Vancomycin Bound to Ti Rods ReducesPeriprosthetic Infection

Preliminary Study

Valentin Antoci, Jr., BS*; Christopher S. Adams, PhD*; Noreen J. Hickok, PhD*;Irving M. Shapiro, PhD*; and Javad Parvizi, MD†

A major challenge in treating periprosthetic infection is thepredilection of certain bacteria to colonize implants, formbiofilms, and resist treatment. We engineered an innovativeself-protective implant with covalently bound antibiotics thatprevents bacterial colonization and remains stable for ex-tended periods of time. To test this surface in vivo, we de-veloped a rat periprosthetic infection model with an intra-medullary implant in S. aureus-infected femora. Using themodel, we then evaluated the effect of vancomycin-modifiedtitanium rods on the clinical presentation of bone infection.Finally, assuming delayed and chronic periprosthetic infec-tions originate from biofilms atop contaminated implants,the numbers of surface adherent bacteria were measured toassess the capability of the implant to prevent biofilms. S.aureus (1.5 × 103 colony forming units) with no known re-sistance were injected into the femoral canal of Wistar rats,followed by the implant. Signs of infection were assessedweekly by direct clinical observation of the animals, radio-graph, and microCT, and counts of bacteria adherent to theimplant. Vancomycin-modified implants showed superior in-hibition of bacterial attachment and proliferation comparedto control titanium surfaces.

Implementation of stringent anti-infection measures, in-cluding prophylactic antibiotics and clean air environ-ments, has reduced the rate of periprosthetic infection.18

Nevertheless, periprosthetic infection occurs in 1% to 4%

of primary arthroplasties and up to 30% of revision arthro-plasties.3,5,15,20 This is a tremendous problem, as all pa-tients with infection have to deal with extreme and unnec-essary suffering and disability. In some cases, despite mul-tiple surgeries and extended periods of antibiotic therapy,periprosthetic infection treatment remains ineffective. Ef-fective treatment usually involves a combination of im-plant removal, extensive débridement, and two-stage re-implantation, often with use of antibiotic spacers and ce-ments,1,8,16,21,22 However, there are drawbacks to currentsystems for local antibiotic delivery,2,4,11,14,17 includingunpredictable elution kinetics, insufficient antibiotic con-tent, and adverse local tissue effects. Further, biofilms arethought to play an important role in delayed periprostheticinfection and delayed clinical symptoms. Given these con-siderations, an ideal local antibiotic delivery system doesnot currently exist.16

We developed an innovative self-protective implantsurface that does not depend on controlled release. Instead,the titanium surface was engineered with a covalentlybound antibiotic that is stable and long-term bactericidal.We have previously described the in vitro performance ofthis modified surface in which vancomycin was covalentlyattached to Ti powder.10,19

We report here the use of this technology in vivo. Totest the efficacy of the antibiotic-modified implant, wedeveloped a rat periprosthetic infection model that issimple, cost-effective, and reproducible. Once establishedwe used the model to evaluate the effect of vancomycin-modified titanium implants on the clinical presentation ofbone infection. Finally we measured the capacity of themodified surface to inhibit colonization by bacteria and toprevent biofilm-formation.

MATERIALS AND METHODS

We first developed a rat model of periprosthetic infection using12 Wistar rats injected with either S. aureus bacteria (200-�Lsuspension of 0, 103, 105, or 107 CFU of bacteria) or saline

From the *Department of Orthopaedic Surgery and †The Rothman Instituteof Orthopaedics, Thomas Jefferson University, Philadelphia, PA.One or more of the authors has received funding from NIH grants DE-13319(IMS, NJH, CSA, JP), DE-10875 (IMS, NJH, CSA, JP), and AR-051303(IMS, NJH, CSA, JP), and the Department of Defense grant DAMD17-03-1-0713 (IMS, NJH, CSA, JP), and the Orthopaedic Research and EducationFoundation (JP). Results presented are not the statement or policy of thefunding agencies.Each author certifies that his or her institution has approved the animalprotocol for this investigation and that all investigations were conducted inconformity with ethical principles of research.Correspondence to: Javad Parvizi, MD, Rothman Institute of Orthopaedics,925 Chestnut Street, Philadelphia, PA 19107. Phone: 267-339-3617; Fax:215-503-0580; E-mail: parvj@aol.com.DOI: 10.1097/BLO.0b013e318073c2b2

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(negative control), and implanted with 1 × 25 mm Ti rods (ret-rograde insertion through the intercondylar notch). Three ani-mals were harvested at 10, 14, 21, and 28 days. This model wastested for reproducibility, presence of contamination, and simi-larity to actual clinical presentation of bone infection and osteo-myelitis. Next, an additional 12 rats were used for evaluation ofvancomycin-modified rats against the induced infection. Due tounreasonable pain and suffering, statistical outliers, or excessivecontamination during implant extraction, three animals had to beremoved from the microbiological analysis. For each experi-ment, three animals were harvested at 7, 14, and 21 days. Fortesting of the modified surface, titanium or vancomycin cova-lently modified rod was inserted retrograde into the intramedul-lary cavity. The contralateral limb was always used as control.The injected bacteria were a strain of S. aureus that is susceptibleto common antibiotics, without known resistance development,and that has a minimum inhibitory concentration of 1 to 2 �g/mLfor vancomycin. The animals were evaluated daily for clinicalsigns of infection and external anatomy, including pain and suf-fering, hind limb use, swelling, and wound healing or drainage.Weekly radiographs documented progression of infection andbone condition at harvest. To obtain further detail, the femorawere analyzed by microCT. Finally, to evaluate bacterial surfacecolonization and possible biofilm formation, we sonicated theimplants and obtained quantitative cultures for bacterial num-bers. All animal experiments were performed with the approvalof the Institutional Animal Care and Use Committee.

To covalently link vancomycin to titanium alloy, Ti6Al4Vrods (1 × 25 mm) were passivated with H2O2/H2SO4 (1:1);washed four times with dimethylformamide (DMF); reacted, un-der argon, with 5 mmol/L aminopropyltriethoxysilane in anhy-drous toluene; washed with DMF four times. The surface wasthen washed with DMF followed by sequential coupling of twoFmoc-aminoethoxyethylacetate linkers and vancomycin.10

We used S. aureus strain (ATCC 25923) for inoculation of theanimal femora. Before surgery, bacteria were passaged into 5mL trypticase soy broth supplemented with dextrose (1.5%) andincubated shaken (250 rpm) at 37°C for 16 hours. The bacterialsuspensions were washed and resuspended in saline to a con-centration of 1 × 108 colony-forming units (CFU) per mL asdetermined by comparison with a 0.5 McFarland Standard, andfurther diluted to about 1 × 104 CFU per mL. For animal use, 100�L was drawn into 1-mL syringes and stored on ice beforeinoculation into the femur.

For testing the in vivo effect of the vancomycin-modifiedsurface, male Wistar rats (300 and 350 g) were anesthetized withisoflurane gas using oxygen as a carrier. The animals were po-sitioned supine and the intercondylar notch region of the kneewas palpated and identified (Fig 1A). Using a percutaneous stabincision, a 20-G followed by an 18-G needle was inserted intothe femoral canal through the intercondylar notch and advancedby hand reaming to a depth of 3.5 cm (Fig 1B). After reaming,the needle was left in the canal to be used for saline or bacterialdelivery. The bacterial inoculum (100-�L suspension of 1 × 103

CFU) was then slowly injected into the intramedullary space(Fig 1C). After the entire volume of the bacterial suspension wasinjected into the canal, the needle was withdrawn. A vancomy-

cin-modified titanium (Ti6Al4V) rod (Goodfellow Inc, Cam-bridge, UK) measuring 1 × 20 mm was press fit into the canal byretrograde insertion (Fig 1D). Unmodified titanium alloy rodswere inserted in the contralateral control femur. The rods werefully inserted into the canal so that they did not interfere with thefull range of knee motion. The stab incision was then closed.Systemic antibiotics were not administered to animals at anytime.

The animals were examined daily for clinical signs of infec-tion, including swelling and erythema of the knee and the thigh,loss of passive motion of the knee, and non-weightbearing on theaffected extremity.12,13 All examinations were performed on arotating schedule by the authors. The femora were radiographedon a weekly basis.

Animals were euthanized by CO2 asphyxiation. The femorawere radiographed in situ. Surgical dissection was performed onthe bench with no protective airflow. The knee was opened andthe soft tissues around the implant were inspected for grossevidence of inflammation or infection. The soft tissues were thenstripped away from the femur and the implant retrieved andcultured. The femur was then disarticulated at the hip and re-moved in toto. The harvested femora were photographed, sub-jected to microbiologic evaluation, and examined by microCT.

Each femur was radiographed and evaluated for the presenceof periosteal reaction, cortical disruption, abscess formation, andhardware failure or back-out. The anatomical presentation wasalso evaluated with detailed examination of femoral canal diam-eter, cortical bone thickness, appearance of the diaphysis, me-taphysis, and condylar area. The specimens were scanned by amicroCT scanner (Scanco �CT 40; Scanco Medical AG, Bass-ersdorf, Switzerland) at a medium resolution of 20 �m withenergy of 55kVp and a current of 145 �A. Scout, sagittal, andcross-sectional views were examined for changes that are char-acteristic of infection.

To estimate total nonattached bacteria, each retrieved intra-medullary rod was rolled onto a blood agar plate. The plateswere incubated at 37°C for 24 to 48 hours and imaged. Toevaluate adherent bacteria and biofilm formation, the rod wastransferred into 2 mL trypticase soy broth, sonicated for 7 min-utes, and vortexed for 3 minutes. Serial dilutions were plated onagar plates and incubated at 37°C for 24 to 48 hours, and colo-nies were counted.

Statistical comparisons were made with a student’s t-test. Wepresumed a level of significance of p < 0.05.

RESULTS

The rat periprosthetic infection model showed reproduc-ible results within the group. None of the animals were lostto infection, attrition, or systemic illness in this prelimi-nary sample group. Based on autopsy examination, wedeemed infection present in the experimental limb of all 12rats. At the time of harvest, the femora showed consistentsigns of infection on one side, with no infection evident onthe control contralateral leg (Fig 1E). The infected femoradisplayed some inflammation of soft tissues with extensive

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bone remodeling around the distal third of the bone (Fig1F). In most cases, the infected bone was enclosed in afibrous capsule. Based upon the microCT, 1 × 105 CFU S.aureus produced extensive bone loss, disruption of cortical

integrity, and florid bone remodeling (Fig 2A). The me-taphyseal region of the bone showed bone destruction,remodeling, and cortical thinning. In this distal portion,florid infection was easily recognized, as evident by

Fig 1A–F. Proposed rat periprosthetic infectionmodel is easy to learn, reiterates surgical technique,and follows theoretical route of periprosthetic infec-tion initiation. Photographs show the techniques usedto generate the periprosthetic infection model. (A) Af-ter defining the intercondylar notch, (B) the femoralcanal was hand reamed with a hollow-bore 18-Gneedle inserted into the canal to a depth of 25 to 35mm. (C) The canal was then infiltrated with the bac-terial suspension (D) followed by insertion of the in-tramedullary rod. (E) At harvest time, the knee wascarefully dissected and the gross anatomy examinedfor presence of inflammation and pus. (F) The softtissues were carefully removed, and the bone wasfurther evaluated by microbiologic and microCTanalyses.

Fig 2A–B. MicroCT demonstrates clear progressionof infection in the animal model with normal anatomyand no cross-over contamination on the control side.(A) Left femora were injected with 1 × 105 CFU S.aureus and harvested at 21 days. After 21 days, therewas extensive bone loss, disruption of cortical integ-rity, and bone remodeling. In the proximal portion ofthe diaphysis, there was minimum evidence of infec-tion. Progressing distally, the infection was exacer-bated, with more aggressive signs of bone remodel-ing and thinning of the cortex. Finally, full-blown in-fection was evidenced, with disruption of the cortex,widening of the canal, and increased periosteal reac-tion and remodeling. (B) The topography of the con-tralateral bone (control) is shown. The architecture ofthe bone was normal. Cross-sections show no struc-tural changes in bone along the entire length of thefemur.

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cortical disruption, widening of the canal, increased peri-osteal reaction, and remodeling. The control limb showednormal bone topography (Fig 2B). Furthermore, microbio-logic analysis supported the radiographic findings (Fig 3).At all times and with all doses used, the control side evi-denced minimal bacterial growth (Figs 3B, E, H). Infec-tion in the femoral canal was detected in all animals afterinjection with as little as 1 × 103 CFU (Fig 3A). Aftersonication, there were over 1012 bacteria on the treatment

side (Fig 3C); notably, few bacteria were present in thecontrol side (Figs 3B–C). A similar difference betweencontrol and experimental limbs was observed using themiddle dose (1 × 105 CFU, harvested at 21 days, Figs3D–F) and the high infectious doses (1 × 107 CFU, har-vested at 10 days, Figs 3G–I).

Using the described model to test the proposed vanco-mycin-modified titanium implants, most rats experiencedimmediate postoperative pain as evident by a decrease in

Fig 3A–I. Measurements of bacterial numbers further confirm the reproducibility of the rat periprosthetic infection model forfurther use in self-protective implant testing. Bacteria taken from intramedullary rods retrieved from (A, D, G) experimental limbsand (B, E, H) control limbs were plated on agar plates and incubated at 37°C for 24 to 48 hours, and the colonies were counted.(C, F, I) The graphs compare the logs of the bacterial counts for the experimental and control limbs. (A) At a dose of 1 × 103 CFU,there were abundant signs of infection in the femoral canal (harvested at 28 days). (B) Few bacteria were observed on the controlside. (C) At this dose, there are 1012-fold more bacteria in the femoral canal than the control side. (D) For the middle dose (1 ×105 CFU), there were substantial signs of infection in the femoral canal (harvested at 21 days). (E) Fewer than 10 bacteria werepresent on the control rod. (F) Due to the shorter time (21 days), the counts showed a drop in bacterial numbers, with more than106 CFU plated from the experimental rod. (G) When femora were infected with high doses of bacteria (1 × 107), abundantbacteria were evident on the infected side (harvested at 10 days). (H) No bacteria were seen on the control side; this result wasconfirmed by colony counts of bacteria suspended by sonication. (I) Thus, greater than 107 bacteria were adherent to theexperimental surface, while minimum colonization occurred on the control surface.

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locomotor function and hesitation in use of the hind limbs.By 7 days, animals showed a preference for using thelimbs containing the modified implant while avoidingweightbearing on the contralateral limb. No signs of sys-temic infection were evident, and all of the rats were alertand exhibited normal behavior. The wounds all healedwithout skin inflammation or draining. However, in morethan five animals, soft tissue swelling and erythemaaround the knee was evident, and the animals restrictedmotion of these affected joints. Those animals were pref-erentially sacrificed at earlier time points. Dissection andgross examination suggested a prevalence of infection onthe control side, with only limited bacteria being isolatedfrom the side containing the modified implant. Althoughclinical evidence of infection was observed in at least 10limbs receiving the control implant, radiographic analysisconfirmed infection was more prevalent on the control sidein eight of the 12 animals (Fig 4). As early as day 7,evidence of cortical disruption, canal widening, and peri-osteal reaction could be seen on the control limbs, whilethe limbs receiving the modified implants remainedlargely unchanged (Fig 4). Hardware protrusion was seenin some limbs with established infection, perhaps indicat-ing loosening due to decreased bone strength. At 14 days(Fig 4C) and 21 days (Fig 4D), the control side exhibitedaggressive signs of infection, including periosteal reaction,

widening of the canal, cortical disruption, and focal oste-olysis. Compared to immediate postoperative radiographs(Fig 4E), the femora receiving the modified implantsshowed no change in bone anatomy with normal featuresat 7 days (Fig 4F) and 14 days (Fig 4G). At 21 days, thelimbs containing the modified implant (Fig 4H) displayedslight widening of the canal that may have been indicativeof mild infection, but no other associated features could beconfirmed. The microCT cross-sectional images of the fe-mur containing the control implant demonstrated bone re-modeling, periosteal reaction, overall enlargement of thecanal, and loss of cortical bone with extensive abscessformation (Figs 5A, C). In contrast, the limb receiving themodified implant showed minimal to no disruption of nor-mal bone anatomy (Figs 5B, D). Only one femur receivingthe modified implant showed early periosteal reaction (Fig5D).

Finally, 1–3 × 105 bacteria were isolated at 7 days fromthe implants present in three of the four animals that re-ceived control Ti rods. Fewer (p � 0.046) bacteria, (1 ×103 CFU) were isolated from the modified implants (Fig6A). In one animal (Animal 4), bacteria could not be iso-lated from either limb. At 14 days (Fig 6B), the controlimplants contained more than 1.5 × 105 CFU of S. aureus,whereas considerably fewer bacteria were present onmodified implants. One of the animals (Animal 7) dis-

Fig 4A–H. Preliminary radiographs confirm the es-tablishment of infection on the control side with cleardifferences compared to the femora receiving vanco-mycin-modified implants. Radiographs were taken atthe time of surgery and every 7 days up to sacrifice.Overall, 70% of the rats showed more advanced in-fection on the control side when compared to the fe-mur receiving the vancomycin-modified titanium im-plant. In comparison to the surgical radiograph (A),the control side shows a mild periosteal reaction at 7days (B) and aggressive signs of infection at 14 days(C) and 21 days (D). Compared to the radiographs atsurgery (E), femora receiving the vancomycin-modified titanium rod showed no change in boneanatomy at 7 days (F) and at 14 days (G), with somesigns of infection and widening of the canal at 21days (H). Note the control side exhibited more evi-dence of infection with widening of the canal, perios-teal reaction, and some bone cysts.

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played low overall levels of bacteria, while the controlimplant was still colonized by more bacteria than the ex-perimental implant. At 21 days, implants were harvestedfrom two animals (Animals 8 and 9). In both cases, morebacteria were present on the control implant compared tothe experimental surface (Fig 6C).

DISCUSSION

We previously reported a novel implant design that con-tains antibiotics chemically bound to the titanium surface.The vancomycin-modified implant is stable, microbio-cidal, and survives extensive bacterial challenges and ex-treme physiological environments.10,19 In this report, weextended the testing of the new implant design in an ani-mal periprosthetic infection model developed by us. Wepresented the specific protocols associated with the animalmodel. We then described the clinical observations in therat supporting any advantages to using a vancomycin-modified titanium implant compared to untreated normaltitanium. Finally, this antibiotic-modified surface wasshown to inhibit bacterial colonization, possibly prevent-ing biofilm formation in the long run.

Despite the successful results in both establishing a newinfection model and testing a novel self-protective implantsurface, this report is limited to results from 24 animals.

Nonetheless, we identified differences when comparingvancomycin-modified and control Ti implants. The im-plant may not exactly recapitulate clinical scenarios. Al-though the utilized implant was made of the same titaniumalloy that is commonly used for uncemented orthopedicdevices, the difference in size, geometry, and surface char-acteristics may limit the extrapolation of the findings. Fur-thermore, we purposely used a relatively high dose ofbacterial inoculum, which is much higher than expected inclinical periprosthetic infection. The infectious dose wasselected based on previous dose-finding studies and wasan effort to ensure infection could be established in areproducible manner across the entire group. Such bacte-rial number, however, did most likely lead to excessivelydestructive bone infection in all femora receiving the con-trol pin. Despite that, certain variation was still present:one of the animals showed an almost complete absence ofmicroorganisms, whereas another animal had severe infec-tion. Such variations in bacterial number reflect other im-plications of the animal model: anatomic variations of thefemur, differences in reaming, placement of the implant,and retention of the bacteria after implant placement. Animportant confounding variable relates to the technique bywhich these organisms were isolated and cultured. As noanalysis of the organisms was carried out, it is plausiblesome organisms isolated from the implants represent con-

Fig 5A–D. MicroCT cross-sectional analysis of thecontrol and vancomycin-modified titanium rods basedon animals sacrificed at Day 14 further support theinhibition of infection on the treatment side. (A) Cor-tical midshaft cross-sections from the control infectedside are compared to (B) sections from the side re-ceiving the modified rod, where severe changes inbone anatomy are observed. (C) In the control femurof another animal, aggressive remodeling with corti-cal bone penetration and destruction, abundance ofcysts, severe periosteal reaction and reorganization,and enlargement of the entire femoral bone arereadily apparent in distal diaphyseal cross-sectionswhen compared to (D) sections from the side receiv-ing a vancomycin-modified titanium rod.

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tamination that may have occurred during harvest. Thelatter is very likely the case as our previous in vitro datahas shown no bacteria existed on the surface of vancomy-cin-modified implants. Still, most parameters of the

model, including the method of injection of bacteria intothe intramedullary cavity, closely reproduce surgical pro-cedure and route of infection. Despite such limitations tothis animal protocol, we believe it served as an excellenttool for exploring the efficacy of the vancomycin-modifiedsurface in combating bacterial infection. The presence ofthe tethered vancomycin was sufficient to ameliorate theclinical signs of infection, loosening of the implant, de-struction of bone, and the most severe periosteal reactions.The data serve as the starting point for additional work tofurther support the beneficial role of covalently linkedvancomycin in preventing periprosthetic infection.

With further testing and optimization, antibiotic-modified implants could be the ultimate solution againstinfection. Preoperative antibiotics, increased sterility mea-sures in the operating room, better surgical technique, orsuperior implant design have done little to nothing foreliminating the problem of infection.6,9 Antibiotic-impregnated bone cement remains the current gold stan-dard for both treatment and prevention of periprostheticinfection7 but also leads to local toxicity due to unstableelution kinetics and sometimes resistance or the exacerba-tion of infection.4,17,23 Previous studies attempting to coatimplants with antibiotics were met by limited success.21

Our new technology that covalently attaches antibiotics tothe implant seems unique and superior at providing astable antimicrobial surface. The efficacy of the proposedvancomycin-modified titanium implant was evaluated us-ing four different methodologies: clinical observation, ra-diography, microCT analysis, and microbiology. Whileeach of the different procedures produced somewhat dif-ferent results, taken together they suggest the vancomycin-modified titanium implant was in fact effective in prevent-ing bacterial colonization. Microbiologic examination ofthe implants following their removal from the femorademonstrated substantial reductions in the number of ad-herent bacteria, especially in the first 2 weeks of the study.Although a greater reduction in bacterial numbers mightbe expected, considerable variation seen animal to animalmade the analysis difficult. Nevertheless, the data suggestthe vancomycin-modified titanium surface inhibited im-plant colonization by bacteria that subsequently decreasedthe adverse effects associated with periprosthetic infectionand even allowed complete recovery in some cases.

We propose a novel engineered antibiotic implant sur-face for combating device-associated orthopedic infec-tions. This technology is unique as the covalent chemicalbond confers stability to the antibiotic in the long term,potentially allowing endurance to multiple assaults by or-ganisms. The technology may remedy the shortcomings ofthe current antibiotic delivery methods including unpre-dictable elution kinetics, lack of long-term activity, and

Fig 6A–C. Bacterial counts show the effect of the vancomy-cin-modified implant in considerably decreasing bacterial num-bers by as much as two to three orders of magnitude whencompared to control unmodified surfaces. To evaluate bacte-rial adhesion, the rods were sonicated, vortexed, and platedfor counting. Total bacterial numbers (CFU) were plotted for atotal of nine animals at (A) 7 days (four animals), (B) 14 days(three animals), and (C) 21 days (two animals). Each pair ofbars represents one control and one experimental limb fromthe same animal. Note, for all animals, there were more bac-teria on the control side than the vancomycin-modified titaniumside, with the exception of Animal 4, sacrificed at 7 days,where there were insufficient bacteria to count on either side.

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inactivation of antibiotics by methylmethacrylate cement.In this report, the antibiotic-modified surface minimizedclinical signs of infection, reduced bacterial load, and pre-vented osteolysis. We believe these preliminary findingsare encouraging and hold promise for the future clinicalmanagement of periprosthetic infection.

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