Fracture repair with ultrasound: Clinical and cell-based evaluation

Fracture repair continues to be widely investigated, both within the clinical realm and at the fundamental research level, in part due to the fact that 5% to 10% of fractures result in either delayed union or nonunion, depending on the duration of incomplete healing. Beyond the temporal delay in repair, nonunions share the same unifying characteristic: all periosteal and endosteal repair processes have stopped and the fracture will riot heal without surgical intervention. A less-invasive alternative method-low-intensity pulsed ultrasound-has shown promise as a treatment for delayed unions and nonunions and as a method to facilitate distraction osteogenesis. In this paper, we summarize the clinical effectiveness of low-intensity pulsed ultrasound with regard to fracture repair, treatment of nonunion, and distraction osteogenesis and we discuss the results of a multitude of published studies that have sought to elucidate the mechanisms behind that effectiveness through research on low-intensity pulsed ultrasound exposure on osteoblasts and osteoblast precursors. When evaluated clinically, low-intensity pulsed ultrasound was shown to enhance bone repair (most commonly noted as a decrease in healing time), although variations in patient population hindered a definitive claim to clinical effectiveness. In vitro cellular evaluation and in vivo studies on animal models have revealed an increase in cell proliferation, protein synthesis, collagen synthesis, membrane permeability, integrin expression, and increased cytosolic Ca2+ levels as well as other increased indicators of bone repair in response to low-intensity pulsed ultrasound exposure. Many of the cellular responses to low-intensity pulsed ultrasound mirror the cellular responses to fluid-induced shear flow, suggesting a link between the two as one potential mechanism of action. The considerable amount of information that has been revealed about the behavior of osteoblasts under low-intensity pulsed ultrasound exposure suggests that the exact mechanism of action is complex. It is clear, however, that considerable progress is being made toward uncovering these mechanisms, which has served to encourage the use of low-intensity pulsed ultrasound in new applications. It is posited that successful noninvasive treatment strategies such as low-intensity pulsed ultrasound may be combined with other conventional and novel tissue-regeneration strategies to develop new treatments for large-scale bone defects.