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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 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 slow- er 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 min- imize problems with fracture healing, improved methods ofinternalandex- ternal fracture immobilization have been combined with appropriately timed early transmission of physio- logic forces across the fracture sites. 4 Additionally, a number of adjunctive treatment optionstostimulatenormal fracture healing, delayed unions, and nonunions have been developed. 5 These options include direct current (DC), pulsed electromagnetic fields (PEMFs), capacitive couplings, and ultrasound. Over the past two decades, an es- timated 400,000 fracture nonunions, delayed unions, and fusions have been managed by physical fields. In January 2000, the Society for Physi- cal Regulation in Biology and Med- icine sponsored a symposium to review the clinical applications and mechanisms of action for these various modalities. The core material from that symposium has been orga- nized 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 (Ta- ble 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 generate physical forces to influence fracture healing is necessary for their optimal clinical application (Table 2). Dr. Nelsonis Director ofResident Education,Hen- ry FordHospital, Detroit, MI.Dr. Brightonis Paul B. MagnusonProfessor Emeritusof Boneand 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 Resi- dent, Department of Orthopaedic Surgery, Jaco- by Medical Center, Bronx, NY. Dr. Lorich is As- sociate Director, Orthopaedic Trauma Surgery, Hospitals for SpecialSurgery, NewYork, NY. Dr. Bolander is Professor of Surgery, Mayo Clinic, Rochester, MN. Dr. Seelig is Doctorof Neurosur- gery, San Diego, CA. None of the following authors or the departments with which they are affiliated has received any- thing of value from or owns stock in a commer- cial company or institution related directly or in- directly 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. 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;11:344-354 344 Journal of the American Academy of Orthopaedic Surgeons History of Development of Physical Fields In 1841, Hartshorne 6 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.” Lente 7 in 1850 described three cases of delayed unions or nonunions treated with galvanic current. More than 100 years later, electrical stimulation of bone regainedclinicalscientificprom- inence when Fukada and Yasuda 8 described “piezoelectric potentials” generated by mechanical stressonthe crystalline structure of bone. At the same time, ultrasound began to show promise as a method of stimulating fracture healing. In 1953, Corradi used continuous wave ultrasound to stimulate fracture healing, producing an increase in periosteal callus. 9 A central hypothesis in the application of physical forces is that strain- generated electrical potentials may be a regulatory signal for cellular processes of bone formation. The idea that electrical fields might be important in the repair process was described in the early 1960s by Bassett and Becker. 10 AFourier transform was used to break down the electromagnetic signal into its major and minor components to predict the biological- ly important rate of generation of electric potentials in bone by mechanical stress. 10 This was used as the basis for selecting one of the currently used PEMFs. Additional knowledge of the nature of endogenous electric fields in biology led to the development of the direct electric fields now in use. 11 Subsequently there was further development of PEMFs as well Table 1 Terms and Definitions Term Definition Physical forces Include any mechanical, electrical, or sonic force applied to an area of bone fracture healing. This is in distinction from biochemical osteoinductive therapies. Direct electrical stimulation Involves an implanted cathode placed in the area of expected bone stimulation and a battery-based anode placed subcutaneously. A constant 20-µA direct current is delivered. Pulsed electromagnetic fields (PEMFs) Use magnetic coils that receive a specific pulsed electrical current that results in a magnetic flux density ≈0.1 to 18 G in the form of a pulse train with a 15-Hz or sinusoidal 76-Hz frequency. A pulse train is a rapid sequence, typically of twenty 220-µsec repeat- ing spikes. A gauss (G) is a unit of electromagnetic flux. (The earth’s geomagnetic field is approximately 0.6 G.) Capacitive coupling Requires two surface electrodes placed on the skin across a fracture site. A 60-kHz sinusoidal wave signal is generated by a 9-V battery; this results in an internal field of 0.1 to 20 mV/cm and a current density of 300 µA/cm 2 that is not felt by the patient. Table 2 Devices That Generate Physical Forces Device Wave Form Tissue Electrical Field Direct current 20 µA As delivered Pulsed electromagnetic field 4.5-msec–long bursts of twenty 220-µsec 18-G pulses repeated at 15 Hz 1.5 mV/cm; 10 µA/cm 2 Capacitive coupling 60 kHz, 10 µA (rms), 6 V peak to peak delivered by 9-V battery 0.1 to 20 mV/cm and 300 µA/cm 2 at 60 kHz Pulsed electromagnetic field, modified 790-mG field of a burst of twenty-one 260-µsec pulses with repetition rate of 15 Hz 4 mV/cm peak to peak Combined magnetic field 76.6-Hz sinusoidal 40-µT (400 mG) peak-to- peak AC magnetic field superimposed on 20-µT DC magnetic field Magnetic field effect, not induced field Ultrasound Sinusoidal N/A rms = root-mean-square Fred R. T. Nelson, MD, et al Vol 11, No 5, September/October 2003 345 as combined (DC and AC) magnetic fields. Arabbit fibular fracture model was used to define the dose-response curve for capacitive coupling in fracture healing. An internal field of 220 mV with a current density of 250 µA was the most effective for induction of healing. 12 The effects of ultrasound on fracture callus stimulation were studied by numerous investigators using a variety of animal models. 9 Pilla et al 13 found that brief periods (20 min/day) of pulsed ultrasound (a 200-µsec burst of 1.5-MHz sinusoidal waves repeated at 1 kHz) at a low intensity (30 mW/cm 2 ) accelerated the recovery of torsional strength and stiffness in a midshaft fibular osteot- omy of the rabbit. Although most human clinical studies conducted during the development of these devices were retro- spective, prospective controlled studies now exist. However, most of these record only the presence or absence of healing as an end point. 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. Revascularization, as in core decompression for osteonecrosis of the femoral head, and stimulation of articular cartilage repair in osteoarthritis are potential new applications for these methodologies that are currently under investigation. Direct Current Basic Science In 1981, Brighton et al 11 showed that with direct electrical stimulation, the pO 2 is lowered and pH raised in the vicinity of the cathode. A low pO 2 is favorable to bone formation; Brighton et al 11 found lower pO 2 at the bone-cartilage junction of the growth plate and in newly formed bone and cartilage in fracture callus. Among the cellular mechanisms of electric current–induced osteogenesis are increased proteoglycan and collagen synthesis 14 (Table 3). Clinical Data After the initial clinical demonstra- tion of fracture healing in 1971 by Friedenberg et al, 57 Brighton et al 22 in 1977 reported the use of DC by per- cutaneous wire placement for tibial nonunions that had been present for an average of 3.3 years. Treated with a field of 10 to 20 µA over 12 weeks, 39 of 57 nonunions healed. Based on this study and animal models, 20 µA was determined to be the preferred current. In 1981, Brighton et al 11 reported on 178 nonunions managed with 4 percutaneously inserted cath- odes, each delivering a 20-µA DC, resulting in 149 successful unions. Suc- cess rates were 83.3% for tibial nonunions, 66.7% for clavicular nonunions, and 61.5% for humeral nonunions. The presence of a synovial-lined pseudarthrosis prevented healing. Current Indications In 1979, the Food and Drug Ad- ministration (FDA) approved the use of DC in established nonunions. (An established nonunion is one that shows no visible progressive signs of healing. The FDA’soriginaldefinition stipulated no visible signs of healing for at least 3 months after at least 9 months since injury.) Originally the anode was placed on the skin, with a battery pack worn at the waist. Im- plantable batteries acting as anodes were later developed to deliver a consistent 20-µA current. The cathode now can be wrapped in a spiral and shaped to match the area of interest. In contrast with surface induction, implanted DC stimulation eliminates the problem of patient compliance when used in conjunction with a surgical procedure for internal fixation or bone grafting. Direct electrical stimulation also has been approved by the FDA for use in spinal fusion. An open exposure is required,andthe battery/anode is removed 6 months after implantation. 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 current 11-14 O 2 ↓, 11,14 synthesis collagen and proteoglycan 11 Pulsed electromagnetic field (PEMF) 15-20 Cytokines 12,13,21-25 Capacitive coupling 26-28 Bone cell proliferation, 29 activate voltage-gated calcium channels, PGE 2 , cytosolic calcium, activated calmodulin, 26 mRNA TGF-β 30 Modified PEMF 31,32 Vascular ingrowth, osteoblast migration, matrix calcification 33 Combined magnetic field 15,34 Ion transport across cell membranes and ion dependent cell signaling in tissues, 35-37 growth cytokines 38-47 Ultrasound 9,48-51 Influx and efflux of K + , 52 cartilage bone Ca ++ , 53 adenylate cyclase activity, 54 TGF-β, 54 PGE 2 , 55 aggrecan and vascularity, 9 PDGF-AB 56 * Increases, stimulates, or activates Use of Physical Forces in Bone Healing 346 Journal of the American Academy of Orthopaedic Surgeons ilar in magnitude and time course to the endogenous electrical fields pro- duced in response to strain. These fields are thought to underlie the abil- ity of bone to respond to a changing mechanical environment, as described by Wolff’s law.Thesignalcon- sists of 4.5-msec–long bursts of twenty 220-µsec 18-G pulses repeated at 15 Hz. This results in a time-varying extracellular and intracellular electrical field. Research with PEMFs has focused on regulation of messenger RNA (mRNA) and protein synthesis of the transforming growth factor-beta (TGF-β)/bone morphogeneticprotein (BMP) gene family because these cytokines have been shown to modu- late cellular activity of osteochondral progenitor cells, chondrocytes, and osteoblasts. In many animal studies and recently in human clinical trials, TGF-β, BMP-2, and BMP-7 have been shown to enhance fracture repair. In an endochondral ossification model using demineralized bone matrix–induced osteogenesis, PEMF treatment caused an increase in chondrogenesis concomitant with an up-regulation of TGF-β. 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. 58 In a rat calvarial osteoblast culture, 1 hour of stimulation resulted in a threefold increase in BMP-2 mRNA and a sixfold increase in BMP-4 mRNA. 59 Two recent studies describe the effects of PEMF on TGF production. 25,60 In one, 25 confluent cultures of MG63 human osteoblast-like cells were stimulated for 8 hours a day for 4 days and showed a significant (P < 0.05) increase in TGF levels in stimulated versus control cells after 1 and 2 days of stimulation. PEMF enhanc- es differentiation of MG63 cells, as ev- idenced by decreased proliferation and increased alkaline phosphatase activity and osteocalcin and collagen production. These results support earlier observations in the endochondral bone model that PEMF stimulation increases chondrogenesis by enhancing differentiation of osteochondral precursor cells into a chon- drogenic lineage without affecting proliferation. 24 In a second study, 60 nonunion cells derived from patients undergoing surgery were successfully cultured, and PEMF stimulation of these cells resulted in significant (P < 0.05) increases in TGF-β production compared with nonstimulated control cells. 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. Clinical Data More than 250 published basic research and clinical investigations have evaluated the efficacy of PEMF stimulation. 21 In 1990, Sharrard reported a double-blind trial of delayed unions in 45 tibial shaft fractures managed by plaster cast, with active PEMF units (n = 20) or identical dum- my control units (n = 25) for a period of 12 weeks. 19 Nine of 20 fractures (45%) in the active group healed, compared with 3 of 25 fractures (12%) in the control group (P < 0.01). 19 Bas- sett et al 61 reported on a series of 127 diaphyseal tibia nonunions treated with PEMFs that yielded an overall success rate of 87%. Ayear later, Bas- sett et al 62 reported the results of PEMF treatment with surgery and bone grafting in 83 nonunions with wide fracture gaps,synovialpseudar- throsis, and malalignment. These patients achieved an 87% success rate. In a broad literature review comparing PEMF treatment of nonunions with surgical therapy, Gossling et al 16 noted that 81% of reported cases healed with PEMF versus 82% with surgery. Also, the success of surgical treatment for infected nonunions was 69%, whereas 81% of the PEMF- treated group healed. 16 In open fractures, surgical healing exceeded PEMF (89% and 78%, respectively), but in closed injuries, PEMF- managed fractures healed more fre- quently than did surgically treated fractures (85% and 79%, respectively). This study indicates the efficacy of PEMF treatment to be comparable to that of surgical intervention for fracture nonunion. PEMF treatment has applications in the upper extremity, as well. Fryk- man et al 17 reported that 35 of 44 scaphoid nonunions (80%) were managed successfully by PEMFs with cast immobilization. However, in a continuation of that study published 6 years later, the overall success rate had decreased to 69% because of breakdown of some of the fractures originally reported as unions. Prox- imal pole fractures healed in 50%. 63 The daily dosage of PEMF treatment is important in the healing process. A dose-response study demonstrated that an increase in daily treatment time correlates with a reduction in the time to healing of nonunion fractures. 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. Current Indications PEMF treatment is recommended as an adjunct to standard fracture management. Indications for use include nonunions, failed fusions, and congenital pseudarthrosis. Recently, the definition of a nonunion has been modified to failure to exhibit visibly progressive signs of healing. 64 This definition thus permits all forms of electrical stimulation intervention to take place earlier in the treatment than previously and removes contro- versy regarding when a delayed union may be consideredanonunion. Generally, a fracture gap >5 mm, suspected or documented synovial pseudarthrosis, and severe devascu- larization are contraindications for the use of PEMFs. Patients typically Fred R. T. Nelson, MD, et al Vol 11, No 5, September/October 2003 347 are treated for 3 to 9 months depend- ing on fracture location, severity, and time from injury. Some difficult fractures may require management for longer periods. The fracture should progress to healing within 3 to 6 months. If surgery is needed, some patients choose to continue use of the stimulator to enhance healing after surgery. Capacitive Coupling 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 induced field is driven by an oscillating electric current, as opposed to the electromagnetic field induction of PEMF. In an in vitro rat calvarial bone cell model, Brighton et al 29 found that field strength was the dominant factor affecting bone cell proliferative response to a capacitive coupled field. Field strengths calculated at 0.1 to 20 mV/cm (60 kHz and 300 µA/cm 2 ), with various pulse configurations as well as continuous signals, are effective in stimulating bone cell proliferation. 29 The clinical effect of electrically induced osteogenesis is easily recognized. However, the basic phys- iology of how electrical signals stimulate bone is more difficult to demonstrate in the laboratory. Using various metabolic inhibitors, Lorich et al 26 showed that signal transduction in capacitive coupling stimulation activated voltage-gated calcium channels, leading to increases in pros- taglandin E 2 (PGE 2 ), cytosolic calcium, and activated calmodulin. This is in contrast to signal transduction of indirect coupling and combined magnetic fields (CMFs), in which the cytolsolic calcium is secondary to release of calcium from intracellular stores. This leads to an increase in activated calmodulin. Although the initial signal transduction of capacitive coupling is different from inductive coupling of a combined DC and pulsed electromagnetic field, there appears to be a common pathway. 65 In addition, Zhuang et al 30 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. Clinical Data In a prospective, 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), Brighton and Pollack 1 reported a mean healing rate of 77.3% with capacitive coupling after a mean of 22.5 weeks. Brighton et al 66 used lo- gistic regression analysis in a retro- spective study of the healing rate of 271 tibial nonunions treated by DC, capacitive coupling, or bone graft. The authors identified seven risk factors that adversely affected the healing rate of nonunions managed with capacitive coupling: duration of nonunion, prior bone graft surgery, pri- or electrical stimulation, open fracture, osteomyelitis, comminuted or oblique fracture, and atrophic nonunion. With no or one risk factor present, there were no significant dif- ferences among the three treatment methods (96% to 99%). With the presence of two to five risk factors, capacitive coupling yielded poorer results in managing atrophic nonunion; oth- erwise, results were similar regard- less of treatment modality. With six or seven risk factors, all three forms of treatment provided poor results. Unfortunately, this study did not evaluate smoking as a possible risk factor. Scott and King 27 reported the results of a small, prospective double- blind study using capacitive coupling in the management of established nonunions. They found a statistically significant association between the use of capacitive coupling and eventual union. Six of the 10 nonunions in the actively managed group healed, compared with none of the 11 in the placebo group (P = 0.004). There also have been two double-blind prospective lumbar fusion studies using capacitive coupling. Goodwin et al 28 studied 179 patients randomized into groups assigned active or nonactive coils after lumbar fusion. The authors reported a statistically significant (P = 0.0043) increased rate of fusion in the active group (84.7%) compared with the placebo group (64.9%). Pos- terolateral bone graft combined with concurrent instrumentation of the affected levels had a higher rate of fusion than did graft without instrumentation. Within the instrumented group, stimulated patients showed higher fusion rates than did the placebo control subjects. Current Indications Capacitive coupling is indicated for nonunions of long bones and the scaphoid and as an adjunct treatment in spinal fusions. In applying capacitive coupling, cast immobilization typically is used. Two small windows are cut out for the application of the electrodes, which are positioned across the approximate site of the fracture and moistened before application. When the pads dry, the monitor detects the loss of contact and sets off an alarm, indicating that the pads need to be remoistened. Currently available electrodes last up to 1 week without requiring reapplication of gel. The pads are worn 24 hours a day and are changed weekly, or more of- ten as required for hygiene. The device uses a 9-V battery that should be replaced daily. Skin reaction is usually mild. If necessary, electrodes can be moved to a new skin site. Treat- ment is discontinued if there is severe skin reaction. Serial anteroposterior, lateral, and oblique radiographs are used to monitor progression of healing, as in normal fracture manage- Use of Physical Forces in Bone Healing 348 Journal of the American Academy of Orthopaedic Surgeons ment. Device usage is typically 25 weeks and is discontinued when the fracture heals or after 3 months of no progression in healing. Pulsed Electromagnetic Field, Modified Basic Science A modified PEMF was developed to reduce energy requirements. It de- livers an average 790-mG field of a burst of twenty-one 260-µsec pulses repeated at 15 Hz. The devices are horseshoe-shaped, flattened sole- noids; some use a saddle-shaped coil. There are several suggested mechanisms of action. Using the original PEMF signal (also with a repetition rate of 15 Hz), Yen-Patton et al 33 showed that this modified PEMF increased the number of vessels, or “sprouting,” in endothelial tissue by a factor of 10 to 15. The neovascular- ization occurs in vitro after 5 to 8 hours of stimulation. The authors also noted increased migration of osteoblasts and an enhanced mineraliza- tion of new fibrocartilage. 33 A different field was developed for the spine, delivered by dual coils that encom- pass the entire lumbar area. This is a 160-mG field of ninety-nine 260-µsec pulses. 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). 31 The lengthy time of nonunion served as the baseline because spontaneous fracture healing was unlikely to occur. The only intervention applied was the addition of PEMF therapy prescribed for 8 hours a day for at least 90 days. Frac- ture healing was judged by four criteria: cortical bone bridging and absence of motion on stress radiographs, no or minimal pain, no or minimal edema, and no need for casting. On completion of the course of treatment, patients who wore the device for at least 3 hours a day for a minimum of 90 days had a significantly (P < 0.05) better healing rate than did patients who complied to a lesser degree with the treatment regimen (80% versus 19.2%). There was no significant difference in fracture healing rate for the average wear times of 3 to 6 hours, 6 to 9 hours, and >9 hours. Healing occurred in the presence of fracture gaps ≥6 mm whether the patient was a smoker or had comminution, an open fracture, prior infection, or multiple surgical procedures. Long-term follow- up 4 years later revealed essentially the same healing rate with no long- term adverse effects. Mooney 32 reported the results of a prospective, multicenter, randomized, placebo-controlled clinical trial of PEMF stimulation for lumbar spine fusion. One hundred ninety-five patients underwent interbody fusion (an- terior and posterior approaches). (In- terbody fusions are easier to evaluate than posterolateral fusions.) Spine fixation was by hook and rod, predat- ing the use of pedicle screws. Patients were prescribed the device for a to- tal of 8 hours a day for a minimum of 90 days or until healed. 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 = 0.005) increase fusion rates. Consistent use at this level resulted in an overall fusion rate of 92% in the PEMF group compared with 64.9% in the placebo group. In a second phase of this study, 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. No additional surgery was done. The study included both interbody and posterolateral fusions at one or more levels. Of patients who wore the device for at least 2 hours, 67% achieved solid fusion. 32 In a historical cohort study of 42 patients treated with PEMF stimulation and 19 nonstimulated patients, Marks 67 found that the rate of fusion enhancement (97.6% and 52.6%, respectively) was statistically significant (P < 0.001). Current Indications The use of modified PEMF devices is indicated for fracture nonunions that demonstrate no radiographic evidence of progression of bony healing. The recommended dose is 3 hours of daily usage until healing occurs, typically 3 to 6 months. Use of the Spinal-Stim (Orthofix, McKinney, 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 recommended dose is at least 2 hours a day until the patient is healed, typically 3 to 9 months. Combined Magnetic Fields Basic Science The scientific basis of CMFs is predicated on theoretic physics confirmed by experimental demonstra- tions that combinations of dynamic and static magnetic fields affect ion transport across cell membranes and affect ion-dependent cell signaling in tissues. 35-37 Specifically, combined AC and DC magnetic fields are pre- dicted to couple to calcium-dependent and magnesium-dependent cellular signaling processes in tissues. Cellular studies of CMFs have ad- dressed effects on both signal transduction pathways and growth factor production. The resulting working model from the studies of Fitz- simmons and colleagues 38-40 is the proposal that short-duration CMF stimulus of 30 minutes activates secretion of growth factors (eg, insulin- like growth factor-II [IGF-II]). The clinical benefit on bone repair is the result of this up-regulation of growth factor production,withtheshort-term (30-minute) CMF stimulus acting as a triggering mechanism that couples Fred R. T. Nelson, MD, et al Vol 11, No 5, September/October 2003 349 to the normal molecular regulation of bone repair mediated by growth factors. The studies underlying this working model have shown effects of CMFs on calcium ion transport 38 and cell proliferation. 39 In 1995, Fitzsim- mons and colleagues 40,41 reported IGF-II release and increased IGF-II receptor expression in osteoblasts. Ef- fects of CMFs on IGF-I and IGF-II in rat fracture callus were reported by Ryaby et al. 42 Recent studies have shown effects of CMFs on experimental fracture healing 43,44 and on os- teopenic animal models, 45,46 possibly mediated by attenuation of tumor ne- crosis factor α–dependent signaling in osteoblasts. 47 However provoca- tive, the role of growth factors in transduction of CMFs in cells and tissues, and the link to the observedclin- ical benefit of CMFs, require further investigation. Clinical Data In a prospective, randomized pilot study of patients with acute, phase 1 Charcot neuroarthropathy, 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, foot volumes were within 10% of each other, and fracture consolidation had occurred. 68 Subsequently, 10 more patients were added to the CMF-treatment group. Results showed that the mean time to consolidation in the control group was 23.2 ± 7.7 weeks. In contrast, treatment with the CMF device decreased time to consolidation to 11.1 ± 3.2 weeks (P < 0.001). There was no statistically significant difference in entry criteria between the control and CMF groups. The most recent application of CMFs has been as an adjunctive stimulation device for spinal fusion. 69 A prospective, randomized, double- blind, placebo-controlled trial was conducted on primary uninstrument- ed lumbar spine fusion. Patients had one- or two-level fusions (between L3 and S1) with either autograft alone or in combination with allograft. The CMF device configured for spinal fusion has a single posterior coil cen- tered over the fusion site. Treatment was applied for 30 minutes a day for 9 months. The primary end point was assessment of fusion at 9 months, based on radiographic evaluation by a blinded panel consisting of thetreat- ing physician, a musculoskeletal ra- diologist, and a spine surgeon. 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. Of the 243 patients enrolled, 201 were available for evaluation. Of the patients with active devices, 64% healed at 9 months; only 43% of placebo-device patients healed (P = 0.003 by Fisher’s exact test). Among female patients, 67% of those with active devices achieved fusion compared with 35% of those with placebo devices (P = 0.001 by Fisher’s exact test). Of the 201 patients, repeated-measures analyses of fusion outcomes showed a main effect of treatment favoring the active treatment (P = 0.030) in a model with only a main effect. In a model with main effect and a time-by-treatment inter- action, the time-by-treatment interac- tion was significant (P = 0.024), indicating acceleration of healing. The investigators concluded that the adjunctive use of the CMF device for noninstrumented fusions results in higher fusion rates and in earlier fusions. This was the first randomized clinical trial of noninstrumented primary posterolateral lumbar spine fusion with evaluation by a blinded, un- biased panel. The fusion rates in this study were lower than those of other noninstrumented studies reported in the literature. The lower success rates are thought to be because of the high- risk patient group (average age, 57 years) coupled with the use of noninstrumented technique with posterolateral fusion only. 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. Future indications for CMFs may include osteoarthritis and neuroarthropathy, but adoption of additional applications will require increased knowledge of the tissue- level mechanisms combined with well- designed clinical trials. Ultrasound Basic Science Azuma et al 70 confirmed the increased efficiency of the 200-µsec burst (versus 100-µsec and 400-µsec bursts) of 1.5-MHz sinusoidal waves repeated at 1 kHz (versus 2 kHz) at a low intensity of 30 mW/cm 2 . Ad- ditional 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. 70 There is a wide range of proposed mechanisms by which low-intensity ultrasound stimulates fracture healing. 9 Minimal heating effect (well below 1°C) may increase some enzymes, such as matrix metalloproteinase 1 (interstitial collagenase), which are exquisitely sensitive to small varia- tions in temperature. 71 Ultrasound has been shown to change the rate of influx and efflux of potassium ions, increase calcium incorporation in both differentiating cartilage and bone cell cultures, and increase second messenger activity paralleled by the modulation of adenylate cyclase activity and TGF-β synthesis in osteoblastic cells. 52 In primary chondrocytes, the application of ultrasound at 50 mW/cm 2 increased release of cellular calcium. 53 Increased PGE 2 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- Use of Physical Forces in Bone Healing 350 Journal of the American Academy of Orthopaedic Surgeons li. 55 Ultrasound has been shown to increase the expression of genes in- volved in the inflammation and remodeling stages of fracture repair. 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. 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. Given the effect of low-intensity ultrasound on hundreds of genes working in a com- plex biologic system to achieve the healing response, it would likely be misleading to overemphasize the im- pact of a single gene. Low-intensity ultrasound treatment over a 10-day period stimulated a greater degree of vascularity in an osteotomized dog ulna model of fracture healing. 73 It is generally believed that greater blood flow serves as a principal factor in the acceleration of fracture healing. In- deed, one of the main biologic goals of the inflammatory response is to re- establish the blood supply to the in- jured area. Clinical Data The initial clinical trials for ultrasound were focused on reduction of healing time. Arandomized, double- blind, placebo-controlled study of 67 closed or grade 1 open tibial fractures using ultrasound treatment of 20 minutes a day at 30 mW/cm 2 led to a significant (P < 0.01) 24% reduction in the time of clinical healing (86 ± 5.8 days in the active-treatment group compared with 114 ± 10.4 days in the control group). 48 Using both clinical and radiographic criteria, a 38% de- crease in the time to overall healing was apparent. Twelve of 34 placebo- treated patients (35%) developed delayed union, whereas only 2 of 33 ultrasound-treated patients (6%) had delayed union (P < 0.01). In another multicenter, prospective, randomized, double-blind, placebo-controlled clinical trial of 61 dorsally angulated fractures of the distal radius, the mean time to union was significantly (P < 0.0001) reduced by 38% for ultrasound-treated patients (61 ± 3 days) comparedwithplacebo-treated patients (98 ± 5 days). 49 Ultrasound treatment resulted in a significantly (P < 0.01) smaller loss of reduction (20 ± 6%) compared with placebo (43 ± 8%). 49 Other successful clinical trials have demonstrated reduction of healing time with ultrasound, including leg-lengthening procedures. 9 Ultrasound treatment of nonunions resulted in an 85% healing rate in 385 nonunions, with a mean healing time of 14 months. 9 Ultrasound is not effective in all settings requiring bone healing (ie, tibial fractures stabilized with in- tramedullary fixation). Other clinical studies have demonstrated enhanced rate of fracture healing in smokers, patients with diabetes, and patients with renalinsufficiencyorwhoare using steroids. Current Indications In October 1994, low-intensity ultrasound was approved for the stimulation of healing of fresh fractures. In February 2000, approval was ex- tended to the treatment of established nonunions. The device requires a daily 20-minute application of the ultrasound head on the skin through a win- dow in the immobilization device. The device is not portable; it must be at- tached to a wall power source while in use. With the depth of penetration at 3.5 cm, the device must be close to the bone to be effective. Clinical Management In the management of nonunions with physical fields, the degree of immobilization required for patient comfort is usually similar to that for gradual healing without stimulation. Nonunions should be adequately stabilized and have good healing potential (adequate soft-tissue coverage and evidence of a good blood supply). The presence of a synovial pseudarthrosis (articular-like surface) is a contraindication for all physical stimulation devices. A fracture with palpable motion is generally immo- bilized a joint above and below; however, some humeral, forearm, and leg fractures may be more effectively im- mobilized in a fracture brace. Delayed unions and nonunions that are mala- ligned require surgical correction before healing can occur. Weight bear- ing is determined by the same criteria as those used for nonstimulated management of a slow-healing fracture. If physical stimulation is to be used after internal fixation and/or grafting of a nonunion, postoperative management is generally the same as for cases in which no external stimulation is used. The cost effectiveness of any fracture stimulation device de- pends on knowing which fractures respond best, the requirements for fixation or grafting, and the patient’s employment, personal, and social cir- cumstances. Summary Physical stimulation in the form of electrical fields and ultrasound is important in orthopaedic applications, including for nonunions and spinal fusions. The common effect of these forces appears to be an increase in intracellular calcium by a variety of cellular mechanisms. This results in an increase in osteoblastic function in cells capable of bone formation. In selected cases, the success rate approximates that of surgical procedures. Physical forces also can be used to enhance open techniques such as bone grafts for fracture healing, arthrodeses, and spinal fusions. Outcomes such as return to specific activities or work have not yet been reported. This information will be important to assess these devices comparatively with alternative tech- Fred R. T. Nelson, MD, et al Vol 11, No 5, September/October 2003 351 niques of stimulating fracture repair. Future research directions for electrical fields will include fractures at risk, failed fusion, porous ingrowth, osteoporosis, and revascularization after core decompression for osteonecrosis of the femoral head. Stimulation of articular cartilage synthesis in osteoarthritis currently is being investigated. Ultrasound is being evaluated for stimulation of fresh fractures in patients with co- morbidities including older patient age, diabetes, active smoking status, vascular insufficiency, and obesity. References 1. Brighton CT, Pollack SR: Treatment of recalcitrant non-union with a capacitively coupled electrical field: Aprelim- inary report. J Bone Joint Surg Am 1985; 67:577-585. 2. Praemer A, Furner S, Rice DP: Muscu- loskeletal Conditions in the United States, ed 2. Rosemont, IL:American Academy of Orthopaedic Surgeons, 1999. 3. 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