Radial extracorporeal shock wave therapy (reswt) induces new bone formation in vivo: results of an animal study in rabbits

Copyright ! 2012 World Federation for Ultrasound in Medicine & Biology Printed in the USA. All rights reserved 0301-5629/$ - see front matter d Original Contribution RADIAL EXTRACORPOREAL SHOCK WAVE THERAPY (RESWT) INDUCES NEW BONE FORMATION IN VIVO: RESULTS OF AN ANIMAL STUDY IN RABBITS HANS GOLLWITZER,TIMO GLOECKMICHAELA ROESSNER,RUPERT LANGER,y CARSTEN HORN,z UDGER GERDESMEYER,x and PETER DIEHL * Orthopedic Clinic, Technical University Munich, Munich, Germany; y Institute of Pathology and Pathological Anatomy, Technical University Munich, Munich, Germany; z Orthop€adische Klinik, K€onig-Ludwig-Haus, Universit€at W€urzburg, W€urzburg, Germany; x Sektion onkologische und rheumatologische Orthop€adie, im Universit€atsklinikum Schleswig Holstein, Kiel, Germany; and jj Orthopedic Clinic, University Rostock, Rostock, Germany (Received 11 June 2012; revised 28 August 2012; in final form 30 August 2012) Abstract—The aim of this study was to investigate if radial extracorporeal shock wave therapy (rESWT) induces new bone formation and to study the time course of ESWT-induced osteogenesis. A total of 4000 impulses of radial shock waves (0.16 mJ/mm2) were applied to one hind leg of 13 New Zealand white rabbits with the contralateral side used for control. Treatment was repeated after 7 days. Fluorochrome sequence labeling of new bone formation was performed by subcutaneous injection of tetracycline, calcein green, alizarin red and calcein blue. Animals were sacrificed 2 weeks (n 5 4), 4 weeks (n 5 4) and 6 weeks (n 5 5) after the first rESWT and bone sections were analyzed by fluorescence microscopy. Deposits of fluorochromes were classified and analyzed for significance with the Fisher exact test. rESWT significantly increased new bone formation at all time points over the 6-week study period. Intensity of ossification reached a peak after 4 weeks and declined at the end of the study. New bone formation was significantly higher and persisted longer at the ventral cortex, which was located in the direc- tion to the shock wave device, compared with the dorsal cortex, emphasizing the dose-dependent process of ESWT- induced osteogenesis. No traumata, such as hemorrhage, periosteal detachment or microfractures, were observed by histologic and radiologic assessment. This is the first study demonstrating low-energy radial shock waves to induce new bone formation in vivo. Based on our results, repetition of ESWT in 6-week intervals can be recommen- ded. Application to bone regions at increased fracture risk (e.g., in osteoporosis) are possible clinical indications.
! 2012 World Federation for Ultrasound in Medicine & Biology.
Key Words: Lithotripsy, Shockwave, Osteogenesis, Bone growth, ESWL.
fracture healing have been reported ; Extracorporeal shock wave therapy (ESWT) has been Focused shock waves have demonstrated to induce introduced to treat a variety of soft tissue pathologies new bone formation in various animal models, both on and high-quality randomized trials demonstrated effec- normal, fractured and osteomized bone and bone defects tiveness especially for enthesiopathies like plantar fascii- tis or calcific tendonitis of the shoulder ( Disclosed mechanisms include the induction of oxygen radicals and membrane hyperpolarization, fol- ). Furthermore, multiple studies indicated that lowed by the expression of growth factors and stimulation high-energy focused ESWT might also be appropriate of osteoprogenitor cells ( to stimulate bone healing in delayed unions and To activate bone healing in nonunions ().
the clinical setting, ESWT is commonly performed with Recently, activation of bone regeneration in a vascular high-energy shock waves requiring some kind of anes- bone necrosis ) and stimulation of thesia and repeated interventions in intervals of 4–6 weeks (; ). However, Address correspondence to: Hans Gollwitzer, Klinik f€ur there are neither data available on the minimum energy Orthop€adie und Sportorthop€adie der Technischen Universit€at M€unchen, required for bone stimulation, nor data on the dynamic Ismaninger Str. 21, 81675 M€unchen, Germany. E-mail: and persistence of ESWT-induced osteogenesis. Current FLA 5.1.0 DTD ! UMB9316_proof ! 26 September 2012 ! 4:03 pm ! ce 49 Ultrasound in Medicine and Biology Volume -, Number -, 2012 treatment recommendations are mainly based on empir- Table 1. Treatment interventions, fluorochrome ical rather than controlled experimental data.
application and end points Radial ESWT (rESWT) is a relatively new and cost- effective method of shock wave application. Radial shock waves are generated ballistically by accelerating tetracycline (25 mg/kg s.c.) rESWT (4000 impulses, a bullet to hit an applicator, which finally transforms 0.16 mJ/mm2, 4 bar, 8 Hz) the kinetic energy into radially expanding pressure rESWT (4000 impulses, waves (). Compared with the 0.16 mJ/mm2, 4 bar, 8 Hz) calcein green (20 mg/kg s.c.) commonly used focused shock waves, rESWT is charac- terized by a larger treatment area, which simplifies appli- alizarin red (30 mg/kg s.c.) cation by reflecting pathology zone rather than a point calcein blue (30 mg/kg, s.c).
). Furthermore, radial shock Group III (n 5 5) waves miss the typical steepening of focused shock- waves and, therefore, are physically more correctly clas- rESWT 5 radial extracorporeal shock wave therapy.
sified as pressure waves. rESWT is considered critically with bone pathologies because of to its unfocused distri- with tetracycline was started prior to treatment to label bution and lower energy level, both resulting in reduced the baseline value, followed by injection of calcein green, tissue penetration.
alizarin red and calcein blue after completion of both The present study was conducted to investigate the shock wave sessions ).
effect of rESWT on bone formation and to study the time course of ESWT-induced osteogenesis, which is mandatory to establish the most effective treatment Analysis of new bone formation protocol for bone stimulation.
Animals were sacrificed at 2 weeks (n 5 4), 4 weeks (n 5 4) and 6 weeks (n 5 5) after the first rESWT (with an overdose of pentobarbital. Rabbit femurs with adjacent soft tissues were removed carefully Shock wave treatment and contact radiographs were taken. Fixation was carried The present study was approved by the animal use out in 100% (v/v) methanol for one week, followed by and care committee of the regional government (Regier- dehydration in ethanol 100% (v/v) for 5 days, and defat- ung von Oberbayern). A total of 13 female New Zealand ting in xylol for 24 h. Bone samples were embedded in white rabbits (3.5–4.5 kg) were included in the animal PMMA. Thereafter, sagittal sections with a thickness of model. Radial shock waves were applied with a Swiss approximately 75 mm were cut and investigated with Dolorclast shock wave device (EMS Electro Medical broad-band fluorescence microscopy. Visualization of Systems, Nyon, Switzerland) to one randomized femur tetracycline, calcein green and alizarin red was achieved of each animal, while the contralateral side served as in- with Filter 09 (Carl Zeiss MicroImaging GmbH, Jena, traindividual control. Prior to each treatment, the animals Germany). Filter 02 (Carl Zeiss MicroImaging GmbH) were anesthetized with medetomidine, ketamine and was used to investigate alizarin red and calcein blue metamizole, and the left hind-leg was shaved. The appli- bands of new bone formation. The fluorescing bands cation site was localized at the ventral thigh, precisely were analyzed, and type of fluorochrome, intensity, superior to the patella with the rabbit in supine position extension and localization (endosteal/periosteal; ventral/ and the knee joint in 45 degree flexion. rESWT was dorsal cortex) were documented.
applied with an ultrasound transmission gel used as The magnitude and distribution of newly formed contact medium with the following parameters: impulse bone was evaluated by blinded review according to the count 4000 per intervention, impulse rate 8/s, pressure classification provided in The total accumulated 4 bar, and energy flux density 0.16 mJ/mm2. The treat- ossification bands (independent of the type of fluoro- ment was repeated with similar preparation 7 days after chrome) were classified with rating system A, which the first intervention. A flowchart of the study protocol was modified after Maier et al. (). For is provided in .
the assessment of osteogenetic activity at the different time points (analyses of the single fluorochrome bands), Polychrome sequence labeling of newly formed bone the rating system was modified to a total of five different To allow microscopic work-up of new bone forma- intensities (rating system B). Microscopic work-up tion, polychrome sequence labeling was performed with further included a qualitative histologic analysis for mi- different clearly contrasting fluorescent dyes adminis- crotraumata such as fractures, hematomas and periosteal tered subcutaneously once per day. Intravital staining FLA 5.1.0 DTD ! UMB9316_proof ! 26 September 2012 ! 4:03 pm ! ce 49 Radial shock wave therapy for bone stimulation d H. GOLLWITZER et al.
Table 2. Classification of new bone formation (whereas examination of the untreated contralat- eral femurs demonstrated only sporadically weak signs of Rating system A: total accumulated new bone formation new bone formation that persisted at this very minor Intensity of new bone formation grade over the entire study period (and Significant induction of bone formation by rESWT No signs of new bone formation Sporadic new endosteal and/or periosteal bone formation, could be demonstrated already in the first week after without covering the entire bone surface shock wave application and persisted at least until week New endosteal and/or periosteal bone formation, covering 6, which was documented by the newly formed fluores- the entire bone surface cent bands with dyes administered in the late phase of Rating system B: new bone formation at specific time points the experiment (alizarin red and calcein blue, and ). New bone formation reached a peak after 4 weeks Intensity of new bone formation and declined to lesser intensity 6 weeks after shock wave No signs of new bone formation or only weak, application (Nevertheless, osteogenesis after inhomogeneous fluorescent band rESWT was significantly increased compared with the Homogeneous band of new bone formation at one cortex only, with low intensity/smooth borders untreated control at all time points (p , 0.05).
Homogeneous band of new bone formation at one cortex Differentiation of rESWT-induced osteogenesis at only, with high intensity/sharp delineation the ventral and dorsal femoral cortex was carried out Homogeneous bands of new bone formation at both cortices, with low intensity/smooth borders because shock waves were applied to the ventral thigh Homogeneous bands of new bone formation at both cortices, and a distance-related decline of shock wave energy in with high intensity/sharp delineation bone was expected. Compared with the untreated control side, osteoneogenesis was significantly increased at the ventral cortex at all time points and at the dorsal Radiologic work-up was performed with contact cortex for approximately 4 weeks after rESWT b).
radiographs (3 mA, 35 kV, 60 s) before and microradio- Thereafter, new bone formation declined at the dorsal graphs (3 mA, 15 kV, 45 s) after sectioning of the ex- cortex to values indifferent of the untreated control planted femurs. Assessment included new periosteal (b). When both cortices were compared, rESWT- and endosteal bone formation, callus formation, cortical induced bone formation reached significantly higher and trabecular fractures, and periosteal detachment. The levels at the ventral cortex compared with the dorsal lungs of all animals were also harvested and examined cortex in the early phase (calcein green, p 5 0.031) and both macroscopically and histologically for signs of em- in the late phase of the experiment (calcein blue, p , bolism or dislocated bone trabeculae within pulmonary 0.008) but not during the peak of osteogenesis at 4 weeks vessels, which had been previously described after the (alizarin red, p 5 0.206). No significant differences were application of high-energy ESWT ).
observed with regard to endosteal and periosteal bone Statistical analysis of new bone formation in formation (p . 0.05) and no significant signs of new treated and untreated femora was performed with the bone formation were observed in trabecular bone.
Fisher exact test, with p , 0.05 considered statistically Contact radiographs and or microradiographs were negative for calcified bone remodeling, bone resorption, osteolysis or callus formation. Furthermore, no trabecular or cortical fractures were detected. Qualitative histology did not show intraosseous bleeding, periosteal detach- The present study was conducted to investigate the ment or microfractures. Furthermore, neither signs of effect of low-energy radial shock waves on osteogenesis pulmonary embolisms nor displaced bone fragments and to study the dynamics of ESWT-induced new bone were observed in the lung sections. No side effects of formation. Thus, radial shock waves were applied to the rESWT were found but some hematoma at the application distal femur of New Zealand white rabbits and fluorescent sequence labeling of newly formed bone was realized with different fluorescent dyes. Integration of the fluores- cent dyes into bands of newly deposited bone was shown by fluorescence microscopy and was significantly In an effort to achieve bone healing in a noninvasive increased after rESWT ). The different way, several experimental and clinical studies investi- colored fluorescent dyes allowed a description of the gated ESWT for bone stimulation and indicated time course of new bone formation. Sharp and improved bone union and increased bone turnover after homogeneous bands of integrated fluorochromes were the application of focused high-energy shock waves observed in all bone specimens treated with rESWT FLA 5.1.0 DTD ! UMB9316_proof ! 26 September 2012 ! 4:03 pm ! ce 49

Ultrasound in Medicine and Biology Volume -, Number -, 2012 Fig. 1. Fluorochrome sequence labeling of new bone formation at the ventral cortex of rabbit femurs, investigated 4 weeks after the first radial extracorporeal shock wave therapy (rESWT) application: (a) untreated bone (magnification 350, Zeiss Filter 09); (b) rESWT treated bone (magnification 350) and (c) rESWT treated bone (magnification 3100). Arrows indicate bands of both periosteal and endosteal new bone formation.
). Whereas a positive effect of ESWT on heal- larger treatment areas, has not been investigated so far.
ing of nonunions has been described in most published The present study is the first investigation on the studies, proof of effectiveness by means of a experimental dynamics of ESWT-induced bone formation and the os- study is still lacking (Further- teogenetic potential of radial shock waves.
more, recommendations on treatment parameters such as energy flux density, impulse rate, number of treatment Principles of shock wave therapy interventions and treatment free intervals vary consider- Shock waves can be generated by electrohydraulic, ably and are mainly based on empirical data of uncon- electromagnetic or piezoelectric methods or (like radial trolled trials Basic research has shock waves in the present study) by pneumatic acceler- provided a better understanding on the mechanisms of ation of an applicator bullet within the hand piece ESWT and its interaction with bone. However, data on (Whereas ‘‘conven- the dynamics of ESWT-induced osteogenesis are rare in tional'' shock waves known from lithotripsy are focused spite of the high clinical relevance to determine the to a zone of highest energy in front of the applicator, most appropriate treatment protocols. Furthermore, new radial shock waves are unfocused and distributed in bone formation after the application of radial, unfocused a radial manner. Consequently, radial shock waves reach ESWT, which might be advantageous by addressing lower energy flux densities but address greater treatment areas (Shock waves are single high amplitude sound waves that propagate in tissue with a sudden rise from ambient pressure to its Fig. 2. Endosteal fluorochrome deposition of alizarin red and Fig. 3. Accumulated new bone formed at the ventral femoral calcein blue documented persisting new bone formation 6 weeks cortex 2 to 6 weeks after the first radial extracorporeal shock after first radial extracorporeal shock wave therapy (rESWT) wave therapy (rESWT) (rating system A). Stars indicate statis- (magnification 3100, Zeiss filter 02).
tically significant differences (*p 5 0.029; **p 5 0.008).
FLA 5.1.0 DTD ! UMB9316_proof ! 26 September 2012 ! 4:03 pm ! ce 49

Radial shock wave therapy for bone stimulation d H. GOLLWITZER et al.
Fig. 4. Assessment of new bone formation 2 to 6 weeks after the first radial extracorporeal shock wave therapy (rESWT) (1 to 5 weeks after second rESWT) with evaluation of the single fluo- rochromes applied (means and standard deviations, rating system B). Stars indicate statistically significant differences (*p , 0.0005; **p , 0.0005; ***p 5 0.008). Significant stim- ulation of bone formation was demonstrated already 2 weeks (calcein green) after the first rESWT with a peak of osteogenesis at 4 weeks (alizarin red) and a consecutive decline until the study end at week 6 (calcein blue).
maximum pressure at the wave front, followed by a lower tensile amplitude Radial shock waves are missing the typical steepening effect of focused shock waves and, therefore, physically resemble simple pressure waves. The most important mechanical effects of shock waves are reflection with Fig. 5. New bone formation (a) at the ventral femoral cortex, and pressure and tension forces at borders of different imped- (b) at the dorsal femoral cortex at different time points 2 to 6 weeks after the first radial extracorporeal shock wave therapy ances as well as the generation of cavitation bubbles in (rESWT) represented by the corresponding bands of single fluo- liquids, which induce shear forces by high velocity liquid rochromes (rating system B). Stars indicate statistically signifi- streams (‘‘jet-streams'') ( cant differences: (a) ventral femoral cortex: *p , 0.0005; **p , 0.0005; ***p 5 0.008. (b) dorsal femoral cortex: *p , 0.0005; **p , 0.0005. Ossification declined at the dorsal cortex compared with the ventral cortex that was closely oriented Mechanism of ESWT-induced new bone formation to the shock wave device emphasizing the energy-dependent Various studies have investigated the effect of manner of new bone formation (p 5 0.008, calcein blue).
focused shock waves on normal, osteotomized and frac- tured bone in different animal models and cell culture factors like TGF-b1, VEGF-A and mitogen-activated protein kinases (MAPK) ). Consequently, increased proliferation and Whereas the effectiveness of ESWT to stimulate differentiation of mesenchymal stem cells to osteoblasts bone healing after fracture is discussed controversially, was observed. G-proteins of the cell membrane, which the positive osteogenic effect on normal bone and bone respond to mechanical stresses, were supposed to play defects has been proven. Wang and coworkers intensively a role in translating the kinetic energy of shock waves studied shock wave induced reactions in bone on the to Ras activation. Furthermore, shock waves were shown molecular level and were able to reveal some of the basic to produce oxygen radicals, which are also supposed to play a key role in connecting the mechanical shock Thereby, two major mechanisms have been de- wave energies and the resulting biological effects tected to be involved in the translation of mechanical shock wave energy to biologic responses: membrane Wang et al. further showed that oxygen radical produc- hyperpolarization and the formation of free radicals.
tion was followed by a stimulation of a cascade of kinases Wang et al. and Chen et al. demonstrated shock waves and growth factors like VEGF, TGF-b1, BMP-1, BMP-2, to induce hyperpolarization of cell membranes, followed BMP-7 etc., followed by an increased growth and differ- by Ras activation and a local increase of stimulating entiation of mesenchymal cells toward osteoprogenitor FLA 5.1.0 DTD ! UMB9316_proof ! 26 September 2012 ! 4:03 pm ! ce 49 Ultrasound in Medicine and Biology Volume -, Number -, 2012 controversially (; ; ). In our qualitative analysis, we neither observed any histologically detectable traumata (like Dose-dependent effects fractures, hematomas or periosteal detachments) nor frac- Dose-dependent stimulation of bone cells in vitro tures or callus formation detectable by microradiography.
was observed by Kusnierczak et al. after shock wave Our data are in accordance with results published by application, with minimum threshold energy necessary others demonstrating that cortical fractures and periosteal to effect bone cell growth ).
detachment are no prerequisites for new bone formation However, bone cell stimulation was contributed to the total amount of energy applied, rather than single param- new bone formation was limited to endosteum and perios- eter like energy flux density or number of administered teum in our investigation, whereas other studies also impulses. Furthermore, cell damage by excessive energy demonstrated trabecular new bone formation related to flux densities was described. Wang et al. and Chen et al.
trabecular microfractures ). We confirmed those findings in vivo proving a dose- conclude that iatrogenic fractures are not mandatory for dependent effect of ESWT on bone mass and bone periosteal and endosteal new bone formation; however, strength in acute fracture healing in rabbits it remains to be clarified if microfractures provide an ) and in bone defect models in rats additional stimulus for new bone formation in cancellous ). Furthermore, suppres- sion of osteogenetic influence was observed with the application of excessive energy levels. Maier et al. also Dynamic of ESWT-induced bone formation provided data about deleterious effects of very high In the treatment of bone pathologies, ESWT is energy flux densities ($0.9 mJ/mm2), demonstrating usually repeated to complete three to six interventions soft tissue edema, cortical fractures, periosteal detach- with treatment free intervals ranging from 4–8 weeks ment, intraosseous bleeding and even displacement of (However, these recommenda- bone fragments to pulmonary vessels with the risk of tions are based on empirical clinical observations and pulmonary embolism (, ).
not on controlled experimental data. In our study, osteo- Apart from the studies with bone defects, other authors genesis was induced significantly by rESWT already described osteostimulative effects with lower energies.
within the first week after shock wave treatment. A Tischer et al. detected signs of new bone formation in peak of new bone formation was observed 4 weeks after areas located well outside the focus zone the first rESWT with a consecutive decline of osteogene- sis at week 6. The decline of new bone formation was Our study is the first proving a significant induction most prominent at the dorsal femoral cortex, whereas of new bone formation by rESWT, thereby applying low increased bone formation persisted at the ventral cortex energy flux densities (0.16 mJ/mm2) but relatively high for at least 5 weeks after the last shock wave application.
impulse numbers (2 3 4000 impulses). Once induced, We, therefore, anticipate that both the intensity of new new bone formation persisted for at least 5 weeks after bone formation as well as its persistence over time is the last shock wave application. Bone growth was also dose-dependent. Our results suggest repeating shock activated at the dorsal femoral cortex in spite of the rela- wave treatment after approximately 5–6 weeks, since tively low energy flux density, proving penetration of a significant decline of new bone formation was observed radial shock waves through soft tissue and bone.
after that period.
However, induction of new bone formation was signifi- Interestingly, fluorescent microscopy also demon- cantly greater and lasted longer at the ventral cortex strated inhomogeneous and weak bands of tetracycline that had been directed toward the shock wave device, in the rESWT treated bone, whereas no tetracycline depo- compared with the dorsal femoral cortex. These observa- sition was observed in the control group. Thus, we antic- tions can be explained by a distance-related decline of shock wave energy while penetrating the thigh and immediately after ESWT followed by integration of re- confirm the dose-dependency of shock-wave induced os- maining circulating tetracycline that had been injected teogenesis. Consequently, the application of shock waves prior to shock wave treatment.
from different sides of the treated bone is recommended Abundant experimental and clinical evidence exist in the clinical setting to provide relevant energy levels that mechanical stimuli can both positively and nega- to all cortices.
tively influence fracture healing, bone regeneration and The significance of microtraumata like periosteal detachment and cortical and trabecular microfractures Apart from focused shock waves, for the induction of osteogenesis has been discussed especially, cyclic loading and vibrational stimulation FLA 5.1.0 DTD ! UMB9316_proof ! 26 September 2012 ! 4:03 pm ! ce 49 Radial shock wave therapy for bone stimulation d H. GOLLWITZER et al.
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ERK-dependent angiogenic transcription (HIF-1a) and VEGF-A Wang FS, Yang KD, Chen RF, Wang CJ, Sheen-Chen SM. Extracorpo- expression in shock wave-stimulated osteoblasts. J Biol Chem real shock wave promotes growth and differentiation of bone- FLA 5.1.0 DTD ! UMB9316_proof ! 26 September 2012 ! 4:03 pm ! ce 49 Our reference: UMB 9316 AUTHOR QUERY FORM Please e-mail or fax your responses and any corrections to: Article Number: 9316 Fax: 1-845-883-5682 Please check your proof carefully and mark all corrections at the appropriate place in the proof (e.g., by using on-screenannotation in the PDF file) or compile them in a separate list. Note: if you opt to annotate the file with software other thanAdobe Reader then please also highlight the appropriate place in the PDF file. To ensure fast publication of your paper pleasereturn your corrections within 48 hours.
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