Commentary & Perspective

Commentary & Perspective on
"Low-Intensity Pulsed Ultrasound Accelerates Maturation of Callus in Patients Treated with Opening-Wedge High Tibial Osteotomy by Hemicallotasis"
by Noriyuki Tsumaki, MD, et al.

Commentary & Perspective by
Clinton T. Rubin, PhD*,
Center for Biotechnology and the Department of Biomedical Engineering, State University of New York at Stony Brook, Stony Brook, New York.
E-mail address: clinton.rubin@sunysb.edu

We are now acutely aware of the sensitivity of bone to mechanical signals, and of the potential of mechanical signals to serve as anabolic factors in the homeostasis of skeletal tissue. In the form of low-intensity ultrasound, acoustic pressure waves provide a surrogate for functionally based mechanical signals and, as of this writing, represent the sole intervention approved by the United States Food and Drug Administration for the accelerated healing of fresh fractures. This regulatory approval is based primarily on a series of rigorous double-blind placebo-controlled clinical trials^1,2 that showed that ultrasound can reduce the time required for healing of fresh (within three months) fractures. Just as important, there is substantive basic-science evidence that shows that ultrasound has a strong positive influence on several key phases that are inherent to the healing process, including angiogenesis³, chondrogenesis⁴, and osteogenesis⁵. In a critical clinical test of the ability of ultrasound to be of benefit during a vulnerable stage of healing after tibial osteotomy, Dr. Tsumaki and colleagues have demonstrated, with the use of a rigorous and unique randomized trial design, that this low-level physical intervention can also serve to bolster the mineralization of the callus and thus reduce the time required for external fixation during the consolidation phase.

Leveraging a unique opportunity to use each patient as his or her own control, the experimental design allowed an explicit a priori demonstration that ultrasound can effectively improve the controlled healing environment of the osteotomy site. While this possibility is encouraging, it also leaves many questions unanswered. Principal among these questions is how such a low-level (30 mW/cm²) pressure wave can influence the complex biologic processes of fracture-healing. Thousands of genes are involved in orchestrating the key phases of the healing response⁶, and it has been postulated that only large mechanical displacements can initiate the biologic response⁷. Indeed, the ultrasound signal is several orders of magnitude smaller than the strain generated by functional load bearing, but the rates of loading induced by ultrasound are several orders of magnitude larger. Perhaps the work of Tsumaki and colleagues is further evidence that it is not the amplitude of the mechanical signal that is important, but instead, the nature of the signal. Although it may be large mechanical events that singularly instigate fractures, or an accumulation of mechanical events that conspire to cause joint degeneration, it is also essential to understand that mechanical signals, whether in the form of exercise, continuous passive motion, implant geometry, or ultrasound for that matter, are potent determinants of bone quality and quantity, and that "big" isn't necessarily "better."

As we try to further understand how mechanical factors can modulate bone biology, it is important to consider that factors other than strain (bone deformation), per se, may represent the defining element of success or failure. There is growing evidence that "byproducts" of strain, such as fluid flow, streaming potentials, strain gradients, intramedullary pressure, and frequency, are as critical as—if not more critical than—the magnitude of the stimulus to the establishment of a structurally sound and biologically viable skeleton. As musculoskeletal science evolves, and as our ability to harness mechanical signals as a potent growth factor improves, it is entirely possible that the complex biological processes of bone remodeling and repair will be effectively controlled not only by the future of biologics, but by the future of biophysics.

*The author did not receive grants or outside funding in support of his research or preparation of this manuscript. He did not receive 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, educational institution, or other charitable or nonprofit organization with which the author is affiliated or associated.

References

1. Heckman JD, Ryaby JP, McCabe J, Frey JJ, Kilcoyne RF. Acceleration of tibial fracture-healing by non-invasive, low-intensity pulsed ultrasound. J Bone Joint Surg Am. 1994;76:26-34.
2. Kristiansen TK, Ryaby JP, McCabe J, Frey JJ, Roe LR. Accelerated healing of distal radial fractures with the use of specific, low-intensity ultrasound. A multicenter, prospective, randomized, double-blind, placebo-controlled study. J Bone Joint Surg Am. 1997;79:961-73.
3. Azuma Y, Ito M, Harada Y, Takagi H, Ohta T, Jingushi S. Low-intensity pulsed ultrasound accelerates rat femoral fracture healing by acting on the various cellular reactions in the fracture callus. J Bone Miner Res. 2001;16:671-80.
4. Parvizi J, Wu CC, Lewallen DG, Greenleaf JF, Bolander ME. Low-intensity ultrasound stimulates proteoglycan synthesis in rat chondrocytes by increasing aggrecan gene expression. J Orthop Res. 1999;17:488-94.
5. Rubin C, Bolander M, Ryaby JP, Hadjiargyrou M. The use of low-intensity ultrasound to accelerate the healing of fractures. J Bone Joint Surg Am. 2001;83:259-70.
6. Hadjiargyrou M, Lombardo F, Zhao S, Ahrens W, Joo J, Ahn H, Jurman M, White DW, Rubin CT. Transcriptional profiling of bone regeneration: Insight into the molecular complexity of wound repair. J Biol Chem. 2002;277:30177-82.
7. Kenwright J, Goodship AE. Controlled mechanical stimulation in the treatment of tibial fractures. Clin Orthop. 1989;241:36-47.

Copyright © 2004 by the The Journal of Bone and Joint Surgery, Inc.