Use of Physical Forces in Bone Healing

Fred R. T. Nelson, MD, Carl T. Brighton, MD, PhD, James Ryaby, PhD, Bruce J. Simon, PhD,
Jason H. Nielson, MD, Dean G. Lorich, MD, Mark Bolander, MD, PhD, and John Seelig, MD

Abstract
During the past two decades, a number of physical modalities have been approved
for the management of nonunions and delayed unions. Implantable direct current
stimulation is effective in managing established nonunions of the extremities and
as an adjuvant in achieving spinal fusion. Pulsed electromagnetic fields and capacitive coupling induce fields through the soft tissue, resulting in low-magnitude voltage and currents at the fracture site. Pulsed electromagnetic fields may be as effective as surgery in managing extremity nonunions. Capacitive coupling appears
to be effective both in extremity nonunions and lumbar fusions. Low-intensity ultrasound has been used to speed normal fracture healing and manage delayed unions.
It has recently been approved for the management of nonunions. Despite the different mechanisms for stimulating bone healing, all signals result in increased intracellular calcium, thereby leading to bone formation.
J Am Acad Orthop Surg 2003;11:344-354

Nonunion has been defined as no
demonstrated change in healing on
serial radiographs over a 3-month period.1 Delayed union is defined as a
speed of fracture healing that is slower than anticipated, with no implied
expectancy of either eventual healing
or eventual nonunion. Of approximately 6 million extremity fractures
that occur annually in the United
States,2,3 between 5% and 10% result
in either nonunion or delayed
union.3 Assuming an average cost in
lost wages and additional medical
treatment for each of these cases of
$10,000, the annual economic loss is
$3 to $6 billion. In an attempt to minimize problems with fracture healing,
improved methods of internal and external fracture immobilization have
been combined with appropriately
timed early transmission of physiologic forces across the fracture sites.4
Additionally, a number of adjunctive
treatment options to stimulate normal
fracture healing, delayed unions, and
nonunions have been developed.5

344

These options include direct current
(DC), pulsed electromagnetic fields
(PEMFs), capacitive couplings, and
ultrasound.
Over the past two decades, an estimated 400,000 fracture nonunions,
delayed unions, and fusions have
been managed by physical fields. In
January 2000, the Society for Physical Regulation in Biology and Medicine sponsored a symposium to review the clinical applications and
mechanisms of action for these various modalities. The core material
from that symposium has been organized into a format to help clinicians
become more effective in and
knowledgeable about application of
these physical signals. Physicians
should be familiar with commonly
used terms and their definitions (Table 1) and appreciate the history of
the clinical use of these physical
forces. A thorough understanding of
the mechanisms of action, indications for use, and clinical outcomes
of commonly used devices that gen-

erate physical forces to influence
fracture healing is necessary for
their optimal clinical application
(Table 2).

Dr. Nelson is Director of Resident Education, Henry Ford Hospital, Detroit, MI. Dr. Brighton is Paul
B. Magnuson Professor Emeritus of Bone and Joint
Surgery, Department of Orthopaedic Surgery,
University of Pennsylvania, Philadelphia, PA. Dr.
Ryaby is Senior Vice President, OrthoLogic,
Tempe, AZ. Dr. Simon is Director of Research,
EBI, Parsippany, NJ. Dr. Nielson is Chief Resident, Department of Orthopaedic Surgery, Jacoby Medical Center, Bronx, NY. Dr. Lorich is Associate Director, Orthopaedic Trauma Surgery,
Hospitals for Special Surgery, New York, NY. Dr.
Bolander is Professor of Surgery, Mayo Clinic,
Rochester, MN. Dr. Seelig is Doctor of Neurosurgery, San Diego, CA.
None of the following authors or the departments
with which they are affiliated has received anything of value from or owns stock in a commercial company or institution related directly or indirectly to the subject of this article: Dr. Nelson,
Dr. Nielson, Dr. Lorich, and Dr. Seelig. Dr.
Brighton or the department with which he is affiliated has received research or institutional support from Biolectron. Dr. Brighton or the department with which he is affiliated has received
royalties from Biolectron. Dr. Brighton or the department with which he is affiliated serves as a
consultant to or is an employee of Biolectron. Dr.
Ryaby or the department with which he is affiliated serves as a consultant to or is an employee
of OrthoLogic. Dr. Simon or the department with
which he is affiliated has stock or stock options
held in Biomet. Dr. Bolander or the department
with which he is affiliated has received research or
institutional support from Simth & Nephew and
Exogen.
Reprint requests: Dr. Nelson, K-12, 2799 W.
Grand Boulevard, Detroit, MI 48202.
Copyright 2003 by the American Academy of
Orthopaedic Surgeons.

Journal of the American Academy of Orthopaedic Surgeons

A 60-kHz sinusoidal wave signal is generated by a 9-V battery. modified Combined magnetic field Ultrasound 0. At the same time.1 to 20 mV/cm and 300 µA/cm2 at 60 kHz 4 mV/cm peak to peak Magnetic field effect. ultrasound began to show promise as a method of stimulating fracture healing. September/October 2003 345 . 10 µA/cm2 Pulsed electromagnetic field. The idea that electrical fields might be important in the repair process was de- scribed in the early 1960s by Bassett and Becker.Fred R.1 to 18 G in the form of a pulse train with a 15-Hz or sinusoidal 76-Hz frequency.11 Subsequently there was further development of PEMFs as well Table 2 Devices That Generate Physical Forces Device Wave Form Tissue Electrical Field Direct current Pulsed electromagnetic field Capacitive coupling 20 µA 4. not induced field N/A rms = root-mean-square Vol 11. Nelson. No 5. or sonic force applied to an area of bone fracture healing.5-msec–long bursts of twenty 220-µsec 18-G pulses repeated at 15 Hz 60 kHz. (The earth’s geomagnetic field is approximately 0. 6 V peak to peak delivered by 9-V battery 790-mG field of a burst of twenty-one 260-µsec pulses with repetition rate of 15 Hz 76. typically of twenty 220-µsec repeating spikes. Use magnetic coils that receive a specific pulsed electrical current that results in a magnetic flux density ≈0.6-Hz sinusoidal 40-µT (400 mG) peak-topeak AC magnetic field superimposed on 20-µT DC magnetic field Sinusoidal As delivered 1. producing an increase in periosteal callus. Hartshorne6 described a case of fracture nonunion that was treated with “shocks of electric fluid passed daily through the space between the ends of the bone. electrical stimulation of bone regained clinical scientific prominence when Fukada and Yasuda8 described “piezoelectric potentials” generated by mechanical stress on the crystalline structure of bone. Involves an implanted cathode placed in the area of expected bone stimulation and a battery-based anode placed subcutaneously.” Lente7 in 1850 described three cases of delayed unions or nonunions treated with galvanic current.10 AFourier transform was used to break down the electromagnetic signal into its major and minor components to predict the biologically important rate of generation of electric potentials in bone by mechanical stress. T.9 A central hypothesis in the application of physical forces is that straingenerated electrical potentials may be a regulatory signal for cellular processes of bone formation. Direct electrical stimulation Pulsed electromagnetic fields (PEMFs) Capacitive coupling History of Development of Physical Fields In 1841. This is in distinction from biochemical osteoinductive therapies.5 mV/cm.10 This was used as the basis for selecting one of the currently used PEMFs. A gauss (G) is a unit of electromagnetic flux. MD. More than 100 years later.) Requires two surface electrodes placed on the skin across a fracture site. In 1953. this results in an internal field of 0. A constant 20-µA direct current is delivered. 10 µA (rms). electrical.1 to 20 mV/cm and a current density of 300 µA/cm2 that is not felt by the patient.6 G. et al Table 1 Terms and Definitions Term Definition Physical forces Include any mechanical. Corradi used continuous wave ultrasound to stimulate fracture healing. A pulse train is a rapid sequence. Additional knowledge of the nature of endogenous electric fields in biology led to the development of the direct electric fields now in use.

12 The effects of ultrasound on fracture callus stimulation were studied by numerous investigators using a variety of animal models. activated calmodulin. The cathode now can be wrapped in a spiral and shaped to match the area of interest.35-37 growth cytokines38-47 Ultrasound9. prospective controlled studies now exist. cytosolic calcium.14 synthesis collagen and proteoglycan11 Cytokines12.34 Bone cell proliferation. stimulates. 39 of 57 nonunions healed. In contrast with surface induction. or activates Journal of the American Academy of Orthopaedic Surgeons . Implantable batteries acting as anodes were later developed to deliver a consistent 20-µA current. the Food and Drug Administration (FDA) approved the use of DC in established nonunions. resulting in 149 successful unions. Outcomes such as return to work or specific activities have not been reported but are important for assessing the role of these devices compared with alternative techniques to stimulate fracture repair. and stimulation of articular cartilage repair in osteoarthritis are potential new applications for these methodologies that are currently under investigation. and the battery/anode is removed 6 months after implantation.48-51 Influx and efflux of K+.52 cartilage bone Ca++.5-MHz sinusoidal waves repeated at 1 kHz) at a low intensity (30 mW/cm2) accelerated the recovery of torsional strength and stiffness in a midshaft fibular osteotomy of the rabbit.7% for clavicular nonunions.26 mRNA TGF-β30 Vascular ingrowth. with a battery pack worn at the waist. osteoblast migration.54 TGF-β. Pulsed Electromagnetic Fields Basic Science The PEMF signal was developed to induce electrical fields in bone sim- Table 3 Physical Forces in Bone Healing: Mechanisms of Action Device (Clinical Studies) Mechanism* Direct current11-14 O2↓. However.55 aggrecan and vascularity.Use of Physical Forces in Bone Healing as combined (DC and AC) magnetic fields.13.9 PDGF-AB56 * Increases. 66. most of these record only the presence or absence of healing as an end point. the pO2 is lowered and pH raised in the vicinity of the cathode. In 1981. Among the cellular mechanisms of 346 electric current–induced osteogenesis are increased proteoglycan and collagen synthesis14 (Table 3). Direct Current Basic Science In 1981.54 PGE2. Brighton et al11 found lower pO2 at the bone-cartilage junction of the growth plate and in newly formed bone and cartilage in fracture callus.53 adenylate cyclase activity.11.) Originally the anode was placed on the skin. The FDA’s original definition stipulated no visible signs of healing for at least 3 months after at least 9 months since injury.29 activate voltage-gated calcium channels.57 Brighton et al22 in 1977 reported the use of DC by percutaneous wire placement for tibial nonunions that had been present for an average of 3. Brighton et al11 showed that with direct electrical stimulation. Clinical Data After the initial clinical demonstration of fracture healing in 1971 by Friedenberg et al. Direct electrical stimulation also has been approved by the FDA for use in spinal fusion. An internal field of 220 mV with a current density of 250 µA was the most effective for induction of healing. implanted DC stimulation eliminates the problem of patient compliance when used in conjunction with a surgical procedure for internal fixation or bone grafting. 20 µA was determined to be the preferred current. Although most human clinical studies conducted during the development of these devices were retrospective.3 years. An open exposure is required. Current Indications In 1979. Arabbit fibular fracture model was used to define the dose-response curve for capacitive coupling in fracture healing.5% for humeral nonunions. Brighton et al11 reported on 178 nonunions managed with 4 percutaneously inserted cathodes. Treated with a field of 10 to 20 µA over 12 weeks. A low pO2 is favorable to bone formation. Based on this study and animal models. matrix calcification33 Ion transport across cell membranes and ion dependent cell signaling in tissues. The presence of a synovial-lined pseudarthrosis prevented healing. each delivering a 20-µA DC. Revascularization. Success rates were 83. PGE2.3% for tibial nonunions. as in core decompression for osteonecrosis of the femoral head. and 61. (An established nonunion is one that shows no visible progressive signs of healing.9 Pilla et al13 found that brief periods (20 min/day) of pulsed ultrasound (a 200-µsec burst of 1.21-25 Pulsed electromagnetic field (PEMF)15-20 Capacitive coupling26-28 Modified PEMF31.32 Combined magnetic field15.

but in closed injuries. Research with PEMFs has focused on regulation of messenger RNA (mRNA) and protein synthesis of the transforming growth factor-beta (TGF-β)/bone morphogenetic protein (BMP) gene family because these cytokines have been shown to modulate cellular activity of osteochondral progenitor cells.01).5-msec–long bursts of twenty 220-µsec 18-G pulses repeated at 15 Hz. These results support earlier observations in the endochon- Vol 11. Sharrard reported a double-blind trial of delayed unions in 45 tibial shaft fractures managed by plaster cast. Current Indications PEMF treatment is recommended as an adjunct to standard fracture management. Indications for use include nonunions. Proximal pole fractures healed in 50%. Nelson. and severe devascularization are contraindications for the use of PEMFs.59 Two recent studies describe the effects of PEMF on TGF production. Gossling et al16 noted that 81% of reported cases healed with PEMF versus 82% with surgery. These patients achieved an 87% success rate. Bassett et al62 reported the results of PEMF treatment with surgery and bone grafting in 83 nonunions with wide fracture gaps. A year later.63 The daily dosage of PEMF treatment is important in the healing process. as evidenced by decreased proliferation and increased alkaline phosphatase activity and osteocalcin and collagen production. et al ilar in magnitude and time course to the endogenous electrical fields produced in response to strain. In a broad literature review comparing PEMF treatment of nonunions with surgical therapy. 1 hour of stimulation resulted in a threefold increase in BMP-2 mRNA and a sixfold increase in BMP-4 mRNA.05) increase in TGF levels in stimulated versus control cells after 1 and 2 days of stimulation.18 Patients treated for 10 hours per day healed an average of 76 days earlier than did those treated fewer than 3 hours per day. and PEMF stimulation of these cells resulted in significant (P < 0. with active PEMF units (n = 20) or identical dummy control units (n = 25) for a period of 12 weeks.05) increases in TGF-β production compared with nonstimulated control cells. Clinical Data More than 250 published basic research and clinical investigations have evaluated the efficacy of PEMF stimulation.60 In one. failed fusions. TGF-β. in a continuation of that study published 6 years later.19 Bassett et al61 reported on a series of 127 diaphyseal tibia nonunions treated with PEMFs that yielded an overall success rate of 87%. and BMP-7 have been shown to enhance fracture repair.24 In a second study. Recently. This study indicates the efficacy of PEMF treatment to be comparable to that of surgical intervention for fracture nonunion. Patients typically 347 . compared with 3 of 25 fractures (12%) in the control group (P < 0. as well. synovial pseudarthrosis.25.16 In open fractures. MD. respectively).23 A several-fold increase in BMP-2 and BMP-4 mRNA occurred in chick calvarial osteoblasts in vivo after 15 days of stimulation with this same signal. T. a fracture gap >5 mm. BMP-2. as described by Wolff’s law. Also. Generally.60 nonunion cells derived from patients undergoing surgery were successfully cultured. surgical healing exceeded PEMF (89% and 78%. September/October 2003 dral bone model that PEMF stimulation increases chondrogenesis by enhancing differentiation of osteochondral precursor cells into a chondrogenic lineage without affecting proliferation. However. PEMFmanaged fractures healed more frequently than did surgically treated fractures (85% and 79%. and malalignment.64 This definition thus permits all forms of electrical stimulation intervention to take place earlier in the treatment than previously and removes controversy regarding when a delayed union may be considered a nonunion.Fred R. the success of surgical treatment for infected nonunions was 69%.21 In 1990. This results in a time-varying extracellular and intracellular electrical field. and congenital pseudarthrosis. chondrocytes. whereas 81% of the PEMF- treated group healed.16 Cells derived from hypertrophic nonunion tissue were more responsive than cells derived from atrophic tissue. a result that supports the clinical observation that patients with hypertrophic nonunions respond more favorably to electromagnetic stimulation than do patients with atrophic nonunions. suspected or documented synovial pseudarthrosis.58 In a rat calvarial osteoblast culture. PEMF treatment caused an increase in chondrogenesis concomitant with an up-regulation of TGF-β. the definition of a nonunion has been modified to failure to exhibit visibly progressive signs of healing. The signal consists of 4. These fields are thought to underlie the ability of bone to respond to a changing mechanical environment. A dose-response study demonstrated that an increase in daily treatment time correlates with a reduction in the time to healing of nonunion fractures.25 confluent cultures of MG63 human osteoblast-like cells were stimulated for 8 hours a day for 4 days and showed a significant (P < 0. and osteoblasts. In an endochondral ossification model using demineralized bone matrix–induced osteogenesis. Frykman et al17 reported that 35 of 44 scaphoid nonunions (80%) were managed successfully by PEMFs with cast immobilization. PEMF enhances differentiation of MG63 cells.19 Nine of 20 fractures (45%) in the active group healed. respectively). the overall success rate had decreased to 69% because of breakdown of some of the fractures originally reported as unions. PEMF treatment has applications in the upper extremity. In many animal studies and recently in human clinical trials. No 5.

29 The clinical effect of electrically induced osteogenesis is easily recognized. severity.004).9%). Current Indications Capacitive coupling is indicated for nonunions of long bones and the scaphoid and as an adjunct treatment in spinal fusions. compared with none of the 11 in the placebo group (P = 0. with various pulse configurations as well as continuous signals.1 to 20 mV/cm (60 kHz and 300 µA/cm2). or more often as required for hygiene. Some difficult fractures may require management for longer periods. leading to increases in prostaglandin E2 (PGE2). Brighton and Pollack1 reported a mean healing rate of 77. prior bone graft surgery. all three forms of treatment provided poor results. cytosolic calcium. The device uses a 9-V battery that should be replaced daily. open fracture. the monitor detects the loss of contact and sets off an alarm. Two small windows are cut out for the application of the electrodes. otherwise. and atrophic nonunion. Brighton et al29 found that field strength was the dominant factor affecting bone cell proliferative response to a capacitive coupled field. Goodwin et al28 studied 179 patients randomized into groups assigned active or nonactive coils after lumbar fusion.Use of Physical Forces in Bone Healing are treated for 3 to 9 months depending on fracture location. the basic physiology of how electrical signals stimulate bone is more difficult to demonstrate in the laboratory. and oblique radiographs are used to monitor progression of healing. lateral. as in normal fracture manage- Journal of the American Academy of Orthopaedic Surgeons . Zhuang et al30 demonstrated that an appropriate capacitively coupled electrical field increased levels of mRNA for TGF-β1 in osteoblastic cells by a mechanism involving the calcium/calmodulin pathway. If surgery is needed. The authors identified seven risk factors that adversely affected the healing rate of nonunions managed with capacitive coupling: duration of nonunion.3% with capacitive coupling after a mean of 22.7%) compared with the placebo group (64. With no or one risk factor present. Serial anteroposterior. some patients choose to continue use of the stimulator to enhance healing after surgery. and activated calmodulin. Within the instrumented group. Currently available electrodes last up to 1 week without requiring reapplication of gel. or bone graft. results were similar regardless of treatment modality. capacitive coupling yielded poorer results in managing atrophic nonunion. With six or seven risk factors.65 In addition. and time from injury. Skin reaction is usually mild. Field strengths calculated at 0. The induced field is driven by an oscillating electric current. in which the cytolsolic calcium is secondary to release of calcium from intracellular stores.0043) increased rate of fusion in the active group (84. Lorich et al26 showed that signal transduction in capacitive coupling stimulation activated voltage-gated calcium channels. there appears to be a common pathway. Treatment is discontinued if there is severe skin reaction. Brighton et al66 used logistic regression analysis in a retrospective study of the healing rate of 271 tibial nonunions treated by DC. comminuted or oblique fracture. However. as opposed to the electromagnetic field induction of PEMF. This leads to an increase in activated calmodulin. indicating that the pads need to be remoistened. Posterolateral bone graft combined with concurrent instrumentation of the affected levels had a higher rate of fusion than did graft without instrumentation. this study did not evaluate smoking as a possible risk factor. Using various metabolic inhibitors. stimulated patients showed higher fusion rates than did the placebo control subjects. Scott and King27 reported the results of a small. prior electrical stimulation. With the presence of two to five risk factors. cast immobilization typically is used. The pads are worn 24 hours a day and are changed weekly. In an in vitro rat calvarial bone cell model. Although the initial signal transduction of capacitive 348 ly significant association between the use of capacitive coupling and eventual union.5 weeks. In applying capacitive coupling. They found a statistical- Basic Science Use of capacitive coupling for fracture healing stimulation involves the application of two surface electrodes placed on the skin with the fracture between the electrodes. The authors reported a statistically significant (P = 0. osteomyelitis. there were no significant differences among the three treatment methods (96% to 99%). If necessary. prospective doubleblind study using capacitive coupling in the management of established nonunions. There also have been two double-blind prospective lumbar fusion studies using capacitive coupling. coupling is different from inductive coupling of a combined DC and pulsed electromagnetic field. Capacitive Coupling Clinical Data In a prospective. are effective in stimulating bone cell proliferation. electrodes can be moved to a new skin site. capacitive coupling. Six of the 10 nonunions in the actively managed group healed. The fracture should progress to healing within 3 to 6 months. This is in contrast to signal transduction of indirect coupling and combined magnetic fields (CMFs). Unfortunately. nonrandomized multicenter study comparing patients with 17 recalcitrant nonunions (who had undergone prior surgery or electrical stimulation) with 5 who had routine nonunions (no previous treatment). which are positioned across the approximate site of the fracture and moistened before application. When the pads dry.

Combined Magnetic Fields Basic Science The scientific basis of CMFs is predicated on theoretic physics confirmed by experimental demonstrations that combinations of dynamic and static magnetic fields affect ion transport across cell membranes and affect ion-dependent cell signaling in tissues. On completion of the course of treatment. The recommended dose is 3 hours of daily usage until healing occurs. insulinlike growth factor-II [IGF-II]). 67% achieved solid fusion. Of patients who wore the device for at least 2 hours. combined AC and DC magnetic fields are predicted to couple to calcium-dependent and magnesium-dependent cellular signaling processes in tissues. Use of the Spinal-Stim (Orthofix. some use a saddle-shaped coil. Clinical Data Amulticenter open trial of the modified PEMF device was conducted with 139 patients who had one or more fractures that had not healed for at least 9 months (some >5 years). There are several suggested mechanisms of action. et al ment.35-37 Specifically. multicenter. Mooney32 reported the results of a prospective.31 The lengthy time of nonunion served as the baseline because spontaneous fracture healing was unlikely to occur. The recommended dose is at least 2 hours a day until the patient is healed. McKinney.05) better healing rate than did patients who complied to a lesser degree with the treatment regimen (80% versus 19. No 5. no or minimal pain. The clinical benefit on bone repair is the result of this up-regulation of growth factor production. Yen-Patton et al33 showed that this modified PEMF increased the number of vessels. delivered by dual coils that encompass the entire lumbar area. In a second phase of this study. with the short-term (30-minute) CMF stimulus acting as a triggering mechanism that couples 349 . No additional surgery was done. Nelson. placebo-controlled clinical trial of PEMF stimulation for lumbar spine fusion. There was no significant difference in fracture healing rate for the average wear times of 3 to 6 hours. Current Indications The use of modified PEMF devices is indicated for fracture nonunions that demonstrate no radiographic evidence of progression of bony healing. typically 3 to 6 months. randomized. Long-term followup 4 years later revealed essentially the same healing rate with no longterm adverse effects. Using the original PEMF signal (also with a repetition rate of 15 Hz).2%).6%.001).33 A different field was developed for the spine. The only intervention applied was the addition of PEMF therapy prescribed for 8 hours a day for at least 90 days. 126 patients with a failed fusion who were at least 9 months from prior surgery were given an active device to use for 8 hours a day for at least 90 days. (Interbody fusions are easier to evaluate than posterolateral fusions.005) increase fusion rates. It delivers an average 790-mG field of a burst of twenty-one 260-µsec pulses repeated at 15 Hz. Fracture healing was judged by four criteria: cortical bone bridging and absence of motion on stress radiographs. Vol 11. Device usage is typically 25 weeks and is discontinued when the fracture heals or after 3 months of no progression in healing.32 In a historical cohort study of 42 patients treated with PEMF stimulation and 19 nonstimulated patients. 6 to 9 hours. predating the use of pedicle screws. Pulsed Electromagnetic Field. or “sprouting. no or minimal edema.9% in the placebo group. The study included both interbody and posterolateral fusions at one or more levels. TX) is indicated as an adjunct to spinal fusion surgery to increase the probability of fusion success and as a nonsurgical treatment to salvage a failed spinal fusion. The authors also noted increased migration of osteoblasts and an enhanced mineralization of new fibrocartilage. prior infection.” in endothelial tissue by a factor of 10 to 15. flattened solenoids. typically 3 to 9 months. T. Cellular studies of CMFs have addressed effects on both signal transduction pathways and growth factor production.Fred R. and no need for casting. September/October 2003 patients who wore the device for at least 3 hours a day for a minimum of 90 days had a significantly (P < 0.) Spine fixation was by hook and rod. An analysis of usage versus fusion success demonstrated that a dosage of only 4 hours a day for 90 days was enough to significantly (P = 0. or multiple surgical procedures. respectively) was statistically significant (P < 0. MD. The devices are horseshoe-shaped. One hundred ninety-five patients underwent interbody fusion (anterior and posterior approaches). The neovascularization occurs in vitro after 5 to 8 hours of stimulation. Modified Basic Science A modified PEMF was developed to reduce energy requirements. The resulting working model from the studies of Fitzsimmons and colleagues38-40 is the proposal that short-duration CMF stimulus of 30 minutes activates secretion of growth factors (eg. Patients were prescribed the device for a total of 8 hours a day for a minimum of 90 days or until healed. an open fracture. This is a 160-mG field of ninety-nine 260-µsec pulses.6% and 52. Marks67 found that the rate of fusion enhancement (97. Consistent use at this level resulted in an overall fusion rate of 92% in the PEMF group compared with 64. and >9 hours. Healing occurred in the presence of fracture gaps ≥6 mm whether the patient was a smoker or had comminution.

Fitzsimmons and colleagues40. Future indications for CMFs may include osteoarthritis and neuroarthropathy.44 and on osteopenic animal models. foot volumes were within 10% of each other. the application of ultrasound at 50 mW/cm2 increased release of cellular calcium.47 However provocative. which are exquisitely sensitive to small variations in temperature. increase calcium incorporation in both differentiating cartilage and bone cell cultures. unbiased panel.Use of Physical Forces in Bone Healing to the normal molecular regulation of bone repair mediated by growth factors. Treatment was applied for 30 minutes a day for 9 months.69 A prospective. such as matrix metalloproteinase 1 (interstitial collagenase).70 There is a wide range of proposed mechanisms by which low-intensity ultrasound stimulates fracture healing. The investigators concluded that the adjunctive use of the CMF device for noninstrumented fusions results in higher fusion rates and in earlier fusions. placebo-controlled trial was conducted on primary uninstrumented lumbar spine fusion. require further investigation.or two-level fusions (between L3 350 and S1) with either autograft alone or in combination with allograft.001). doubleblind.46 possibly mediated by attenuation of tumor necrosis factor α–dependent signaling in osteoblasts. and increase second messenger activity paralleled by the modulation of adenylate cyclase activity and TGF-β synthesis in osteoblastic cells.2 ± 7.39 In 1995. Results showed that the mean time to consolidation in the control group was 23. This panel evaluation differed from those of other spinal fusion studies with noninvasive bone growth stimulators in that the treating surgeon’s assessment of fusion could be overruled by the blinded panel.5-MHz sinusoidal waves repeated at 1 kHz (versus 2 kHz) at a low intensity of 30 mW/cm2. randomized. 64% healed at 9 months. treatment with the CMF device decreased time to consolidation to 11.2 weeks (P < 0. In contrast.71 Ultrasound has been shown to change the rate of influx and efflux of potassium ions.68 Subsequently. 57 years) coupled with the use of noninstrumented technique with posterolateral fusion only. a musculoskeletal radiologist.030) in a model with only a main effect.53 Increased PGE2 production via the induction of cyclooxygenase-2 mRNA occurs in mouse osteoblasts in a manner similar to that which is effected by fluid shear stress and tensile force stimu- Journal of the American Academy of Orthopaedic Surgeons .003 by Fisher’s exact test). and fracture consolidation had occurred. 201 were available for evaluation. 10 more patients were added to the CMF-treatment group. repeated-measures analyses of fusion outcomes showed a main effect of treatment favoring the active treatment (P = 0. 10 control subjects and 11 patients treated with CMFs were followed weekly and treated until the difference in temperature between the two feet was less than 2°C.001 by Fisher’s exact test).42 Recent studies have shown effects of CMFs on experimental fracture healing43.9 Minimal heating effect (well below 1°C) may increase some enzymes. and a spine surgeon. only 43% of placebo-device patients healed (P = 0. Current Indications Application of CMFs for 30 minutes a day has been shown to be effective for management of nonunions and as adjunctive stimulation for primary spinal fusion.45. Clinical Data In a prospective. the role of growth factors in transduction of CMFs in cells and tissues. The most recent application of CMFs has been as an adjunctive stimulation device for spinal fusion. based on radiographic evaluation by a blinded panel consisting of the treating physician. There was no statistically significant difference in entry criteria between the control and CMF groups. the time-by-treatment interaction was significant (P = 0. Of the 243 patients enrolled. Among female patients. Of the patients with active devices.7 weeks. Ultrasound Basic Science Azuma et al70 confirmed the increased efficiency of the 200-µsec burst (versus 100-µsec and 400-µsec bursts) of 1. and the link to the observed clinical benefit of CMFs. This was the first randomized clinical trial of noninstrumented primary posterolateral lumbar spine fusion with evaluation by a blinded. The lower success rates are thought to be because of the highrisk patient group (average age.41 reported IGF-II release and increased IGF-II receptor expression in osteoblasts. randomized pilot study of patients with acute. The studies underlying this working model have shown effects of CMFs on calcium ion transport38 and cell proliferation. 67% of those with active devices achieved fusion compared with 35% of those with placebo devices (P = 0. Patients had one. The fusion rates in this study were lower than those of other noninstrumented studies reported in the literature. indicating acceleration of healing. phase 1 Charcot neuroarthropathy. Effects of CMFs on IGF-I and IGF-II in rat fracture callus were reported by Ryaby et al. In a model with main effect and a time-by-treatment interaction.52 In primary chondrocytes. The primary end point was assessment of fusion at 9 months. Additional animal data suggest that the biology of fracture healing can be accelerated by the use of ultrasound but that no specific stage of healing is more sensitive than another.024). Of the 201 patients.1 ± 3. but adoption of additional applications will require increased knowledge of the tissuelevel mechanisms combined with welldesigned clinical trials. The CMF device configured for spinal fusion has a single posterior coil centered over the fusion site.

some humeral. Clinical Management In the management of nonunions with physical fields.5 cm. and patients with renal insufficiency or who are using steroids. The common effect of these forces appears to be an increase in intracellular calcium by a variety of cellular mechanisms. The device is not portable.01) smaller loss of reduction (20 ± 6%) compared with placebo (43 ± 8%).9 Ultrasound treatment of nonunions resulted in an 85% healing rate in 385 nonunions. Other clinical studies have demonstrated enhanced rate of fracture healing in smokers.01) 24% reduction in the time of clinical healing (86 ± 5.8 days in the active-treatment group compared with 114 ± 10. it must be attached to a wall power source while in use. tibial fractures stabilized with intramedullary fixation). it would likely be misleading to overemphasize the impact of a single gene. Weight bearing is determined by the same criteria as those used for nonstimulated management of a slow-healing fracture. placebo-controlled clinical trial of 61 dorsally angulated fractures of the distal radius. September/October 2003 double-blind. Current Indications In October 1994.48 Using both clinical and radiographic criteria. approval was extended to the treatment of established nonunions. This information will be important to assess these devices comparatively with alternative tech- 351 .49 Ultrasound treatment resulted in a significantly (P < 0. one of the main biologic goals of the inflammatory response is to reestablish the blood supply to the injured area. the degree of immobilization required for patient comfort is usually similar to that for gradual healing without stimulation. the requirements for fixation or grafting. Outcomes such as return to specific activities or work have not yet been reported. With the depth of penetration at 3. MD. including for nonunions and spinal fusions. T. No 5. In another multicenter. Summary Physical stimulation in the form of electrical fields and ultrasound is important in orthopaedic applications. arthrodeses. Physical forces also can be used to enhance open techniques such as bone grafts for fracture healing. Low-intensity ultrasound stimulates an up-regulation of aggrecan gene expression in cultured chondrocytes and stimulates proteoglycan synthesis in rat chondrocytes by increasing aggrecan gene expression. A randomized. The presence of a synovial pseudarthrosis (articular-like surface) is a contraindication for all physical stimulation devices. forearm.55 Ultrasound has been shown to increase the expression of genes involved in the inflammation and remodeling stages of fracture repair.73 It is generally believed that greater blood flow serves as a principal factor in the acceleration of fracture healing. including leg-lengthening procedures. and spinal fusions. and social circumstances.01). Nonunions should be adequately stabilized and have good healing poten- tial (adequate soft-tissue coverage and evidence of a good blood supply). Twelve of 34 placebotreated patients (35%) developed delayed union. the device must be close to the bone to be effective. Vol 11.49 Other successful clinical trials have demonstrated reduction of healing time with ultrasound. doubleblind. the mean time to union was significantly (P < 0. low-intensity ultrasound was approved for the stimulation of healing of fresh fractures. Nelson. In selected cases. Given the effect of low-intensity ultrasound on hundreds of genes working in a complex biologic system to achieve the healing response. patients with diabetes.9 Ultrasound is not effective in all settings requiring bone healing (ie. however. Clinical Data The initial clinical trials for ultrasound were focused on reduction of healing time. with a mean healing time of 14 months. whereas only 2 of 33 ultrasound-treated patients (6%) had delayed union (P < 0. and the patient’s employment.4 days in the control group). Low-intensity ultrasound treatment over a 10-day period stimulated a greater degree of vascularity in an osteotomized dog ulna model of fracture healing.0001) reduced by 38% for ultrasound-treated patients (61 ± 3 days) compared with placebo-treated patients (98 ± 5 days).Fred R. Delayed unions and nonunions that are malaligned require surgical correction before healing can occur. postoperative management is generally the same as for cases in which no external stimulation is used. and leg fractures may be more effectively immobilized in a fracture brace. The cost effectiveness of any fracture stimulation device depends on knowing which fractures respond best. This results in an increase in osteoblastic function in cells capable of bone formation. prospective. In February 2000. a 38% decrease in the time to overall healing was apparent. personal. the success rate approximates that of surgical procedures. Indeed. randomized. If physical stimulation is to be used after internal fixation and/or grafting of a nonunion. placebo-controlled study of 67 closed or grade 1 open tibial fractures using ultrasound treatment of 20 minutes a day at 30 mW/cm2 led to a significant (P < 0.72 This might explain the role of ultrasound in augmenting endochondral ossification and thus increasing the mechanical strength and overall repair of the fractured bone. et al li. The device requires a daily 20-minute application of the ultrasound head on the skin through a window in the immobilization device. A fracture with palpable motion is generally immobilized a joint above and below.

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