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Ultrasonics 48 (2008) 330–338 www.elsevier.com/locate/ultras
Low intensity pulsed ultrasound for fracture healing: A review of the clinical evidence and the associated biological mechanism of action
Neill M. Pounder *, Andrew J. Harrison
Orthopaedic Trauma and Clinical Therapies, Smith and Nephew, Inc., Memphis, TN 38116, United States Received 13June 2007; received in revised form 15 November 2007; accepted 28 February 2008 Available online 27 March 2008
Abstract Low intensity pulsed ultrasound is used in the clinical treatment of fractures and other osseous defects. Level I clinical studies demonstrate the ability of a specific ultrasound signal (1.5 MHz ultrasound pulsed at 1 kHz, 20% duty cycle, 30 mW/cm2 intensity (SATA)) toaccelerate the healing time in fresh tibia, radius and scaphoid fractures by up to 40%. Additionally, the same ultrasound signal has been shown to be effective at resolving all types of nonunions of all ages, following a wide range of fracture types and primary fracture management techniques. Recently, significant efforts have resulted in a more comprehensive understanding of the biological mechanism ofaction that produces the documented clinical outcomes. Low intensity pulsed ultrasound has been demonstrated to accelerate in vivo all stages of the fracture repair process (inflammation, soft callus formation, hard callus formation). In particular, accelerated mineralisation has been demonstrated in vitro with increases in osteocalcin, alkaline phosphatase, VEGF and MMP-13 expression. Integrins, afamily of mechanoreceptors present on a wide range of cells involved in the fracture healing process, have been shown to be activated by the ultrasound signal. Downstream of the integrin activation, focal adhesions occur on the surface of cells with the activation of multiple signalling pathways, including the ERK, NF-jb, and PI3 kinase pathways. These pathways have been directly linked to theproduction of COX-2 and prostaglandin, which are key to the processes of mineralisation and endochondral ossification in fracture healing. Ó 2008 Elsevier B.V. All rights reserved.
Keywords: Bone; Fracture healing; Low intensity pulsed ultrasound; Mechanism of action
Contents 1. 2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . Biological mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Physical interaction with biological material . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Biological response infracture healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Transduction processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Integrins transduce the ultrasound signal. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330 331 331 332 333334 337 337
3.
1. Introduction
*
Corresponding author. E-mail address: neill.pounder@smith-nephew.com (N.M. Pounder).
Ultrasound may be applied clinically in a number of different product formats with a range of different medical
0041-624X/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.ultras.2008.02.005
N.M. Pounder, A.J. Harrison / Ultrasonics...
Ultrasonics 48 (2008) 330–338 www.elsevier.com/locate/ultras
Low intensity pulsed ultrasound for fracture healing: A review of the clinical evidence and the associated biological mechanism of action
Neill M. Pounder *, Andrew J. Harrison
Orthopaedic Trauma and Clinical Therapies, Smith and Nephew, Inc., Memphis, TN 38116, United States Received 13June 2007; received in revised form 15 November 2007; accepted 28 February 2008 Available online 27 March 2008
Abstract Low intensity pulsed ultrasound is used in the clinical treatment of fractures and other osseous defects. Level I clinical studies demonstrate the ability of a specific ultrasound signal (1.5 MHz ultrasound pulsed at 1 kHz, 20% duty cycle, 30 mW/cm2 intensity (SATA)) toaccelerate the healing time in fresh tibia, radius and scaphoid fractures by up to 40%. Additionally, the same ultrasound signal has been shown to be effective at resolving all types of nonunions of all ages, following a wide range of fracture types and primary fracture management techniques. Recently, significant efforts have resulted in a more comprehensive understanding of the biological mechanism ofaction that produces the documented clinical outcomes. Low intensity pulsed ultrasound has been demonstrated to accelerate in vivo all stages of the fracture repair process (inflammation, soft callus formation, hard callus formation). In particular, accelerated mineralisation has been demonstrated in vitro with increases in osteocalcin, alkaline phosphatase, VEGF and MMP-13 expression. Integrins, afamily of mechanoreceptors present on a wide range of cells involved in the fracture healing process, have been shown to be activated by the ultrasound signal. Downstream of the integrin activation, focal adhesions occur on the surface of cells with the activation of multiple signalling pathways, including the ERK, NF-jb, and PI3 kinase pathways. These pathways have been directly linked to theproduction of COX-2 and prostaglandin, which are key to the processes of mineralisation and endochondral ossification in fracture healing. Ó 2008 Elsevier B.V. All rights reserved.
Keywords: Bone; Fracture healing; Low intensity pulsed ultrasound; Mechanism of action
Contents 1. 2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . Biological mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Physical interaction with biological material . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Biological response infracture healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Transduction processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Integrins transduce the ultrasound signal. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330 331 331 332 333334 337 337
3.
1. Introduction
*
Corresponding author. E-mail address: neill.pounder@smith-nephew.com (N.M. Pounder).
Ultrasound may be applied clinically in a number of different product formats with a range of different medical
0041-624X/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.ultras.2008.02.005
N.M. Pounder, A.J. Harrison / Ultrasonics...
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