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1 E ff ec ts o f El ec tr ic al ly -S ti mu la te d Si lv er -C oa te d Im pl an ts a nd B ac te ri al C on ta mi na ti on i n a Ca ni ne R ad iu s Fr ac tu re G ap M od el B y R us se ll E ri c Wr ig ht, DV M T he si s su bm it te d to t he f ac ul ty o f th e Vi rg in ia P ol yt ec hn ic I ns ti tu te a nd S ta te U ni ve rs it y in p ar ti al f ul fi ll me nt o f th e re qu ir em en t fo r th e de gr ee o f M as te r of S ci en ce I n V et er in ar y Me di ca l Sc ie nc es A pp ro ve d: P et er K. Sh ir es, Ch ai rm an J er yl C. Jo ne s Ro be rt B. Du nc an J r. J ul y 7, B la ck sb ur g, V ir gi ni a K ey W or ds : S il ve r, i on to ph or es is, ra di us, fr ac tu re, ef fe ct s, o st eo my el it is C op yr ig ht , R us se ll E ri c Wr ig ht

2 E ff ec ts o f El ec tr ic al ly -S ti mu la te d Si lv er -C oa te d Im pl an ts a nd B ac te ri al C on ta mi na ti on i n a Ca ni ne R ad iu s Fr ac tu re G ap M od el B y R us se ll E ri c Wr ig ht ( Ab st ra ct ) T he p ur po se o f t hi s p ro je ct w as t o s tu dy t he e ff ec ts o f a no di c e le ct ri ca ll y s ti mu la te d s il ve r- co at ed s ta in le ss s te el i mp la nt s a nd b ac te ri al c on ta mi na ti on i n a c an in e r ad iu s f ra ct ur e g ap m od el. T we lv e s ke le ta ll y m at ur e c an in es w ei gh in g k g w er e u se d. D og s w er e r an do ml y a ss ig ne d t o i nt o c on tr ol a nd c on ta mi na te d g ro up s. A 5 m m o st ec to my g ap w as m ad e i n b ot h r ad ii o f e ac h d og. O ne r ad iu s o f e ac h d og w as s ta bi li ze d w it h a s il ve r- c oa te d s ta in le ss s te el b on e p la te a nd t he o th er w it h a n u nc oa te d s ta in le ss s te el b on e p la te. T he o st ec to my s it es w er e i no cu la te d w it h s te ri le P BS i n 6 d og s a nd S. i nt er me di us i n t he o th e r 6 d og s. E ac h i mp la nt s et w as e le ct ri ca ll y s ti mu la te d w it h d ir ec t c ur re nt f or 20 m in ut es d ai ly, f or 10 d ay s. A ni ma ls w er e t re at ed w it h C ep ha le xi n o ra ll y f or 10 d ay s. R ad io gr ap hs w er e o bt ai ne d a t t wo w ee k i nt er va ls. A ni ma ls w er e e ut ha ni ze d a t 1 2 w ee ks a nd e ac h p la te w as c ul tu re d. R ad io gr ap hi c, h is to lo gi c a nd

3 b ac te ri ol og ic e va lu at io ns o f e ac h r ad iu s w er e p er fo rm ed. T he d if fe re nc e i n b on e h ea li ng b et we en s il ve r- co at ed a nd s ta in le ss s te el t re at ed r ad ii w as d et er mi ne d f or e ac h d og b y s ub je ct iv e r ad io gr ap hi c e va lu at io n a nd q ua nt it at iv e a na ly si s o f r ad io gr ap hi c d en si ty u si ng c om me rc ia l s of tw ar e. A t w ee k 12, a s ig ni fi ca nt d ec re as e i n b on e h ea li ng w as f ou nd o n r ad io gr ap hi c e va lu at io ns a nd q ua nt it at iv e b on e a re a a na ly si s o f c on ta mi na te d r ad ii t ha t w er e t re at e d w it h e le ct ri ca ll y s ti mu la te d s il ve r- co at ed i mp la nt s ( p- va lu e a nd r es pe ct iv el y). I no cu lu m o r i mp la nt t re at me nt t yp e s ho we d n o s ig ni fi ca nt d if fe re nc e o n r ad io gr ap hi c e va lu at io ns o r q ua nt it at iv e b on e a re a a na ly si s. N o s ig ni fi ca nt d if fe re nc es w er e d et ec te d i n r ad io gr ap hi c e va lu at io ns o f o st eo my el it is o r h is to lo gi c e va lu at io ns o f b on e h ea li ng, i nf la mm at io n a nd p er i- im pl an t r es or pt io n. C ul tu re r es ul ts w er e n ot i nd ic at iv e o f S. i nt er me di us i no cu la t e d o st eo my el it is. T he u se o f a b il at er al r ad ia l o st ec to my m od el a ll ow ed c om pa ri so n o f e le ct ri ca ll y st im ul at ed s il ve r- co at ed a nd u nc oa te d i mp la nt s w it hi n e ac h d og. B on e h ea li ng i n t he s ta bl e 5 m m f ra ct ur e g ap r ad ia l o st ec to my m od el, w as p ro gr es si ve i n b ot h c on ta mi na te d a nd n on -c on ta mi na te d s it ua ti on s. O ur s tu dy f ou nd a n eg at iv e e ff ec t o n b on e h ea li ng w he n e le ct ri ca ll y- st im ul at ed s il ve r s te ar at e c oa te d i mp la nt w er e u se d i n S. i nt er me di us c on ta mi na te d r ad iu s o st ec to mi es. T hi s t re nd b ec am e a pp ar en t a t 6 w ee ks p os t- op er at iv el y, b ut w as n ot s ta ti st ic al ly e vi de nt u nt il 12 w ee ks. F ur th er s tu di es a re iii

4 w ar ra nt ed t o e va lu at e t he a pp ro pr ia te p ro to co l, t he e ff ec ts o f, a nd i nd ic at ed u se o f t hi s t re at me nt m od al it y i n c on ta mi na te d f ra ct ur es a nd c li ni ca l o st eo my el it is s it ua ti on s. iv

5 G ra nt I nf or ma ti on T hi s p ro je ct w as m a de p os si bl e t hr ou gh t he g en er ou s f in an ci al s up po rt o f t he V ir gi ni a V et er in ar y M ed ic al A ss oc ia ti on V et er in ar y M em or ia l F un d a nd T he A O N or th A me ri ca R es id en t C li ni ca l T ra um a R es ea rc h P ro gr am. v

6 D ed ic at io n I w ou ld l ik e to d ed ic at e th is m an us cr ip t to m y lo vi ng w if e Sa ra h an d ou r so n Ca le b, w ho se s up po rt a nd u nd er st an di ng w er e un en di ng a nd u nc on di ti on al. vi

7 A ck no wl ed ge me nt s T he a ut ho r w is he s t o t ha nk G er mi ll e C ol ma no, M ar th a M oo n, D an ie l W ar d, J oh n S tr au ss, T ar yn B ra nd t, S us an A ye rs, K im W ri gh t, J en ni fe r L es se r a nd D r. J oh n R ob er ts on f or t he ir a ss is ta nc e w it h t hi s s tu dy. vii

8 T ab le o f Co nt en ts A bs tr ac t G ra nt I nf or ma ti on D ed ic at io n A ck no wl ed ge me nt s L is t of T ab le s L is t of F ig ur es i i v v i v ii x i x ii L it er at ur e Re vi ew 1 O st eo my el it is 1 I mp la nt A ss oc ia te d In fe ct io n 4 P at ho ge ne si s of O st eo my el it is 5 D ia gn os is o f Os te om ye li ti s 6 T re at me nt 8 M od el s of O st eo my el it is 9 B on e He al in g 10 A ss es sm en t of B on e He al in g 11 M od el s of B on e He al in g 13 M ed ic in al S il ve r 14 A nt ib ac te ri al P ro pe rt ie s of S il ve r 15 S il ve r To xi ci ty 15 S il ve r Io nt op ho re si s 16 C li ni ca l St ud ie s 16 viii

9 M ol ec ul ar M on ol ay er in g 17 I nt ro du ct io n 18 M at er ia l an d Me th od s 21 S ub je ct s 21 S il ve r Co at in g 21 B ac te ri al I no cu lu m 22 A ne st he si a an d Su rg ic al P ro ce du re 22 E le ct ri ca l St im ul at io n 23 P os t- op er at iv e Mo ni to ri ng 24 B on e Ar ea A na ly si s 25 R ad io gr ap hi c An al ys is 26 H is to lo gi c An al ys is 27 S ta ti st ic al A na ly si s 28 R es ul ts 30 B on e Ar ea A na ly si s 30 R ad io gr ap hi c An al ys is 30 H is to lo gi c An al ys is 31 C ul tu re R es ul ts 32 D is cu ss io n 3 3 T ab le s 40 F ig ur es 43 R ef er en ce s 51 ix

10 V it a 6 2 x

11 List of Tables T ab le 1 : W ee k 12 M ea n Bo ne A re a an d Me an R ad io gr ap hi c Bo ne H ea li ng 4 7 T ab le 2 : M ea n Di ff er en ce i n Bo ne A re a 4 8 T ab le 3 : M ea n Di ff er en ce i n Ra di og ra ph ic B on e He al in g Sc or es 4 9 xi

12 L is t of F ig ur es F ig ur e 1: P ic tu re o f 5 mm R ad ia l Os te ct om y Mo de l 50 F ig ur e 2: L in ea r Sc or in g Sh ee t: R ad io gr ap hi c An al ys is 51 F ig ur e 3: E xa mp le s of R ad io gr ap hi c Li ne ar S co ri ng a nd Me as ur em en t 52 F ig ur e 4: L in ea r Sc or in g Sh ee t: H is to lo gi c An al ys is 53 F ig ur e 5: E xa mp le s of H is to lo gi c Li ne ar S co ri ng a nd M ea su re me nt 54 F ig ur e 6: I ma ge D ep ic ti ng B on e Ar ea A na ly si s 55 F ig ur e 7: M ea n Di ff er en ce i n Bo ne A re a 56 F ig ur e 8: M ea n D if fe re nc e in R ad io gr ap hi c Bo ne H ea li ng 57 xii

13 L it er at ur e R ev ie w O st eo my el it is i s d ef in ed i n D or la nd s M ed ic al D ic ti on ar y a s i nf la mm at io n o f b on e c au se d b y a p yo ge ni c o rg an is m. ( 26 ) I t m ay r em ai n l oc al iz ed o r s pr ea d t hr ou gh t he b on e t o i n vo lv e t he m ar ro w, c or te x, c an ce ll ou s t is su e, a nd p er io st eu m. E vi de nc e o f o st eo my el it is c an b e f ou nd i n f os si li ze d c re at ur es d at in g b ac k 250 m il li on y ea rs.( 29 ) I n h um an s, t he i nc id en ce o f o st eo my el it is h as b ee n r ep or te d i n t he r an ge b et we en 0.5% a nd 2.7%.( 8, 29) W hi le c on si de re d r ar e i n d og s, t he a ct ua l r at e o f o st eo my el it is o cc ur re nc e h as n ot b ee n r ep or te d. T he s ou rc e o f c on ta mi na ti ng b ac te ri a i n o st eo my el it is c an b e h em at og en ou s, t ra um at ic o r i at ro ge ni c i n o ri gi n. T h e h em at og en ou s f or m o f o st eo my el it is r es ul ts f ro m b ac te ri al i no cu la ti on v ia t he b lo od s tr ea m. I t i s r ar el y r ep or te d i n t he d og a nd c at, b ut m or e c om mo nl y d es cr ib ed i n f oa ls, c al ve s, l am bs a nd h um an s < 16 y ea rs o f a ge.( 14, 38) T he v as cu la r a na t o my o f t he m et ap hy si s i n j uv en il es a p p ea rs t o b e t he p re di sp os in g c au se f or t hi s f or m o f i nf ec ti on.( 14, 2 9) I n j uv en il es, t he n ut ri en t a rt er y e nt er s t he d ia ph ys is o f l on g b on es a nd b ra nc he s p ro xi ma ll y a nd d is ta ll y. T he se b ra nc he s e nd i n n on an as to mo ti c s in us oi ds b en ea th t he e pi ph ys is. T he se s in us oi ds a re s ma ll er i n d ia me te r t ha n t he ir v en ou s d ra in ag e. A s a r es ul t, t ur bu le nt a nd r ed uc ed b lo od f lo w o cc ur s a t t hi s j un ct io n. I t h as b ee n s ug ge st ed t ha t i nf ec ti on b eg in s i n t he se s in us oi ds f ol lo wi ng b ac te re mi a. ( 14 ) T hi s v as cu la r a rr an ge me nt c ha ng es i n m an w it h t he c lo su re o f t he g ro wt h p la te. T he re fo re, i t i s u nc om mo n f or a h em at og en ou s c au se o f o st eo my el it is t o b e i mp li ca te d i n a du lt h um an s a nd m os t o th er a du lt a ni ma ls. 1

14 M os t c as es o f o st eo my el it is i n v et er in ar y m ed ic in e a re t he r es ul t o f l oc al c on ta mi na ti on. B ac te ri al c on ta mi na ti on o f b on e c an o cc ur s ec on da ry t o o pe n f ra ct ur es, s pr ea d f ro m s of t t is su e i nf ec ti on, p en et ra ti ng w ou nd s, o r s ur gi ca l i nv as io n. T hi s i s g en er al ly c la ss if ie d a s p os tt ra um at ic o st eo my el it is s in ce i t i s a ss oc ia te d w it h a t ra um at ic e ve nt o r s ur gi ca l i nt er ve nt io n. ( 8) P os tt ra um at ic o st eo my el it is i s a l oc al b on e i nf ec ti on a nd n ot a s ys te mi c c on di ti on. R et ro sp ec ti ve s tu di es o f c an in e o st eo my el it is h av e b ee n r ep or te d. ( 14, 76, 82) C ay wo od r ep or ts t ha t 55% o f o st eo my el it is c as es w er e a ss oc ia te d w it h o pe n r ed uc ti on o f c lo se d f ra ct ur es, w hi le o nl y 6 % o f o st eo my el it is c as es w er e a tt ri bu te d t o a h em at og en ou s s ou rc e. S of t t is su e e xt en si on o f i nf ec ti on a cc ou nt ed f or 26% a nd o pe n f ra ct ur es f or 10% o f c as es.( 14 ) S te ad r ep ot s t ha t 70% o f o st eo my el it is c as es a re r el at ed t o o rt ho pe di c c om pl ic at io ns, w hi le n o i nc id en ce o f h em at og en ou s o st eo my el it is i s n ot ed.( 82 ) O st eo my el it is m ay b e a cu te o r c hr on ic. T he se t wo f or ms o f t he s am e d is ea se e xh ib it d if fe re nt c li ni ca l s ig ns d ep en di ng o n t he d ur at io n o f i nf ec ti on. T he a cu te f or m o f o st eo my el it is b eg in s p os t- in oc ul at io n. L oc al s ig ns i nc lu de s of t t is su e s we ll in g, p yr ex ia, p ai n, r ed de ni ng o f t is su es, a nd l am en es s. ( 14, 7 6, 8 2) S ys te mi c s ig ns m ay i nc lu de p yr ex ia, a no re xi a a nd d ep re ss io n. A c om pl et e b lo od c ou nt m ay d em on st ra te a n e le va te d w hi te b lo od c el l c ou nt a nd a n eu tr op hi li c l ef t s hi ft. T he p re do mi na nt r ad io gr ap hi c 2

15 f in di ng i s s of t t is su e s we ll in g. T he se s ig ns a re n on -s pe ci fi c, m ak in g i t d if fi cu lt t o d is ti ng ui sh b et we en a cu te o st eo my el it is a nd p os t- tr au ma ti c i nf la mm at io n. ( 29 ) T he c hr on ic f or m o f o st eo my el it is p re se nt s p ri ma ri ly a s l oc al d is ea se. S ys te mi c s ig ns o f p yr ex ia, a no re xi a a nd d ep re ss io n a re r ar el y p re se nt. C om mo n c li ni ca l c om pl ai nt s i nc lu de d ra in in g f is tu lo us t ra ct s a nd l am en es s. ( 14, 7 6) H em at ol og ic al p ar am et er s m ay b e w it hi n n or ma l l im i ts o r d em on st ra te a m il dl y e le va te d w hi te b lo od c el l c ou nt w it h a s li gh t n eu tr op hi li c l ef t s hi ft.( 14, 7 6) R ad io gr ap hi c c ha ng es m ay i nc lu de s ig ns o f i mp la nt l oo se ni ng, b on e s eq ue st ra, s cl er os is, o st eo ly si s, s of t t is su e s we ll in g, a nd p er io s te al r ea ct io n. R ad io gr ap hi c l es io ns a nd c li ni ca l s ig ns t ha t p er si st o r a re p ro gr es si ve f or g re at er t ha n 4-6 w ee ks a re c on si st en t w it h a d ia gn os is o f c hr on ic o st eo my el it is. M os t c as es o f o st eo my el it is a re b ac te ri al i n o ri gi n. O th er e ti ol og ic a ge nt s s uc h a s f un gi, p ar as it es, v ir us es, f or ei gn b od ie s a nd m et al li c i mp la nt s h av e b ee n r ep or te d. ( 43, 7 5, 8 4, 8 9) S tu di es h av e s ho wn t ha t a er ob ic a nd a na er ob ic, G ra m- po si ti ve a nd G ra m- n eg at iv e b ac te ri a h av e b ee n i mp li ca te d i n o st eo my el it is. C ay wo o d a nd S mi th b ot h r ep or t a s in gl e c au sa ti ve a ge nt i n 5 3% a nd 5 9% o f c as es r es pe ct iv el y. ( 14, 7 6) S ta ph yl oc oc cu s s pp. a re t he m os t c om mo nl y i so la te d o rg an is ms f ro m c an in e o st eo my el it is.( 14, 7 6, 8 2) 3

16 S ta ph yl oc oc cu s i nt er me di u s i s t he m os t c om mo nl y i so la te d b ac te ri a o f n or ma l c an in e s ki n f lo ra.( 72 ) S. i nt er me di us w as p re vi ou sl y i de nt if ie d a s S ta ph yl oc oc cu s a ur eu s u nt il r ec en t n om en cl at ur e c ha ng es.( 13 ) S tu di es s ho w t ha t m or e t ha n h al f o f o st eo my el it is c as es a re r el at ed t o o pe n r ed uc ti on o f f ra ct ur es.( 14, 7 6) S te ve ns on r ep or te d a 4 0% i nc id en ce o f b ac te ri al c on ta mi na ti on, w it h p re do mi na nt ly S ta ph yl oc oc cu s s pp., i n o pe n r ed uc ti on o f c lo se d c an in e f ra ct ur es.( 83 ) A s tu dy p er fo rm ed a t T ul an e U ni ve rs it y f ou nd a n i nc re as e i n i nf ec ti on r at e o f 0.4% t o 1.7% w he n c on se rv at iv el y m an ag ed c lo se d f ra ct ur es w er e c om pa re d t o s ur gi ca ll y r ed uc ed c lo se d f ra ct ur es.( 8) E ve n w it h p ro pe r a se pt ic s ur gi ca l t ec hn iq ue, s ki n c on ta mi na ti on d ur in g o pe n r ed uc ti on o f f ra ct ur es i s t he m os t c om mo nl y i mp li ca te d s ou rc e o f i nf ec ti on. T hi s e xp la in s t he h ig h i nc id en ce o f S ta ph yl oc oc cu s s pp. a ss oc ia te d o st eo my el it is. G ri st in a s pe cu la te d t ha t b io ma te ri al s p ro vi de d a n i ne rt s ub st ra te f or b ac te ri al g ro wt h a nd p ro pa ga ti on.( 35 ) S mi th i so la te d b ac te ri a f ro m 1 7 o f 4 0 b on e p la te s r em ov ed f ro m d og s. ( 78 ) O f t he se c as es, 9 w er e a ss oc ia te d w it h c om pl ic at io ns s uc h a s o st eo my el it is a nd t he o th er 8 s ho we d n o c li ni ca l o r r ad io gr ap hi c s ig ns o f i nf ec ti on. P et ty f ou nd a n i nc re as ed r at e o f i nf ec ti on w he n c an in e f em ur s w er e i no cu la te d w it h b ac te ri a a nd o rt ho pe di c i mp la nt s w er e u se d. ( 61 ) I mp la nt a ss oc ia te d i nf ec ti on c an r es ul t i n a r ec ur re nt s ou rc e o f i nf ec ti on t ha t i s n on re sp on si ve t o a nt ib io ti c t he ra py. R em ov al o f t he i mp la nt i s u su al ly n ec es sa ry t o r es ol ve t he c li ni ca l s ig ns o f i nf ec ti on. 4

17 B ac te ri a p ro du ce a s li my g ly co ca ly x t ha t i s c om po se d o f a m at ri x o f f ib ro us e xo po ly sa cc ha ri de s, g ly co pr ot ei ns, o r b ot h. ( 34 ) T he g ly co ca ly x f un ct io ns t o p ro vi de a dh er en ce, p ro te ct io n a nd n ut ri en t t ra pp in g. T he p ol ys ac ch ar id es o f t he g ly co ca ly x a re s im il ar i n s tr uc tu re t o c om me rc ia l c he mi ca l a dh es iv es.( 21 ) T hi s e na bl es b ac te ri a t o a dh er e t o b io lo gi c i mp la nt s a ft er c on ta mi na ti on d ur in g s ur ge ry o r l at er f ro m a t ra ns ie nt b ac te re mi a. A dh es io n p ro pe rt ie s m ay b e r el at ed t o b ac te ri al v ir ul en ce.( 34 ) T he t hi ck s li me -l ik e c oa ti ng r es is ts p en et ra ti on o f a nt ib io ti cs. F ur th er mo re, t he g ly co ca ly x p ro te ct s b ac te ri a f ro m t he h os t s d ef en se m ec ha ni sm s s uc h a s o ps in iz at io n, s ur fa ct an ts a nd p ha go cy to si s b y m ac ro ph ag es.( 34 ) O nc e a dh er en t t o a n i mp la nt o r f or ei gn b od y, t he g ly co ca ly x f or ms a b io fi lm t ha t e nv el op es m ic ro co lo ni es o f b ac te ri a. T hi s p hy si ca l b ar ri er e na bl es m ic ro co lo ni es o f b ac te ri a t o r es is t a nt ib io ti c t he ra py a nd h os t d ef en se m ec ha ni sm s. T ra um a r es ul ts i n h yp er em ia a nd i nf la mm at io n o f t is su e. I nc re as ed c ap il la ry p er me ab il it y a ll ow s i nf il tr at io n w it h w hi te b lo od c el ls. I f b ac te ri a a re p re se nt t he y c an d es tr oy t he se W BC s r es ul ti ng i n t he r el ea se o f p ro te ol yt ic e nz ym es a nd t he f or ma ti on o f p ur ul en t e xu da te.( 69 ) A dd it io na ll y, h em at om as a nd e de ma c an r es ul t i n l oc al i sc he mi c p re ss ur e n ec ro si s a nd m ic ro va sc ul ar s ta si s p ro mo ti ng t is su e d ea th a nd b ac te ri al c ol on iz at io n. O nc e i nf ec ti on h as b ee n e st ab li sh ed, b ac te ri al a nt ig en s s ti mu la te m ac ro ph ag es a nd n eu tr op hi ls t o p ro du ce i nt er le uk in -1, w hi ch att ra ct s a dd it io na l m ac ro ph ag es, n eu tr op hi ls 5

18 a nd l ym ph oc yt es.( 33 ) I nc re as ed p ro du ct io n o f p ro st ag la nd in E 2 b y t he se c el ls r es ul ts i n i nc re as ed b on e r es or pt io n. I nj ec ti on o f a ra ch id on ic a ci d, t he p re cu rs or o f p ro st ag la nd in s, i nt o r at t ib ia s f ac il it at ed t he f or ma ti on o f o st eo my el it is a nd b on e r es or pt io n. ( 67 ) M od el s o f o st eo my el it is u se s od iu m m or rh ua te, a f is h o il d er iv at iv e c on ta in in g a ra ch id on ic a ci d, t o c re at e b on e n ec ro si s a nd e st ab li sh o st eo my el it is.( 58, 7 0) A s o st eo my el it is p ro gr es se s f ro m t h e a cu te t o c hr on ic f or m, i t b ec om es l es s r es po ns iv e t o a nt ib io ti c t he ra py a nd h os t i mm un e r es po ns e. I nf la mm at or y c el ls a re s ep ar at ed f ro m g ra nu la ti on t is su e a nd a g oo d b lo od s up pl y b y c on ne ct iv e t is su e w hi ch r es ul ts i n b on y a bs ce ss f or ma tion. A s t he p re s su re o f t hi s pur ul en t e xu da te i nc re as es, i t e nt er s c or ti ca l b on e t hr ou gh t he H av er si an a nd V ol km an n s c an al s. ( 77 ) I nc re as ed p or os it y o f b on e s ec on da ry t o i nf la mm at io n c an l ea d t o s ub pe ri os te al e le va ti on a nd f or ma ti on o f a s eq ue st ru m. C li ni ca l s ig ns a nd r ad io gr ap hi c c ha ng es a re h ig hl y s ug ge st iv e o f p os tt ra um at ic o st eo my el it is, b ut c on fi rm at io n o f o st eo my el it is i s b as ed o n i de nt if ic at io n o f a n e ti ol og ic al a ge nt. M ic ro bi al c ul tu re o f c hr on ic d ra in in g t ra ct s r el at ed t o o st eo my el it is h as b ee n s ho wn t o b e n on re pr es en ta ti ve o f t he e ti ol og ic a ge nt o f o st eo my el it is.( 47 ) H is to lo gi c i de nt if ic at io n o f b ac te ri a w as o nl y c or re ct i n 33% o f o st eo my el it is c as es.( 11 ) P os it iv e b on e c ul tu re s a re t he g ol d s ta nd ar d f or t he d ia gn os is o f o st eo my el it is. T hi s c an b e a ch ie ve d b y a s ur gi ca l a pp ro ac h, f in e n ee dl e a sp ir at e, o r J am sh id i n ee dl e b io ps y. 6

19 R ad io gr ap hi c s ig ns o f o st eo my el it is v ar y d ep en di ng o n t he d ur at io n o f d is ea se, s ub je ct s a ge a nd h ea lt h, a nd v ir ul en ce o f t he o rg an is m. A cu te ly, t he o nl y r ad io gr ap hi c e vi de nc e t ha t m ay b e s ee n i s s of t t is su e s we ll in g a nd d ec re as ed d el in ea ti on o f f as ci al p la ne s i n t he s ur ro un di ng s of t t is su es. B on e r es or pt io n i s u su al ly n ot n ot ed i ni ti al ly. B on e d em in er al iz at io n m us t e xc ee d 35% b ef or e i t i s r ad io gr ap hi ca ll y e vi de nt.( 6) L yt ic a re as m ay b e s ee n a s e ar ly a s 3 d ay s p os t- in fe ct io n i n n eo na te s a nd 5 t o 7 d ay s i n a du lt s. ( 69 ) M or e c om mo nl y, r ad io gr ap hi c e vi de nc e i s f ir st s ee n 10 t o 14 d ay s p os t c on ta mi na ti on. C ha ng es i nc lu de i rr eg ul ar o r i nt er ru pt ed p er io st ea l p ro li fe ra ti on, o st eo ly si s, b on e s cl er os is, i mp la nt l oo se ni ng, i nc re as ed m ed ul la ry d en si ty, a nd s eq ue st ru m f or ma ti on. B ra de n r ep or ts t ha t r ad io gr ap hi c e va lu at io n o f o st eo my el it is w as 62% s en si ti ve a nd 57% s pe ci fi c f or t he d ia gn os is o f e xp er im en ta l o st eo my el it is.( 11 ) N uc le ar s ci nt ig ra ph y h as b ee n a dv oc at ed f or e ar ly d ia gn os is o f o st eo my el it is. T ec hn et iu m- 99 p yr op ho sp ha te b on e s ca nn in g h as b ee n s ho wn t o i de nt if y p at ie nt s w it h o st eo my el it is e ve n b ef or e r ad io gr ap hi c c ha ng es a re n ot ed.( 87 ) t ec hn iq ue h as a l ow s en si ti vi ty, p ar ti cu la rl y i n n eo na te s. ( 87 ) U nf or tu na te ly, t hi s I nd iu m l eu ko cy te s ca ns w er e p os it iv e o ne w ee k p os t i no cu la ti on i n 8 3% o f r ab bi ts w it h e xp er im en ta ll y- i nd uc ed o st eo my el it is.( 64 ) W hi le s ci nt ig ra ph y m ay b e h el pf ul i n t he d ia gn os is o f o st eo my el it is, a l oc al iz ed i nc re as ed c ou nt c an b e n on -s pe ci fi c f or i nf la mm at io n, t ra um a, n eo pl as ia a nd o st eo my el it is. 7

20 O th er i ma gi ng m o da li ti es c an b e u se fu l i n t he d ia gn os is o f o st eo my el it is. C om pu te ri ze d t om og ra ph y ( CT ) c an p ro vi de a dd it io na l i nf or ma ti on, e sp ec ia ll y f or i de nt if yi ng s ma ll f or ei gn b od ie s a s a s ou rc e o f r ec ur re nt i nf ec ti on.( 29 ) M ag ne ti c r es on an ce i ma gi ng ( MR I) c an b e m or e s en si ti ve t ha n C T f or d et ec ti ng e ar ly o st eo my el it is i n h um an s. ( 16, 2 8, 4 0) D ia gn os ti c s en si ti vi ti es f or b ot h m od al it ie s a re l im it ed b y t he p re se nc e o f m et al li c i mp la nt s. ( 29 ) E xp er im en ta ll y, e nz ym e l in ke d i mm un os or be nt a ss ay s ( EL IS A) h av e b ee n u se d t o d et ec t a nt ib od ie s t o t he c el l w al l o f S. a ur eu s i n a ni ma ls w it h c on cu rr en t o st eo my el it is.( 42 ) S er um I gg c on ce nt ra ti on s w er e h ig he r i n r ab bi ts w it h o st eo my el it is c om pa re d t o t ho se w it h s ub cu ta ne ou s a bs ce ss es o f t he s am e s tr ai n o f S. a ur eu s. T hi s m ay p ro ve h el pf ul f or i de nt if ic at io n o f o st eo my el it is i n c as es w he re a n e ti ol og ic a ge nt c an n ot b e i de nt if ie d b y s ta nd ar d c ul tu ri ng t ec hn iq ue s. ( 29 ) T re at me nt o f o st eo my el it is c on s is t o f f ou r p ar ts : a nt ib io ti cs, d eb ri de me nt, d ra in ag e a nd f ra ct ur e s ta bi li za ti on.( 29 ) A pp ro pr ia te a nt ib io ti c t he ra py b as ed o n c ul tu re a nd s en si ti vi ty r es ul ts i s i nd ic at ed i n a ll c as es o f o st eo my el it is. H ow ev er, o nc e i nf ec ti on h as b ec om e e st ab li sh ed a nt ib io ti cs a lo ne w il l n ot s uf fi ce.( 8, 2 9) S ur gi ca l d eb ri de me nt o f n ec ro ti c b on e a nd s eq ue st ra i s n ec es sa ry f or r es ol ut io n. E li mi na ti on o f d ea d s pa ce o r s ur gi ca l d ra in ag e m us t t he n b e est ab li sh ed.( 8, 2 9) F in al ly, s ta bi li za ti on o f f ra ct ur es m us t b e p er fo rm ed w he n a pp ro pr ia te t o e li mi na te m ot io n t ha t p re ve nt s 8

21 h ea li ng. B on y d ef ec ts c an b e tre at ed w it h c an ce ll ou s b on e g ra ft s t o f ac il it at e h ea li ng a nd a re as o f s cl er ot ic b on e s ho ul d b e r on ge ur ed t o h el p e st ab li s h b lo od s up pl y. ( 29 ) T he s tu dy o f o st eo my el it is i s m os tl y d ep en de nt o n a ni ma l m od el s. T he e ar li es t a tt em pt t o e st ab li sh a m od el o f o st eo my el it is w as b y R od et i n T hi s w as p er fo rm ed b y i nt ra ve no us i nj ec ti on s o f a S. a ur eu s i no cu lu m i nt o r ab bi ts.( 68 ) L ex er p ro du ce d b on y a bs ce ss es i n r ab bi t t ib ia s b y i nt ra ve no us i nj ec ti on s o f S. a ur eu s, b ut t he m or ta li ty w as h ig h. ( 45, 46) O th er i nv es ti ga to rs w er e a bl e t o p ro du ce s up pu ra ti ve b on y l es io ns w it h l oc al i nj ec ti on s o f S. a ur eu s, b ut n on e o f t he l es io ns w er e p ro gr es si ve.( 48, 66) W hi le i nt ra ve no us a nd l oc al i nj ec ti on S. a ur eu s d id p ro du ce b on y a bs ce ss es, t he se d is ea se m od el s d id n ot a cc ur at el y r ef le ct t he c li ni ca l p ic tu re o f o st eo my el it is i n h um an s. I t w as n ot u nt il 1941, w he n S ch em an i nj ec te d s od iu m m or rh ua te i nt o t he m ed ul la ry c av it ie s o f r ab bi t t ib ia s i no cu la te d w it h S. a ur eu s, t ha t a c li ni ca ll y r el ev an t m od el o f p ro gr es si ve c hr on ic o st eo my el it is w as e st ab li sh ed.( 70 ) S od iu m m or rh ua te i s a s cl er os in g a ge nt t ha t a lo ne c an c au se a se pt ic n ec ro si s o f b on e. ( 66 ) N or de n l at er r ef in ed S ch em an s p ro to co l t o p ro du ce t he c la ss ic m od el o f o st eo my el it is i n t he r ab bi t t ib ia. T hi s m od el c on si st en tl y p ro du ce d s ig ns o f p ro gr es si ve b on y d es tr uc ti on a nd s eq ue st ru m f or ma ti on.( 58 ) W hi le p re vi ou s m od el s w er e u na bl e t o p ro du ce a p ro gr es si ve f or m o f b on e i nf ec ti on, t he a dd it io n o f t hi s s cl er os in g a ge nt a pp ea re d t o b e t he k ey. 9

22 S ev er al c an in e m od el s h av e b ee n d es c ri be d. D ey si ne i nt ra ve no us ly i nj ec te d b ar iu m s ul fa te a nd S ta ph yl oc oc cu s s pp. i nt o t he n ut ri en t t ib ia l a rt er y t o e st ab li sh o st eo my el it is.( 24 ) T hi s p ro ce du re i s t ec hn ic al ly d if fi cu lt t o p er fo rm a nd t he e ff ec ts o f i nt ra ar te ri al b ar iu m s ul fa te a re n ot k no wn.( 66 ) F it zg er al d e st ab li sh ed o st eo my el it is i n t he c an in e t ib ia b y i no cu la ti ng a c ur re tt ed b on e d ef ec t w it h S. a ur eu s a nd f il li ng t he d ef ec t w it h a p ol ym et hy lm et ha cr yl at e p lu g. ( 27 ) P et ty f ou nd t ha t p la ce me nt o f i mp la nt s i n i no cu la te d c an in e f em ur s l ow er ed t he i nf ec ti on d os e n ec es sa ry t o e st ab li sh o st eo my el it is.( 61 ) B ra de n r ep or te d t ha t a n i nf ec te d w ou nd, a va sc ul ar b on e, a nd a f av or ab le m il ie u m us t b e p re se nt t o e st ab li sh o st eo my el it is i n 90% o f e xp er im en ta l c as e o f c an in e o st eo my el it is.( 8) H is m od el i nv ol ve d t re ph in at io n o f a h ol e i n t he c an in e t ib ia, t ra um at iz at io n o f t he m ed ul la ry c an al, i no cu la ti on w it h S. a ur eu s, a nd r ei ns er ti on o f t he b on e p lu g. ( 9, 10) T hi s e st ab li sh ed a m od el o f p os tt ra um at ic o st eo my el it is t ha t d id n ot r el y o n f or ei gn m at er ia ls o th er t ha n t he i no cu lu m. F ol lo wi ng f ra ct ur es, b on e h ea li ng m ay b e p ri ma ry o r s ec on da ry. P ri ma ry b on e h ea li ng r el ie s o n r ig id s ta bi li za ti on o f t he f ra ct ur e a nd b on y c on ta ct.( 60 ) S ec on da ry b on e h ea li ng f ol lo ws s ev er al s te ps o f i nf la mm at io n, s of t c al lu s f or ma ti on, h ar d c al lu s f or ma ti on a nd b on y r em od el in g. ( 12 ) U nl ik e s ec on da ry b on e h ea li ng, p ri ma ry b on e h ea li ng r es ul ts w it h ou t t he f or ma ti on o f c al lu s. P ri ma ry b on e h ea li ng c an no t o cc ur i f a f ra ct ur e g ap > 0.1 m m e xi st s. ( 62 ) 10

23 F ol lo wi ng a f ra ct ur e, d is ru pt io n o f n or ma l b lo od s up pl y t o b on e a nd s ur ro un di ng s of t t is su es o cc ur s. W it hi n h ou rs, n ec ro si s o f a f ew m il li me te rs o f t he f ra gm en t e nd s r es ul ts f ro m c ap il la ry t hr om bo si s i n H av er si an a nd V ol km an n s c an al s. ( 12 ) S ti mu la ti on o f a ff er en t v as cu la r c om po ne nt s r es ul ts i n i nc re as e i n d ia me te r a nd n um be r o f v es se ls.( 62 ) S ys te mi c r es po ns e t o b on e i nj ur y r es ul ts i n a n e le va ti on o f p ar at ho rm on e, c al ci to ni n, v it am in D m et ab ol it es, a nd a lk al in e p ho sp ha ta se l ev el s. ( 54 ) L oc al ly, p la te le ts, m as t c el ls, n eu tr op hi ls, m ac ro ph ag es, l ym ph oc yt es a nd i nj ur ed c el ls w it hi n t he f ra ct ur e h em at om a r el ea se c he mo at tr ac ta nt s, a ng io ge ni c a nd o th er g ro wt h f ac to rs.( 12 ) P la te le t- de ri ve d g ro wt h f ac to r, e pi de rm al g ro wt h f ac to r, a nd t ra ns fo rm in g g ro wt h f ac to r a re a mo ng t ho se t ha t h av e b ee n i de nt if ie d. ( 7, 41, 74 ) W it hi n a f ew d ay s, t he i ng ro wt h o f c ap il la ri es s er ve s t o e ng ul f t he h em at om a a nd m ac ro ph ag es b eg in t o d eb ri de t he f ra ct ur e s it e. ( 12 ) M ac ro ph ag es a nd n eu tr op hi ls r el ea se i nt er le uk in -1 c au si ng m us cl e a tr op hy. A s a r es ul t, t he se l eu ko cy te s a nd m us cl e c el ls i nc re as e p ro du ct io n o f p ro st ag la nd in E 2 p ro mo ti ng b on e r es or pt io n. T he s of t c al lu s s ta ge b eg in s o nc e i nf la mm at io n h as s ub si de d a nd e nd s w he n f ib ro us a nd /o r c ar ti la gi no us t is su e u ni te t he f ra ct ur e f ra gm en t e nd s. ( 12 ) T hi s p ha se l as ts a pp ro xi ma te ly 2-3 w ee ks l ea vi ng t he f ra ct ur e u ns ta bl e d ur in g t hi s p ro ce ss. O st eo cy te s, p er io st ea l c el ls a nd e nd os te al c el ls c ha ng e f un ct io n t o b ec om e o st eo bl as ts a nd c ho nd ro bl as ts. O st eo cl as ts b eg in t o r em ov e d ea d b on e. I nd uc ed o st eo pr o ge ni to r c el ls c an b e f ou nd i n a ll c on ne ct iv e t is su es w hi le d et er mi ne d o st eo pr og en it or c el ls c an b e 11

24 f ou nd i n b on e m ar ro w a nd e nd os te um.( 12 ) P er cu ta ne ou s i nj ec ti on o f b on e m ar ro w h as b ee n u se d e xp er im en ta ll y i n r ab bi ts a s a b on e g ra ft in g t e ch ni qu e. ( 59 ) T he h ar d c al lu s s ta ge o cc ur s a s t he f ra ctur e f ra gm en ts b ec om e u ni te d b y b on e. ( 12 ) M in er al iz at io n b eg in s b et we en f ib ro us t is su e a t t he f ra gm en t e nd s a nd p er ip he ry o f t he c al lu s a nd s pr ea ds t ow ar ds t he c en te r. A f ro nt o f o st eo cl as ts r es or b b on e w hi ch i s f ol lo we d i mm ed ia te ly b y n ew b on e d ep os it io n. W ov en a nd c an ce ll ou s- li ke b on e i s r ep la ce d w it h l am el la r b on e. R ad io gr ap hi ca ll y a nd c li ni ca ll y, t he f ra ct ur e a pp ea rs h ea le d. T he r em od el in g p ha se o f b on e h ea li n g c an s ev er al t ak e y ea rs.( 12 ) O nc e t he b ri dg in g h ar d c al lu s i s f or me d, p er io st ea l a nd e nd os te al c al lu se s a re r es or be d. T he c an ce ll ou s c or te x o f t he f ra ct ur e a re a i s r em od el ed o ve r t im e i nt o t he n or ma l a rc hi te ct ur e o f H av er si an b on e. ( 12 ) W hi le c li ni ca l a nd r ad io gr ap hi c a ss es sm en t c an d et er mi ne f ra ct ur e h ea li ng, t he y a re b ot h s ub je ct iv e a na ly se s m ak in g c om pa ri so ns o f b on e h ea li ng i n d if fe re nt s it ua ti on s d if fi cu lt t o q ua nt if y a nd d oc um en t. P ro gr es si ve r ad io gr ap hi c b on e h ea li ng i s d ef in ed b y g ra du al m in er al iz at io n o f c al lu s a nd l os s o f v is ua li za ti on o f t he f ra ct ur e g ap.( 55 ) M ul ti pl e m od al it ie s h av e b ee n u se d t o q ua nt if y b on e h ea li ng. D ua l x -r ay a bs or pt io me tr y ( DE XA ) i s c ur re nt ly o ne o f t he s ta nd ar d t ec hn iq ue s f or m ea su re me nt o f b on e m in er al iz at io n. ( 51 ) A d ua l- en er gy s ou rc e i s u se d t o q ua nt if y d if fe re nc es i n 12

25 r ad io gr ap hi c d en si ti es o f a n o bj ec t. ( 51 ) Q ua nt it at iv e C T a nd M RI s ho w s im il ar r es ul ts t o D EX A. ( 49, 50, 52) Q ua nt if ic at io n o f m in er al c on te nt a nd d en si ty b y t he se D EX A, C T a nd M RI a ll ow s c om pa ri so n o f b on e h ea li ng i n f ra ct ur e m od el s. T he se f or ms o f a na ly si s r eq ui re s pe ci al e qu ip me nt t o a cq ui re t he d at a. M et al li c o rt ho pe di c i mp la nt s c au se i nt er fe re nc e w it h C T a nd M RI m ea su re me nt s m ak in g t he m l es s e ff ec ti ve f or ms o f e va lu at io n. D ig it al s ub tr ac ti on r ad io gr ap hy i s a t ec hn iq ue f or m ea su ri ng b on e d en si ty t ha t i s c ur re nt ly b ei ng u se d i n t he f ie ld o f d en ti st ry.( 65 ) T he re a re r ep or ts o f i ts u se i n a ng io gr ap hi c a nd t ho ra ci c s tu di es.( 25, 3 6) T he t ec hn iq ue i nv ol ve s r ep ea te d r ad io gr ap hs o ve r t im e o f t he s am e a re a o f i nt er es t. T he r ad io gr ap hs a re t he n o ve rl ai d a nd t he d if fe re nc e i n b on e a re a i s m ea su re d. T hi s t ec hn iq ue i s h in de re d b y t he n ee d f or p re ci se r ad io gr ap hi c a li gn me nt t o p ro du ce e xa ct o ve rl ay s o f r ad io gr ap hs f or a na ly si s. ( 65 ) T he r ad iu s p ro vi de s a g oo d a na to mi ca l m od el f or t he e va lu at io n o f b on e h ea li ng. C om pa re d t o o th er l on g b on es, t he re i s r el at iv e ly l it tl e s of t t is su e s ur ro un di ng t he r ad iu s. T he r ad iu s i s a me na bl e t o m ul ti pl e f or ms o f s ta bi li za ti on. B on e p la ti ng a nd e xt er na l s ke le ta l f ix at io n, a re a pp ro pr ia te f ix at io n c ho ic es f or f ra ct ur e r ep ai r. T he s ur gi ca l a pp ro ac h t o t he b on e i s s im pl e a nd l es s t ra um at ic c om pa re d t o m os t o th er l on g b on es.( 62 ) 13

26 S ev er al b on e e xi st f or e va lu at io n o f h ea li ng m od el s i n t he r ad iu s. M il li s u se d a 5 m m r ad ia l o st ec to my t o e va lu at e t he e ff ec t o f s om at ot ro pi n o n b on e h ea li ng.( 55, 88) T hi s w as a n u ns t a bl e f ra ct ur e m od el, t hu s c om bi ni ng t he e ff ec t s o f i ns t a bi li t y a nd g ro wt h f ac to r o n f ra ct ur e h ea li ng. M ul ti pl e s tu di es e va lu at in g r ad ia l o st eo to mi es h av e b ee n r ep or te d. ( 15, 17, 23) M os t w er e s ta bi li ze d w it h e xt er na l f ix at io n o r b on e p la ti ng. W hi le t he se s tu di es a ll ow e ff ec ti ve t es ti ng o f t he m ec ha ni ca l s tr en gt h o f b on e h ea li ng, r ad io gr ap hi c a na ly si s i s m or e d if fi cu lt t o e va lu at e d ue t o t he l ac k o f a f ra ct ur e g ap. R ad iu s f ra ct ur e g ap m od el s o f 2.0 t o 2.5 c m i n l en gt h h a ve a re r ep or te d. ( 44, 71) T he se m od el s a re m ai nl y u se d t o e va lu at e o st eo in du ct iv e a nd c on du ct iv e p ro pe rt ie s o f i mp la nt s a nd b on e g ra ftin g m at er ia ls. M os t con tr ol s i n t he se s tu dies p ro gr es se d t o b on y n on -u ni on s d ue t o t he l ar ge f ra ct ur e g a p a nd w er e n ot g oo d m od el s o f n or ma l f ra ct ur e h ea li ng. S il ve r h as b ee n l on g k no wn f or i ts t he ra pe ut ic q ua li ti es.( 39 ) W hi le u nc er ta in o f i ts m ed ic in al u se s, s il ve r n it ra te w as p ub li sh ed i n a R om an p ha rm ac op ei a i n 69 B.C. T hr ou gh ou t h is to ry, s il ve r h as b ee n u se d t o t re at m ul ti pl e i ll ne ss es r an gi ng f ro m h al it os is t o e pi le ps y. C on fi rm ed m ed ic in al u se s o f s il ve r w er e n ot d oc um en te d u nt il t he e ig ht h c en tu ry.( 39 ) S ev er al f or ms o f s il ve r a nd i ts s al ts a re c ur re nt ly u se d f or m ed ic al t he ra py.( 32 ) S il ve r n it ra te i s a s cl er os in g a ge nt t ha t i s u se d a s a t op ic al c he mi ca l c au te ri zi ng a ge nt, p re ve nt at iv e t re at me nt f or g on or rh ea l o ph th al mi a n eo na to ru m a nd w ar t a nd c or n 14

27 r em ov al.( 32 ) S il ve r s ul fa di az in e i s a c om bi na ti on o f s il ve r a nd a s ul fa b as ed a nt ib io ti c. I t i s w id el y u se d f or the t op ic al t re at me nt of b ur n w ou nd s. ( 1, 30) M or e r ec en tl y s il ve r- c oa te d u ri na ry a nd p er it on ea l d ia ly si s c at he te rs w er e i nv es ti ga te d f or t he p re ve nt io n o f c on ta mi na ti on a ss oc ia te d i nf ec ti on s. ( 31 ) T he u se o f c ol lo id al s il ve r p re pa ra ti on s i s c on tr ov er si al. I t i s c ur re nt ly n ot a pp ro ve d b y t he U ni te d S ta te s F oo d a nd D ru g A dm in is tr at io n, b ut h as b ee n a dv oc at ed a s a m in er al s up pl em en t a nd a n an ti bi ot ic. ( 32 ) T he e xa ct a nt ib ac te ri al m ec ha ni sm o f s il ve r i s u nk no wn. S il ve r r ea di ly d en at ur es p ro te in s b y b in di ng t o t he ir r ea ct iv e g ro up s, c au si ng p re ci pi ta ti on.( 32 ) S il ve r c om po un ds i na ct iv at e e nz ym es b y f or mi ng h em is il ve r s ul fi de s w it h s ul fh yd ry l g ro up s. S il ve r c an a ls o b in d a mi no, c ar bo xy l, p ho sp ha te, a nd i mi da zo le g ro up s. S hi no gi f ou nd t ha t s il ve r c an d im in is h t he a ct iv it ie s o f l ac ta te d eh yd ro ge na se, g lu ta th io ne p er ox id as e, a nd p er ox id at io n o f m em br an e l ip id s. ( 73 ) W hi le t op ic al u se o f s il ve r i s r el at iv el y s af e, c hr on ic i ng es ti on o f s il ve r c an r es ul t i n t ox ic s id e e ff ec ts. K no wn a s g en er al iz ed a rg yr os is, t he c la ss ic s ig ns a re a g re en is h- g re y o r b lu is h- gr ey d is co lo ra ti on t o t he s ki n a nd v is ce ra.( 53, 63, 86) T ox ic it y c an r es ul t i n l iv er a nd r en al d ys fu nc ti on.( 86 ) P ro gr es si ve t as te a nd s me ll d is or de rs, v er ti go, h yp er es th es ia a nd g en er al iz ed w ea kn es s h av e a ls o b ee n a ss oc ia te d w it h a rg yr os is.( 86 ) 15

28 T he d if fu si ve p ro pe rt ie s o f s il ve r i on s f ro m m et al li c s ur fa ce s a re p oo r d ue t o i ts l ow s ol ub il it y i n a qu eo us s ol ut io ns.( 4) T op ic al s il ve r a ge nt s t ha t d if fu se m or e r ea di ly, l ik e s il ve r n it ra te, a re l oc al ly s cl er os in g a nd t ox ic i n l ar ge r a mo un ts. T ho se s il ve r c om po un ds t ha t a re n on -t ox ic, l ik e s il ve r s ul fa di az in e, p oo rl y d is so ci at e. ( 39 ) A no di c e le ct ri ca l s ti mu la ti on o f s il ve r o r s il ve r i on to ph or es is, l ib er at es s il ve r i on s a ll ow in g d if fu si on a nd m ig ra ti on a lo ng a v ol ta ge g ra di en t. T hi s a ll ow s p en et ra ti on o f s il ve r i on s i nt o a qu eo us e nv ir on me nt s e ve n w he n s tr uc tu re s o r t is su es a re a va sc ul ar.( 4) T he s il ve r i on s a re m in im al ly t ox ic a nd a t l ev el s f ar b el ow t ho se n ec es sa ry t o p ro du ce a n a pp re ci ab le w ho le b od y t o xi c b ur de n. ( 4, 39) A nt ib ac te ri al e ff ec ts o f s il ve r i on to ph or es is h av e b ee n d em on st ra te d b ot h e x v iv o a nd i n v iv o. ( 2, 3, 5, 80) T he s il ve r c at io n h as a b ro ad a nt ib ac te ri al s pe ct ru m i nc lu di ng G ra m- po si ti ve, G ra m- ne ga ti ve, a er ob ic a nd a na er ob ic b ac te ri a w it h r ar e r ep or te d r es is ta nc e. ( 5, 37) C ol ma no f ou nd 100 % i nh ib it io n o f b ac te ri al g ro wt h o n e le ct ri ca ll y s ti mu la te d i nt ra me du ll ar y p in s t ha t w er e c oa te d w it h 100 m on om ol ec ul ar l ay er s o f s il ve r s te ar at e a nd i n oc ul at ed w it h S. a ur eu s. ( 19, 20) C li ni ca l u se o f s il ve r i on to ph or es is f or t he t re at me nt o f o st eo my el it is h as b ee n r ep or te d i n t hr ee h um an s tu di es. B ec ke r r ep or te d c on tr ol o f b on e i nf ec ti on a nd h ea li ng o f b on y n on -u ni on s i n 12 o f 15 c as e s u si ng a n e le ct ri ca ll y s ti mu la te d i nt ra me du ll ar y s il ve r w ir e o r s il ve r n yl on d re ss in g. ( 4) W eb st er r ep or te d r es ol ut io n o f d ra in in g t ra ct s i n 16 o f 25 p at ie nt s t re at ed w it h e le ct ri ca ll y- st im ul at ed s il ve r n yl on d re ss in gs a nd 9 o f 12 16

29 u ni on s o f b on y n on -u ni on s. ( 85 ) I t s ho ul d b e n ot ed t ha t t he p at ie nt s i n b ot h t ri al s w er e n on -r es po ns iv e t o t ra di ti on al t he ra py f or o st eo my el it is. M or e r ec en tl y, N an d r ep or te d a s er ie s o f 920 h um an c as e o f o st eo my el it is t ha t w er e t re at ed w it h e le ct ri ca ll y s ti mu la te d i nt ra me du ll ar y s il ver w ir es a nd e le ct ri ca l o st eo gene si s. I n t ha t s er ie s, a n 85% c on tr ol o f i nf ec ti on a nd a n 83% r es ol ut io n o f p at ho lo gi c f ra ct ur es w er e r ep or te d. ( 56 ) T he se s tu di es s ho we d t ha t s il ve r i on to ph or es is f or t he t re at me nt o f c hr on ic n on - r es po ns iv e o st eo my el it is i s p ro mi si ng. M ol ec ul ar m on ol ay er in g o f m et al s i nv ol ve s a pp li ca ti on o f a s in gl e m ol ec ul e t hi ck l ay er, o r m ul ti pl e l ay er s, o f a m et al o nt o t he s ur fa ce o f a n o bj ec t. ( 20 ) M os t m et al s a n d t he ir s al ts c an b e u se d t o c oa t a n o bj ec t. C ol ma no d ev el op ed a p ro ce du re f or m ul ti pl e m on om ol ec ul ar c oa ti ng o f m et al li c o rt ho pe di c i mp la nt s w it h s il ve r s te ar at e. ( 19, 20) B y c om bi ni ng t hi s si lv er -c oa ti ng w it h s il ve r i on to ph or es is h e w as a bl e t o i nh ib it b ac te ri al c ol on iz at io n i n r ab bi t f em ur s i no cu la te d w it h S. a ur eu s. 17

30 I nt ro du ct io n C on ta mi na ti on o f f ra ct ur es b y t ra um a, s ur ge ry a nd h em at og en ou s s ou rc es i nc re as es t he r is k o f d ev el op in g o st eo my el it is a ft er s ur gi ca l s ta bi li za ti on ( 38, 77). T he c ur re nt t re at me nt f or o st eo my el it is c on si st s o f a pp ro pr ia te a nt ib io ti c t he ra py a nd s ur gi ca l d eb ri de me nt. S ys te mi c a nt ib io ti cs a lo ne h av e a p oo r s uc ce ss r at e d ue t o t he i na bi li ty t o a ch ie ve l oc al t is su e c on ce nt ra ti on i n a re as t ha t h a ve p oo r v as cu la ri ty ( un de r o rt ho pe di c i mp la nt s, a ro un d f or ei gn b od ie s, i n b on y a bs ce ss es a nd i n s eq ue st ra e). S ur gi ca l d eb ri de me nt c ar ri es a b et te r p ro gn os is t ha n a nt ib io ti c t he ra py a lo ne a nd c an r ea ch r es ol ut io n r at es a s h ig h a s 90%, b ut s uc ce ss i s d ep en d en t o n s ev er it y, e xt en t a nd s ur gi ca l a cc es si bi li ty ( 8, 14). T he c os t o f s ur gi ca l i nt er ve nt io n c an b e p ro hi bi ti ve i n v et er in ar y m ed ic in e a nd i n h um an c as es i n u nd er de ve lo pe d c ou nt ri es ( 56 ). A lt er na ti ve a nd /o r a dj uv an t n on -i nv as iv e t he ra pi es f or t he p re ve nt io n o r t re at me nt o f o st eo my el it is w ou ld b e u se fu l i n b ot h t he v et er in ar y a nd m ed ic al c om mu ni ti es. S ta ph yl oc oc cu s s pp. a re t he m os t c om mo nl y i so la te d b ac te ri a i n c an in e o st eo my el it is ( 14, 76). A h ig he r r at e o f o st eo my el it is h as b ee n a ss oc ia te d w it h o pe n r ed uc ti on o f f ra ct ur es ( 14 ). T hi s i mp li ca te s s ur gi ca l c on ta mi na ti on a s t he l ea di ng c au se o f b ac te ri al c on ta mi na ti on ( 38 ). S. i nt er me di us i s t he m os t c om mo nl y i so la te d o rg an is m o f s ki n f lo ra i n t he d og ( 72 ). I t s ho ul d b e n ot ed t ha t m an y s tr ai ns o f S. i nt er me di us w er e p re vi ou sl y i de nt if ie d a s S. a ur eu s, s pe ci fi ca ll y t ho se r ec ov er ed f ro m d og s ( 13 ). 18

31 C on ta mi na ti on o f o rt ho pe di c i mp la nt s i nc reas es t he r is k o f c hr on ic i nf ec ti on ( 61 ). P oo r b lo od s up pl y, b ac te ri al b io fi lm o r g ly co ca ly x p ro du ct io n c on tr ib ut e t o a p oo r r es po ns e w it h c om mo n m od es o f t he ra py ( 34 ). T hu s s ur gi ca l r em ov al o f i mp la nt s, f or ei gn b od ie s o r s eq ue st ra e i s u su al ly n ec es sa ry t o r es ol ve r ec ur re nt o st eo my el it is i nf ec ti on s. C ur re nt ly t he re a re n o a dd it io na l r ec om me nd at io ns f or a dd it iv e t he ra pi es t o p re ve nt o r t re at d ev ic e r el at ed i nf ec ti on s o th er t ha n t he s ta nd ar d u se o f a pp ro pr ia te a nt ib io ti c t he ra py a nd i mp la nt r em ov al. I nv es ti ga ti on i nt o t he u se o f o rt ho pe di c i mp la nt s c oa te d w it h a nt is ep ti c s ol ut io ns a nd s il ve r h as s ho wn s om e s uc ce ss ( 18, 2 2). S il ve r h as b ee n l on g k no wn f or i ts b ro ad -s pe ct ru m a nt ib ac te ri al p ro pe rt ie s ( 4, 3 9, 8 5). S il ve r a nd i ts c om po un ds h av e p oo r t is su e p en et ra ti on a nd i t i s u su al ly l im it ed t o t op ic al a pp li ca ti on s. D ir ec t c ur re nt ( an od ic ) s ti mu la ti on o f s il ve r, o r s il ve r i on i on to ph or es is, l ib er at es s il ve r i on s a ll ow in g t is su e p en et ra ti on b y d if fu si on a nd i on ic m ig ra ti on a lo ng a v ol ta ge g ra di en t. S il ve r i on i on to ph or es is h as e xp er im en ta ll y p ro ve n a nt ib ac te ri al e ff ec ts i n e x v iv o a nd i n v iv o s tu di es ( 5, 20, 81). S il ve r i on i on to ph or es is a ll ow s t is su e p en et ra t i on o f a nt ib a ct er ia l s il ve r i on s t ha t i s n ot p os si bl e w it h t op ic al s il ve r p re pa ra ti on s. C at ho di c e le ct ri ca l s ti mu la ti on o f s il ve r h as s ho wn a f av or ab le o st eo ge ni c r es po ns e a nd h as p ro ve n o st eo ge ni c a ct iv it y i n h ea li ng b on e ( 79 ). A no di c e le ct ri ca l s ti mu la ti on m ay h av e n eg at iv e e ff ec ts o n b on e h ea li ng, b ut t hi s h as n ot b ee n 19

32 d oc um en te d. W hi le t he a nt i- ba ct er ia l e ff ec ts o f a no di c s ti mu la ti on o f s il ve r h av e b ee n p ro ve n, t he e ff ec ts o n b on e h ea li ng h av e n ot b ee n e va lu at ed. T he u se o f s ol id s il ve r i mp la nt s f or o rt ho pe di c s ta bi li za ti on i s n ot f ea si bl e d ue t o t he w ea k b io me ch an ic al p ro pe rt ie s o f s il ve r. S ev er al c li ni cal t ri al s i n p eo pl e h av e s ho wn f av or ab le r es ul ts f or t he t re at me nt o f c hr on ic o st eo my el it is w it h s il ve r i on i on to ph or es is ( 4, 56, 85). T he se t re at me nt s i nc lu de d i nt ra le si on al p la ce me nt o f i nt ra me du ll ar y s il ve r w ir e o r t he u se o f s il ve r- co at ed n yl on w ou nd d re ss in gs. B ot h m et ho ds w er e i nv as iv e a nd r eq ui re d c on st an t m on it or in g a nd c ar e. C ol ma no f ou nd t ha t c oa ti ng s ta in le ss s te e l i nt ra me du ll ar y p in s w it h s il ve r s te ar at e c au se d 100 % i nh ib it io n o f b ac te ri al c on ta mi na ti on i n t he r ab bi t f em ur ( 20 ). S il ve r c oa ti ng o f s ta nd ar d m et al li c o rt ho pe di c i mp la nt s c om bi ne s s il ve r i on i on to ph or es is a nd p ro ve n o rt ho pe di c t re at me nt m od al it ie s w it ho ut a dd in g t im e o r t ra um a t o t he p ro ce du re. T he p ur po se o f t hi s s tu dy w as t o e va lu at e t he e ff ec ts o f a no di c e le ct ri ca ll y- st im ul at ed s il ve r- co at ed s ta in le ss s te el o rt ho pe di c i mp la nts t ha t w er e u se d to s ta bi li ze a c onta mi na te d f ra ct ur e g ap m od el o f t he c an in e r ad iu s. 20

33 M at er ia l a nd M et ho ds : S ub je ct s: T we lv e s ke le ta ll y m at ur e, n on -c ho nd ro dy st ro ph oi d, m ix ed b re ed d og s w ei gh in g b et we en k g ( me an k g) w er e u se d. T he p ro je ct w as a pp ro ve d b y t he V ir gi ni a P ol yt ec hn ic I ns ti tu te a nd S ta te U ni ve rs it y A ni ma l C ar e a nd U se C om mi tt ee. D og s w er e i nc lu de d i n t he s tu dy i f n o s ig ni fi ca nt a bn or ma li ti es w er e n ot ed o n p hy si ca l e xa mi na ti on, c om pl et e b lo od c ou nt a nd d if fe re nt ia l, b io ch em is tr y p ro fi le, l am en es s e va lu at io n, o rt ho pe di c e xa mi na ti on, a nd b il at er al c ra ni o- ca ud al a nd m ed ia l- la te ra l r ad io gr ap hs o f t he a nt eb ra ch ia. S il ve r c oa ti ng : A s ur gi ca l s ta in le ss s te el i mp la nt s et c on si st in g o f a 6 -h ol e, 3.5 m m n ar ro w d yn am ic c om pr es si on p la te ; 6, 3.5 m m c or ti ca l b on e s cr ew s; a nd a l en gt h o f 24 g au ge o r th op ed ic w ir e w er e a ss ig ne d t o e ac h r ad iu s o f e ac h d og 1. T he b on e p la te s w er e p re co nt ou re d t o t he m id -d ia ph ys ea l c ra ni al c or te x o f e ac h r ad iu s f ro m m ed ia l- l at er al r ad io gr ap hs. S cr ew l en gt hs w er e s im il ar ly s el ec te d f or t he a pp ro pr ia te s cr ew h ol es. O ne i m pl an t s et w as r an do ml y c ho se n f or e ac h d og a nd 100 m on om ol ec ul ar l ay er s o f s il ve r s te ar at e w er e a pp li ed.( 20 ) 2 E ve ry d og h ad a s ta in le ss s te el i mp la nt s et a ss ig ne d t o o ne r ad iu s a nd a s il ve r- co at ed s ta in le ss s te el i mp la nt s et a ss ig ne d t o t he c on tr al at er al r ad iu s. A ll i mp la nt s et s w er e g as s te ri li ze d p ri or t o s ur ge ry. T he s ur ge on s a nd e va lu at or s w er e b li nd ed t o t he s il ve r t re at me nt s ta tu s o f e ac h i mp la nt s et. 1 Synthes Paoli, PA Colmano Inc. 21

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