literature describing its influence on fracture healing. Surprisingly, we could find no prior literature concerning the responses of large segmental defects to their mechanical environment. To remedy this, we developed customized external fixators of different stiffness for use in conjunction with a 5 millimeter (mm) femoral defect in the rat. The external fixator design allows the stiffness to be changed on living animals as they heal.

The concept of modulating the rigidity of fixation to promote bone healing goes back to the late 1970’s when Dr. Giovanni de Bastiani of the University of Verona, Italy, proposed the application of “dynamization” for external fracture fixation treatment. According to Dr. de Bastiani’s concept, the fracture site is initially fixed very rigidly to provide stability and to allow healing to commence. Once woven bone is laid down, the fixator is loosened to allow the bone to bear greater load and thus remodel more rapidly.

Based upon certain information from the literature, we wondered whether the healing of large segmental defects would benefit from the opposite strategy – loose fixation first, followed by rigid fixation. This is called reverse dynamization. We tested the reverse dynamization process in the study described here.

Methods
Five mm, critical-sized, mid-femoral defects were created in rats. These do not spontaneously heal, but do heal in response to 11 μg recombinant, human BMP-2.
We maintained groups of rats for 8 weeks with fixators of low (114 N/mm), medium (185 N/mm) and high (254 N/mm) stiffness. An additional group underwent reverse dynamization, where low stiffness fixation was applied for the first 2 weeks, after which time we imposed high stiffness fixation. All defects also received BMP-2.

Animals were euthanized at 8 weeks. Healing was assessed by radiologic evaluation, mechanical testing, histology, dual-energy ray absorptiometry (DXA) and μCT.

Results
Surprisingly, radiologic evaluation suggested that the least stiff fixator gave the most rapid and complete healing after 8 weeks. Reverse dynamization, however, improved upon this considerably. Histology (see figure), confirmed that defects subjected to reverse dynamization were narrower in cross section, and had an organized tissue structure with better architecture and well-formed evenly distributed neocortices, and only a small amount of trabecular bone. All other defects had persistent callus, and contained disorganized woven bone with poor cortication. Defects stabilized for 8 weeks with medium stiffness fixators contained a central gap in the defect surrounded by unmineralized soft tissue. Defects stabilized for 8 weeks with the highest stiffness fixator contained a prominent band of cartilage, raising the possibility of developing into a non-union. Cartilage was not seen in any of the other groups at 8 weeks.

Figure 1: Histological appearance at 8 weeks of defects stabilized with low, medium and high stiffness fixators and subjected to reverse dynamization.
Histology of critical defect fracture healing in Trauma Rounds

The μCT, DXA and mechanical testing data were in broad agreement with the radiological and histological data.

Discussion
These data support the concept of reverse dynamization to improve the healing of large segmental defects. Only one regimen of reverse dynamization was evaluated in this study. It is possible that a different stiffnesses or timing of reverse dynamization would provide even better results. Optimization of the strategy remains a future goal.

Although these experiments used a rat model, the results are relevant to clinical orthopaedics. They show that the healing of critical-sized segmental defects is highly responsive to the ambient mechanical environment. The use of reverse dynamization runs counter to present clinical practice, where large segmental defects are subject to immediate rigid fixation. Further study of reverse dynamization could lead to improved clinical management of patients with these difficult injuries.

Future Research
Using funding from the Department of Defense we are determining whether reverse dynamization reduces the need for BMP-2 to achieve healing, and whether it accelerates the acquisition of mechanical strength. The former would reduce health care costs and the latter would allow earlier load bearing. We have also applied for additional funding to undertake a study of reverse dynamization in sheep.

Funding
Supported by the AO Foundation (Grant S-08-42G) and the Department of Defense (Grant W81XWH-10-1-0888).

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