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Ultrasound Produced by aConventional Therapeutic UltrasoundUnit Accelerates Fracture Repair

Background and Purpose. A recent novel appliciition of ultrasotind therathe treatment of bone fractures. The aim of this study was to investigateffect on fracture repair of ultrasound produced by a conventional tliera

tic ultrasound luiit as used by physical therapists. Subjects and MetBilateral midshaft femur fractures were created in 30 adult male Long-Erats. Ultrasound therapy was commenced on the first day after fractureintroduced 5 days a week (or 20 minutes a day. Each animal was treunilaterally with active ultrasound and contralaterally with inactive usoun d. Active ultrasound involved a 2-millisecond h urst of1.0-MHz sine wavrepea ting at 100 Hz. Th e spatially averaged, temporally averaged intensitset at 0.1 W/cm^. Animals were killed at 25 and 40 days after frainduction, and the fractures were assessed for hone mass and strength. ResThere were no differences between fractures treated with active ultrasand fractures treated with inactive ultrasound at 25 days. However, at 40 active ultrasound-treated fractures had 16.9% greater bone mineral con tethe fracture site than inactive ultrasound-treated fractures. This chresulted in a 25.8% increase in bone size, as opposed to an increase in density, and con tributed to active ultrasound -treated fractures having 81greater mechanical strength than inactive ultrasound-treated fractures, cussion an d Conclusion. These data indicate that ultrasound produce d conventional therapeutic ultrasound unit as traditionally used by phytherapists may be used to facilitate fracture repair. However, careful intetation of this controlled laboratoiT study is warranted until its findingsconfirmed by clinical trials. [Warden SJ, Fuchs RK, Kessler CK, e ta l. Usound produced hy a conventional therapeutic ultrasound unit accelefracture repair. Phys Ther. 2006;86:l 118-1127.]

K e y W o r d s : Animal, Bone, Fractures, Models, Musculosheletaldiseases, Orth(>f)edic equipment, O iihoj

procedures, Physical therapy techniques. Skeleton, Sports medicine.

Stuart J Warden, Robyn K Fuchs, Chris K Kessler, Keith G Avin, Ryan E Cardinal, Rena L Stewar



Ultrasound is a form of acoustic energy (sound)that possesses a frequency above the limitdetectahle hy the hiun an ear. It has been usedtherapeutically for more than half a centuiy

and currently is one of the most widely and frequentlyused electro therapeu tic modalities applied by physicaltherapists.' However, its full therapeutic potential is farfrom established, with new applications being addedregularly to its repertoire .'' One recen t novel applicationis in the treatment of bone fractures.-'*'*

Fracture repair involves a complex cascade of cellularevents incorporating appropriate cellular recruitment,timed genetic expression, and the sequenced synthesisof numerous compounds. Although it is considered tobe a naturally optimized process, recent evidence hasdemonstrated that fracture repair can he infiuenced byultrasound to occtxr more rapidly without compro-mising the final tissue-level outcome."^-^ The applicationof ultrasound in animal fracture models acceleratedthe return to mechanical strength of intact bone by 30%to ;18%.'^ Similarly, in well-designed clinical trials,ultrasound accelerated the rate of fracture repair inthe tibia, radius, and scaphoid by 30% to38%.*^-^ Bypooling of the clinical trial data, a weighted averageeffect size was calculated to be 6.41 (95% confidenceinten^al [CI] =0.01-11 .81); this value converts into a meanimprovement in healing time of64 days with ultrasound.^

The results of studies of the effect of ultrasound onfractured bone are interesting from the perspectivethat physical therapists tradidonally have been in-structed to avoid the application of ultrasonic energy tobone. When ultrasound is applied to bone, there is aninh ere nt risk of tissue dam age. U ltrasound has selective

interfacial effects at the bone surface resulting frombone ha\ing a high absorption coefficient, a high rela-tive acoustic impedance, and an ability to propagateshear waves.'" When doses at the high end of thetherapeutic range are used, these effects can generateconsiderable tissue damage attributable to heating andinertial cavitadon effects."-^^ To achieve clinically sig-

nificant improvements during fracture repair, withoutthe risk for tissue damage, the ultrasound dose has beenchanged substantially from that traditionally introducedin physical therapist clinical practice. Clinically, ultra-sound is introduced at an intensity commonly in therange of 0.5 to 2.0 W/cm'"^.' In comparison, in investi-gations into the therapeutic effect of ultrasound onbone, low-intensity pulsed ultrasoimd (LIPUS) has beenused. Low-intensity pulsed ultrasound is pulsed-waveultrasound with a spatially averaged, temporally aver-aged intensity of iess than 0.1 W/cm^.'' With LIPUS,heat generation at the soft tissue-bone interface has

been shown both theoretically'^ and experimentally'' tohe insignificant (<1 .0°C ). Similarly, the risk for tissue-damaging inertial cavitation is negligible.'*

Although LIPUS has been found to be effective in theman agem ent of bone fractures, to date th e clinical utilityof this finding in physical therapy is limited. Special-ized ultrasound units (Exogen 2000+*) have been de-veloped for the treatment of fractured hone. Althoughthese units are highly efficacious,"'-'^ their cost is prohibitive because the units are leased on a patient-to-patientbasis rather than purchased by individual clinics. Despitethe benefits observed with LIPUS, the high cost of the

* Smith & Ncphfw, Orth opae dic Division, 14.W Brooks Rd, Memph is. TN 381 !f

SJ Warden, PT, PhD, is Assistant Professor, Department of Physical Therapy and Department of Anatomy and Cell Biology, Indiana University, 1W Michigan St, CF-326, Indianapolis, IN 46202 (USA). Addres.s all correspondence to Dr Warden at: stwarden@iupui,edti.

RK Fuchs. PhD, is A.ssistant Research Professor, Department of Anatomy and Cell Biology, Indiana University.

CK Kessler, BS, is Research Assistant. Department of Physical Therapy, Indiana University, He was completing his MD studies at the Indi

University School of Medicine at the lime of this study.KG Avin, PT. DPT, is Research Assistant, Department of Physical Therapy, Indiana University. He was completing his DPT studies at ihe timethis study.

RE Cardinal, PT, DPT, is Research A.s.sistant, Department of Physical Therapy, Indiana U niversity. He was completing his DPT studies al the lof this study.

RL Stewart, MD, FRCS(C), is Director of Orthopaedic Trauma, Wishard Health Services, and Assistant Professor of Orthopaedic Surgery, IndUniversity School of Medicine, Indianapolis, Ind,

All authors provided concept/idea/research design, data collection, and con.sultation (including review of manuscript hefore submission)Warden, Dr Fuchs, and Dr Stewart provided writing. Dr Warden provided data analysis, project managem ent, and fund procu rement.

All procedures were performed with prior approval of the Institutional Animal Care and Use Committee of Indiana University.

Thk article was received November 16. 2005, and w as accefjted Ff-bruary 15, 2006.



specialized ultrasotind units has led some authors'" toquestion whether conventional therapeutic ultrasoundunits could be used by physical therapists to acceleratefracture repair. At the lower-intensity settings on theseunits, it is possible to prod uce a dose compa rable to tbatsbown to be effective dining fracture repair witb thespecialized units.

The aim of this study was to investigate the effect ofLIPUS produced by a conventional therapeutic ultra-sound unit on fracture repair in an animal model. Webypothesi/ed tbat LIHUS would facilitate fiacture repair,as evidenced by more bone mineral at tbe fracture siteand a stronger fracture calltis at selected time pointsduring healing.

Method

Animals

Thirty adult male Long-Evans rats {weight=350-400 g)were purchased^ and acclimated for 1 week beforeexpe rimen tation. Animals had ad libitum access to stan-dard rat cbow and water at all times.

Fracture Induction

All animals underwent snrger\' upon entry into the studvto create bilateral midshaft femur fractures. The fur wasclipped and cleaned with alternating chlorhexidineand 70% ethanol scrubs. After a preoperative stibcuta-neous dose of btiprenorpbine bydrochloride analgesia^(0.05 mg/kg), surgical anesthesia was achieved with amixture of ketamine^ {60-80 mg/kg) and xylazine^{7.5 mg /kg) introduce d intraperitoneally. With a steriletechnique, a 25-mm longitudinal incision was made overthe lateral thigh, beginningjtist distal to the lateral kneejoint and extending proximally. The intermuscular sep-tum between the vastus lateralis and the hamstringmuscles was divided by blunt dissection to localize thefemur. The lateral structures stabilizing the patella weredivided, and the patella was manually dislocated medi-ally. Tbe fem ur was fractured at its midsbaft by means ofa transverse osteotomy with a Dreniel drill" having anattached diamond-embedded wafer blade (Super Flex

Diamond Disc*). To stabilize the fracture, a l.(>mm-diameter stainless steel K-wire** was in.serted retrogradeinto the intiamedullaiy canal, beginning in the kneebetween tbe femoral condyles and exiting the greatertrochanter. The pin was cut as clcse as possible to tbeknee artictilar cartilage and driven proximallyso that the

' Harlan .Spiasin--r)awlcy lm\ Pt) Biix 2917fi, [iidiatmpulis, IN 46229,' Rcckitt Belli ki,'ic-r PhMrTiiaccmicals LiiJ, Inc, 10710 MidlotliianTiinipikf, Stiiu430, Ritliiiniiid. VA ^-lasr..^ Foit Dw igc A iiinial H ealth , HOII .5ih Si NW. Fun Dod ge, L \.50301,

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tip was flush with the cartilage. Th e patella was relocand stabilized with an ab sorbable su ture, and absorbsutures were tised to close the intermuscular septumskin incision. Tbe procedure was repeated on the tralateral side to create bilateral fractures.

Ultrasound Intervention

Ultrasound therapy commenced on the first day afracture induction . This starting time p oint is consiwith previous studies' '•'-'" and tbe belief tbat ultrasoinfluences early cellular processes immediately abone injury.'-'^'" Each animal was treated unilaterwith active LIPUS and contialaterally witb inacLIPUS (placebo). For intervention, animals were athetized with inhalation of3% isoflurane^^ at 1.5 L/min a plastic container and then with 1.5% isofluoran1.5 L/min via a face mask (for maintenance of anessia). Active LIPUS was produced with an AccusoLIPUS GS 170 ultrasound unit/^ which produce2-miilisecond burst of 1.0-MHz sine waves repeating100 Hz. The spatially averaged, temporally averaintensity on tbis unit is set at 0.1 W/cm'"', which resents the average ultrasound outpu t over the area ofultrasound beam {spatial average) and tbe averagetbis intensity over a cotnplcte pulse cycle (ultraso"on" and "off" periods; temporal average). Tbe mafacturer reported that tbe transducer bad an effecradiating area of5 cm^ and a beam nonuniformity raof less than 6.0. Ultrasound unit performance was firmed at weekly intervals witb a power me ter (UPM-1^^). Active LIPUS and inactive LIPUS were coup

with the skin by use of ultrasound gel (Aquasonic lOand introduced 5 d/wk for 20 min/d by use ostationaiy treatment head. The furwas clipped at weekintenals to facilitate ultrasound propagation. TLIPUS parameters and treatment time were cliosenthe basis of those shown to be beneficial during healing of tissue injuries (reviewed by Warden''').

Assessment Time Points

All animals were evaluated intraoperatively and 1 wpostoperatively to assess tbe rotatoiy stability of fractures. Animals with a fracture tbat was rotationtmstable at postoperative week I, indicating inadequfracture site fixation, were excluded from tbe study. othe r animals were killed at 25 and 40 days after fracinduction by inhalation of anesthetic gases followedcemcal dislocation. Animals in tbe 25- and 40-groups received 16 and 27 LIPUS treatments, resptively. After death, the left and right femurs were h

^^ Abbott I .iihoraiorics. 100 Abbott Park Rtl, Abbott Park. TL fiOO64.^^ Mfl ron Medical .Xiwralia Ply Ltd. PO Bo \21 tifi, Carn ini Down.s, Vic toria .^

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vested, wrapped in saline-soaked gauze, and stored at

RadiographyPostmortem ex vivo radiographs were obtained with aspecimen radiography system.** The femurs were posi-tioned for both anteroposterior and lateral radiographson dental film (Kodak Ultraspeed Dental Film [size4]***). Samples were exposed to a voltage of 18 kV for10 seconds. After film processing, the stage of fracturehealing was qtiantified with a 4-point radiographic scor-ing system (O^no evidence of healing;1-callus forma-tion evident but fracture gap not yet bridged; 2=callusformation evident with possible bridging of the fracturegap; and 3~fracture union). The examinerwas unawareof both femur side and time since fracture duringgrading.

Microcomputed TomographyThe stabilizing steel K-wires were carefully removed fromthe intramedullaiy canal before further assessment, asmetal causes beam-hardening artifacts during quantita-tive radiograpbic imaging. Microcomputed tomographywas performed on a randomly selected subgroup offractures to visualize 3-dimensionally the stage of frac-ture healing at 25 and 40days. Each femur was placed ina 13.S-mm-diameter plastic tube filled with saline andcentered in the gantiy of a desktop microcompntedtomography machine (p.CT-20^^^). A scout scan wasperfonned to enable fracture site localization, and 2B0slices were taken with an isotropic voxel size of 26(xmand an integration time of 150 milliseconds. A standardconvohuion-back projection procedure with a Shepp-Logan filter was used to reconstruct the computedtomography images in 1.024X 1,024-pixel matrices.

Dual-Energy X-ray AbsorptiometryDual-energy X-ray absorptiometry (DXA) was perfo rmedto assess fracture site bone mineral content (BMC, ingrams). Femurs were positioned on their caudal surfaceon a mouse densitometer (PlXlmus^^*) with iiltrahighresolution (0.18X0.18 mm per pixel). Left and rigbtfemur pairs from each animal were scanned side by sideon the same scan. Upon completion of each scan, amutually exclusive region of interest (18X10 mm) wascentered over each fracture site.

Peripheral Quantitative Computed TomographyPeripheral quantiuuive computed tomography (pQCT)was used to assess fracture site volumetric bone mineraldensity (vBMD, in milligrams per cubic centimeter),

BMC (in milligrams per millimeter), and bone area(B.Ar, in sqtiare millimeters). Each femur was placed ina plastic tube Jilled with saline and centred in the gantr)'of a pQCT machine (XCT Research SA+^^^). After ascout view was obtained to enable scan localization, 5cross-sectional scans were obtained with aH)-fxm voxelsize. The middle scan was centered through the frac-

ture line, and the other scans were positioned 1.5 mmand 3.0 mm above and below the center scan. Duringanalyses, the bone edge was detected with co ntour mod e1 at a threshold of 400 mg/cm"' within the Stratecsoftware.^^^ Tbe data for the 5 slices per bone wereaveraged.

Destructive Mechanical TestingTbe mechanical properties of the fracture site wereassessed by testing the femurs in 4-point bending(Fig. lA). Bones were slowly brought to room tempera-ture overnight in a saline bath. Femurs were positionedcranial side up across the lower contacts of a custom-built 4-point bending rig on an Alliance RT/5 MaterialsTesting System.""" The lower contacts had a span widthof 20.0 mm. The upper contacts were pivoted to en-stire that both contacts simultaneously touched tbecranial surface of the bone when the cross head waslowered. The upper contacts had a span width of8.0 mm, centered between tbe lower contacts. Tbeupper contacts were lowered to fix the bone in placewith a 1.0 N static preload. Tbe bone was subsequentlybroken in 4-point bending with a cross-head speed ot20.0 mm/min. During testing, force and displacement

data were collected every 0.1 second (at a frequency of10 Hz) with TestWorks 4 software (version 4.08A)."""Force-displacement curves were visually inspected, andultimate force (in newtons) , stiffness (in newtons permi lhm eter ), and energy- to ultimate force (in millijoules)were recorded (Fig. IB).

Data AnalysisStatistical analyses were performed with the StatisticalPackage for Social Sciences software,"** with a level ofsignificance set at .05 for all tests. The significance ofradiograpbic scores was determined with the Wilcoxonsigned rank test, whereas fracture site bone mass andmechanical properties were compared with pairedttests. Ultraso und intei-vention (active LIPUS versus inac-tive LIPUS) was the within-animal independent variablefor all tests. In addition, effect sizes on fracture site bonemass and mechanical properties were determined withmean percent differences (%diff) and 95% Cls of the

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Ultimate force

Energy toultimate force

0,2 0,4 0.6Displacement (mm)

Figure 1 .(A) Experimental setup for test ing of fracture s i te mecfianical propert iesin 4-point bending, Tfie fracture site [wfiite arrow) was centered betweenttie upper contacts, (B) Representative force-displacement curve generatedfrom a 4-point bending test of a fracture in tfie 40-day group, Mecfionicalproperties de rived from tfiis gra ph included ultimate force (peak of tfie curveon tfie y-Gxis}, stiffness (slope of tfie linear portion of the curve), and energyto ultimate force [area under tfie curve to ultimate force).

mean percent differences between active LIPUS-trfractures and inactive LIPUS-treated fractures.

Results

Animal Characteristics

One animal from the 40-day group died from surcomplications during fracture induction. Three animals (1 animal and 2 animals from the 25-day40-day groups, respectively) were excluded at postative week 1 because of rotatory instability at the frasite. Therefore, 14 and 12 animals were left for stati.analyses in the 25-day and 40-day groups, respectiThe mean (SD) weights at the end of the studanimals in the 25-day and 40-day groups were 394(39.7) and 417.7 g (37.3), respectively.

Effect of LIPUS on Frac ture Site Radiographic HealingRepresentative images of fractures in the 25-day40-day groups are shown in Figure 2. There wersignificant differences in radiographic scoring betwactive LIPUS-treated fractures and inactive LItreated fractures in either the 25-day group(P=.79)the 4()-day group (P=.26) (Table).

Effect of LIPUS on F racture Site Bone M assThere was no significant difierence in BMC betwactive LIPUS-treated and inactive LIPUS-treated tures when assessed by DXA at 25 days (%diff=295% CI=-7.5%-12.5%) {P=.7l) (Fig. 3). SimilaBMC (%diff-4.1%; 95% CI=-6.3%-14.5%), vB(%diff=0.4%, 95% CI=-9.1%-9.9%). and B(%diff= -0 .2%, 95% CI= -24.6%-24.3%) did not dibetween active LIPUS-treated and inactive LIPtreated fractures at 25 days when assessed by pQCT/'va lne s^ .81 -.96) (Fig. 4). In contrast, at 40 days, aLIPUS-treated fractures had 14.3% (95% CI=127.5%) greater fracture site BMC on DXA than inaLIPUS-treated fractures (P<.05) (Fig. 3). This incrwas confirmed by pQCT, which found BMC in acLIPUS-treated fractures to be 16.9% (95% CI= 2.31.4%) greater than that in inactive LIPUS-treated tures (P<.05) (Fig. 4A). The increase in fracture BMC with active LIPUS at 40 days did not result iincrease in the am ount of bone m ineral per unit volas vBMD did not differ from that in inactive LIPtreated fractures (% diff=-4.7%, 95% CI= -1 2.2.9%) (P= .14) (Fig. 4B). Instead, there was an incrin bone size, with active LIPUS-treated fractures ha25.8% (95% CI=3.9%-47.6%) greater B.Ar than itive LIPUS-treated fractures (/*<.O5) (Fig. 4C).

Effect of UPUS on Fracture Site Mechanical PropertiesDuring mechanical testing, all femurs broke at fracture site. At 25 days, there were no signifidifferences between active LIPUS-treated fractures



A

Inactive-LIPUS Active-LIPUStreated treated

B D

Inactive-LIPUStreated

Active-LlPUStreated

Representative images of fractures at 25 ond 4 0 days postinjury, as obtained by rad iograph y (A and B) and microcomputed tomo graphy (C and D),(A) Radiography at 25 days shows the persistence of a visible fracture line in fractures treated by both inactive low-intensity pulsed ultrosound (LIPUS)and active LIPUS (white crrov/s), and associated callus formotion. Both fractures in this animal were radiographicolly scored as 1, (C) This scorew as

confirmed by m icrocomputed tomog raphic imag ing, which clearly shows the fracture defect (block arrow) ond callus, (B) On radiograph y at 40 day s,tfie original frocture is difficult to distinguish [white arrows) because of callus bridging of the fracture gap. Both fractures in this animol wererodiogro phically scored as 3, (D) This score was confirmed by microcomputed tomographic imog ing, which shows fracture site union (block arrow ).

inactive LIPUS-treated fractures in ultimate force(%diff=2.6%, 95% CI= -4 1.2 % -46 .4% ), stiffness(%diff=4.4%, 95% CI=-77.3%-86.0%), or energ>' toultimate force (%diff-2.2%, 95% CI=-33.0%-37.3%)(all /'valu es= .49 -.66 ) (Fig. 5). In contrast, at 40 days-active I.IPUS-treated fractures had 81.3% (95%CI=0.8%-162.7%) greater ultimate force and 63.4%(95% C( = 10 .3% -llb .4% ) grea ter stiffness than inactiveLIPUS-treated fractures (all Fv alues< .05) (Figs. 5A and5B}. Compared with inactive LIPUS, active LIPUS hadno effect on energ>' to ultimate force at 40 days(%diff= 146.3%, 95% CI = -37.8%-330.4%) iP=.lS)(Fig. 5C). However, this latter finding most likelyresulted from insufficient statistical power to detect adifference because of the variance within the data.

Discussion and Conclusions

The present study invcstigaled the effect of LIPUSproduced by a conventional therapeutic ultrasoiind uniton fracture lepair in an animal model. LIPUS did nothave a significant effect on fracture healing whenassessed at 25 days postfracture. This finding may have

been influenced by insufficient statistical power, withpost hoc power analyses indicating that differences ofgrea ter than 11% in side-by-side comparisons werereqtiired in order to achieve 80% statistical power. Incontrast, by 40 days, fractures treated with active LIPUShad significantly greater bone mass than fracturestreated with inactive LIPUS (placebo). This increase inbone mass lesulted in an increase in hone size, asopposed to an increase in bone density, and contributedto active LIPUS-treated fractures having enhancedmechanical properties compared with inactive LIPUS-treated fractures. The latter was indicated by activeLIPUS-treated fractures having 81 % grea ter u ltimateforce and 63% greater stiffness than inactive LIPUS-treated fractures. These data indicate that UPUS pro-duced by a conventional therapeutic ultrasountl unit astraditionally used by physical therapists may be used tofacilitate fracture repair.

The findings of this study are interesting from theperspective that physical therapists traditionally havebeen advised to avoid exposing the skeleton to excessive



Table.Effect of Active Low-Intensity Pulsed Ultrasound (LIPUS)and Inactive LIPUSon Radiographic Scaring of Fracture Healing

Days(No. of Animals)

25(14)

4 0 ( 1 2 )

LIPUS

InactiveActive

InacfiveActive

No. of Animals WithRadiographic Score"

0

1100

1

11106

4

the Following

2

12

23

3

11

45

X

1,11.2

).82,1

S

00

00

' 0 - n o .-videiicf al healing. 1 -ralliis Ioiiimtioii3=fracture union.

bui i raniuT gap nol yti bridgt^d. i;=tallLi,s formation t-ddfin wiili possible uf the tiacii.re L'tu

Inactive-LIPUSActive-LIPUS

0.20 -

0.15 -

O 0.10 -

0.05 -

0.0025 days 40 days

Figure 3.Effect of lovi/-intensity pulsed ultrasound [LIPUS)on fracture site bonemineral content (BMC),as assessed by dual-energy X ray absorptiom-etry. Bars represent mean:!:SD, An asterisk indicates data that weresignificantly different from thosefor inactive LIPUS-treoted fractures(P<.05, paired ftest).

amounts of ultrasoimd energy. Reflecting this fact, only1% of therapists currently introduce ultrasound energywith the intent of treating acute bone injuries.' However,this dogma is historically hased and does n ot incorp oratecurrent research findings. Thereis no douht that ultra-sound energy can produce significant tissue damagewhen applied to the skeleton becauseof uniq ue biophys-ical interactions between ultrasoundand bone. This facthas been confirmed experimentallyby ultrasound caus-ing premature closure, slipping,and displacement ofepiphyseal growth plates, bone sclerosis, diaphyseal frac-tures and fibrosis, and delayed healing during fracturerepair.' '-' However, these effects have been elicited onlyby ultrasound dosesat the high end of the therapeuticdose range (>1.0 W/cm").To date, there are no knownside effects of LIPUS application (<0.1 W/cm^)on theskeleton.^'«"* Supporting this fact,a recent study^"demonstrated that pulsed ultrasound therapyat anintensity of 2.2 W/cm^ produ ced pathologic changesingrowing bone when introduced witha stationary treat-

ment head for 20 minutes a day for 6 weeks. In contrsimilarly introduced ultrasound at a lower inten(0.5 W /cm^) had no adverse effect on bone growth

The dataof the

present study supporttbe

resultsprevious animal studies'^-"^' and clinical studies*'-^ donstradng that LIPUS accelerates fracture repair,afurthers this research by demonstrating that LIPproduced bya conventional therapeutic ultrasound as used by physical therapists may be used to facilitfracture repair. This latter finding addressesan arearecent contention.io it was previously suggested LIPUS produced by conventional therapeutic usound units may delay fracture healing by stimulatthe production of excessive nonmineralized cartilagHowever, the data of the pre.sent study challenge hypothesis. First, we found that fractures treated wactive LIPUS achieved tbe same level of radiographealing and had more mineralized callus format{greater fracture site bone mass) than inactive LIPtreated fractures. Second, fractures treated with acLIPUS had better fracture site mechanical properthan inactive LIPUS-treated fractures. The restoratiomechanical integrity istbe overall function of any repprocess in a load-bearing structure suchas bone. Thefore, we believe that LIPUS produced bya conventiotberapeutic ultrasound unit can be beneficial to thfracture repair processand does not delay bone uni

Although a significant beneficial effect was observedthe present study, therapists are not currently encoaged to introduce LIPUS produced by their convtional therapeutic ultrasound units withthe intentfacilitating clinical fracture repair. Animal studiesanecessary precursors in the initial investigation of thesafety and efficacy of an intervention; however, tbexamination of interventions in laboratory-based studdoes not always accurately predict clinical effects. Tfact is particularly pertinent to ultrasound therapy sties, as the relative size, volume,and depth of tbe tiss

being treated in animals typically differ from tbosetissue being treated clinically. Tbese differencesma



240 1 Inactive-LIPUSActive-LIPUS

25 days 40 days

B 1000 n inactive-LIPUSActive-LIPUS

CD

36 -|

27 -

18 -

9 -

0

25 days

Inactve-LIPUSActive-LIPUS

40 days

25 days 40 days

Figure 4 .Effect of low-intensity pulsed ultrasound (LIPUS) on fracture site bonemineral content (BMC) (A), volumetric bone minerol density (vBMD) (B),and bone area (B.Ar) (C) as assessed by peripheral quantitativecomputed tom ography, Bors represent mean ± SD. An asterisk indicatesdata that were significan tly different from those for ina ctive LIPUS-treatedFractures (P<-05, paired Mest),

A2 4 0 -1 • • Inactive-LIPUS

^ 180 -oo

^120 -B

"to

1 60 -

0 -

^ H Active-LtPUS

T T

25 days

B'-' 25 -

f 20 -

I 15 -o 10 -c

iff

C O 5 -

0 -

' • Inactive-LIPU Sm^ Active-LIPUS

1 1•

•25 days

c -"3 1 2 5 n • • Inactive-LIPUS

8 1 0 0 -o% 75 -

1 5 0 -or, 25 -

erg:

^ B Active-LIPUS

^ 25 days

I40 (

40

1

40

•

T

II••_Jays

*

T

II••sdays

• •

1

mdays

Figure 5.Effect of low-intensity pulsed ultrasound (LtPUS) on fracture site mechan-ical properties. Ultimate force (A), stiffness (B), and energy to ultimateforce (C) were assessed by destructive 4-point bending tests. Barsrepresent meon ± SD, An asterisk indicates data that were significantlydifferent from those for inactive LIRUS-treated fractures (P<,05, pairedftest).

influence ultrasound energy distributions, tissue interac-tions, and ultimately therapeutic responses. In order forthe results of the present study to have clinical relevance,the observed LIPUS effect needs to be confirmed by wayof controlled clinical trials. In addition, before LIPUSintervention can be contemp lated clinically, the ong oingconcern regarding the output performance of ultra-sound units being used in clinical practice needs to be

addressed. Equipment surveys undertaken globallyrepeatedly have found that many ultrasound units beingused in clinical practice are unable to produce anultrasound dose that matches the m etered dose to withinset standards.'-^'-^'-^'' This output variance may not onlyinfluence treatment efficacy during fracture repair butalso elicit detrimental effects. Until these current limita-tions are addressed, the use of conventional therapeutic



ultrasound units in a manner other than that approvedby US Food and Drug Administration market compli-ance could have potential ramifications.

Although the present data confirm that LIPUS facilitatesfracture repair, they do not contribute to the current,limited understanding of the mechanism underlying thiseffect. Considering that LIPUS introduces an intensitywithin a more traditional diagnostic ultrasound range, arange previously considered to have a minimal biologiceffect and no therapeutic value, it is valid to considerhow LIPUS induces its therapeutic eflect. Unfortunately,this mechanism is not yet known, as it is not establishedhow ultrasound signals are transducedin vivo to producea cellular response. It is possible that ultrasound longi-tudinal mechanical waves exert micromcclianical load-ing to manipulate the inherent mechanosensitivity ofbone cells. However, this notion has been disputed bystudies demonstrating that the mechanical loading a,s,so-

ciatcd with LIPUS does not induce adaptation in intactbone.!'''-'-* Alternatively, the beneficial effect of LIPUSduring fracture repair may result from the generation byultrasound of unique phenomena within the propagat-ing tLssiies, such as stable cavitation and microstreaming.These ph eno me na may generate sliear forces on cellularmembranes to induce a cellular response; however, theoccurrence and significance of these phenomenain vivohave been disputed.--' Finally, LIPUS may haveiLs bene-ficial effect during fracture repair via the generation oflocalized heat at the fracture site in response to molec-ular vibration and collisions. However, this mechanism

lacks the support of a recent study,^^ which found thatultrasound therapy augmented fracture repair but thatan equivalent level of hyperthe nnia generated by micro-wave therapy did not.

Despite the fact that the underlying biophysical mecha-nism of action of ultrasound durin g fracture repairis notknown, a number of studies have investigated potentialcellular processes influenced by LIPUS.hi vitro, LIPUShas been shown to influence direcdy a number of cellsassociated with the repair process, including fibro-blasts/-''-^^ chondrocytt's,29-'*' and osteoblasts.'^-'" Theinduced changes suggest that ultrasound may have adirect effect on the reparative processes of angiogenesis,chondrogenesis, and osteogenesis. This suggestion issupported by in vivo investigations.'^"'^'' Principally,Azuma et aV-' showed that LIPUS influenced multiplecellular reactions during fracture repair. This findingwas evident from the advancement of healing irrespec-tive of the phase of repair during which LIPUS wasintroduced.

In summary, the present study showed that LIPUS

produced by a conventional therapeutic ultrasound unitcan facilitate fracture repair. This finding was evident by

active LIPUS-treated fractures having greater frsite bone mass, size, and strength than within-ainactive LIPUS-treated fractures. These data ppreliminary evidence to support a beneficial effLIPUS as produced by an ultrasound unit traditiused by physical therapists on fracture repair. Howcareful interpretation of this controlled laboratoryis warranted until its findings are confirmed by ctrials. Until these trials are performed and untaccurate outp ut perform ance of their ultrasound lensured, therapists are not encouraged to intrLIPUS produced by a conventional therapeutic sound unit with the intent of facilitating clinical frrepair.

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