SAFE Nail - Interlocking Nail with a Long Acting Antibiotic Releasing Core.

An in Vitro Experimental Study and Preliminary Clinical Results. Nuno Craveiro Lopes, M.D. Carolina Escalda, M.D. and Carlo Villacreses, M.D. Orthopedic and Trauma Dpt., Garcia de Orta Hospital, Almada, Portugal Isabel Carvalho, M.D. and Cristina Marques, M.D. Clinical Pathology Dpt., Garcia de Orta Hospital, Almada, Portugal Jos Fernandes, Eng. and Pedro Ferreira, Eng. Instalation and Equipment Dpt., Garcia de Orta Hospital, Almada, Portugal Antnio Urgeira, Ass. Prof. Eng. Mechanical and Industrial Engineering Dpt, FCT, New University of Lisbon Introduction The treatment of bone infection is a challenge for the orthopedic surgeon and a difficult process for the patient. Traditionally, the treatment strategy is a two step procedure: First infection control, including extensive debridement of devitalized bone and soft tissue and intravenous antibiotics, with or without local polymethylmethacrylate cement (PMMA) spacers or beads, impregnated with antibiotics and bone stabilization with external fixators. When the infection is controlled, a second phase is done extracting the cement, bone grafting, and where possible, replacement of external fixation by a method of internal fixation that allows for rapid recovery of limb function. Intramedullary nails covered with PMMA cement impregnated with antibiotics is an attractive method for the treatment of long bone infections, because they allow both the control of infection by release of high doses of local antibiotic and provide internal stabilization with the possibility of immediate loading and walking, preventing many of the complications associated with external fixation. Several such devices are described, including Ender and interlocking nails, externally covered with PMMA cement impregnated with antibiotic. However such devices or do not have enough stability to allow immediate loading as in the 1st case, or the preparation procedure has proved to be time consuming, and the weak coverage of cement with a high rate of associated complications, due to cement debonding and incarceration of the nail, as in the 2nd case.

Prototype of the pilot study

To overcome these problems, the authors carried out a pilot study including a experimental work to assess the rigidity and levels of release of antibiotic of a modified interlocking nail with a core of PMMA cement impregnated with vancomycin, developed by the author (NCL) and named SAFE ( Self-releasing Antibiotic Fixation Endomedular) Nail. Material and Methods To test the release of the antibiotic, we prepared a cylinder of 350X15mm with 40gr of PMMA impregnated with 2g of vancomycin and a femoral interlocking nail made of 316L steel (Grosse & Kempf - Stryker) 360X12mm in size, in which ten 5mm transfixing holes were performed in the lateral plane. The interior of this nail was filled with 20 grams of PMMA mixed with 1 g of vancomycin, with the aid of a cementation gun. The pieces were put into test tubes with 500cc Hartmann solution (Viaflo), with temperature control to 37 and stirring with a bubbler. The elution liquid was replaced within 1, 6, 12, 24 and 48 hours, 1 and 2 weeks, 1 and 2 months and samples were taken from each period of time. To determine the concentration of vancomycin we used the immune fluorescence polarization method (Integra 800).

We also used a binocular microscope with magnification of 50X, with tangential lighting for the study of the cement-metal interface.

Antibiotic release test

For the tests of resistance, we used 3 femoral interlocking nails, 360X12mm in size, one original, a second one with ten 5mm transfixing holes and a third with the same holes and filled with 20 grams of PMMA and 1g of vancomycin. Tests of flexural strength were performed in a WP300 Universal Material Tester equipment (Gunt-Hmbg), with incremental bend of the nails up to 20mm (about 22).

Mechanical resistence test

The authors present the first 12 patients treated with this type of nail, from January 2009 to January 2010, including 6 cases of conversion of external to internal fixation, 2 cases of stabilization of open fracture and 4 cases of fracture in an osteomyelitis focus. Results The concentration of vancomycin released from the PMMA cylinder with 2g of vancomycin was found to be biphasic: during the 1st 12 hours it was released at a higher rate (3.28%) after which there was release in lower amount, keeping a level between 0.35 % and 0.38% in each reading until 2 months of experiment, corresponding to a concentration of 13 to 15ug/ml. The concentration of vancomycin released from the perforated nail filled with PMMA and 1g of vancomycin, showed a more sustained release over the time of experimentation, which lasted for 12 months, releasing up to 1.79% during the first 12 hours and maintaining a level of 0.39% to 0,4%, corresponding to doses from 7.7 to 12.7 ug/ml during more than 12 months.

40 35 30 25 20 15 10 5 0 1h 6h 12h 24h 48h 1s 2s 1m 2m 4m 7m MIC 9m 11m 12m

Cilinder

Prototype

Expected Release

Levels of antibiotic release from the SAFE Nail (red) Observation of the cement-metal interface showed the existence of a space ranging between 0.15 and 0.2 mm in all areas where cement was visible, including top upper and lower screw locking holes, the posterior longitudinal slot and the perforations.

Force kN 1,2
1

Stairs (1,3)

0,8

+10%
0,6 0,4

Walking (0,6)
0,2

0 0

Deformation

mm

Standard

Perfurada 1

Perfurada + PMMA

Levels of mechanical resistance of the SAFE Nail (red) When subjected to a transverse pressure of 0.4 kN, the original nail had a deformation of 2.4 mm (4.3) and at pressure of 1kN, presented 6mm (10) of deformation. From that point the original nail continued to deform more rapidly, reaching 20mm (22) at 1.6 kN.

The perforated nail filled with PMMA and vancomycin presented at 0.4 kN a deformation of 2.2 mm (3.6 ), at 1kN, a 6mm (10) deformation and continued to deform up to 14mm (17), when at the pressure of 1.36 kN, fracture of the inner core of PMMA was produced. The perforated nail had a deformation of 2.6 mm (4.9 ) at 0.4 kN and deformed progressively to 20mm (22) at 0.95 kN. Discussion The PMMA cement spacer or beads impregnated with antibiotics have been in use since 1970 (Buchholz) in the treatment of bone infection, and have proved effective for long term local administration of high doses of antibiotics, with very low systemic levels of antibiotic. This experimental work showed that when the cement is within a perforated metal nail, the percentage of antibiotic released is similar to a cylinder of cement and not proportional to the exposed area of the cement that is within the nail as initially expected. The authors found that this is due to the existence of a gap between the cement and the interior of the nail caused by the contraction of the cement by cooling after polymerization, allowing the movement of fluids and the release of the antibiotic of the entire surface of the cement. The tests performed also showed that the antibiotic concentrations released from the core of PMMA cement impregnated with 1g of vancomycin maintained a prolonged plateau, about 5 to 10 times higher than the minimum inhibitory concentration of the antibiotic, for at least 2 months of our experiment and there are indications in the literature that this release may remain in therapeutic doses for more than a year. Higher doses of antibiotic release can be achieved with the impregnation of higher amount of antibiotic in the cement.

Space between the interior wall of the nail and cement.

The levels of bending forces acting on the femur of a normal adult, reach 0.6 times its body weight during walking and 1.3 times when climbing stairs. These benchmarks are never achieved in a patient suffering from lower limb fractures or diseases, fixed with an interlocking nail and using crutches. However, within these levels of activity, the perforated nail with a core of PMMA have shown to have better mechanical behavior compared to the original nail, with an increase of resistance of about 10%. On the 12 patients operated on with this technique, we prevented or cured the infection except in one case of open fracture which presented latter a strain of Beta-Hemolytic streptococcus resistant to vancomycin, the antibiotic used for impregnation. He underwent a nail replacement with another, impregnated with 2 g of Flucloxacillin, the antibiotic that the bacteria isolated was sensitive, achieving a cure of the infection.

Lengthening over nail with an external fixator, after a failed TRSH nail. Reconversion with a SAFE Nail

We have not detected in this series of cases, intolerance or breakage of the implant, adverse reactions or other complications. Conclusions The authors conclude that this new device represents an added value compared to current methods of treatment of open fractures, conversion of external fixation to internal fixation and treatment of infection with bone fragility, because the procedure is simpler and faster to perform, the device has a strength 10% higher than the standard interlocking nail, because it allows the choice of appropriate antibiotic with local release of higher and prolonged therapeutic doses and because the preliminary clinical results were promising, without added complications. Bibliography Raghuram Thonse and Janet D. Conway.: Antibiotic Cement-Coated Nails for the Treatment of Infected Nonunions and Segmental Bone Defects. J Bone Joint Surg Am. 2008;90:163-174. Adams K, Couch L, Cierny G, Calhoun J, Mader JT. In vitro and in vivo evaluation of antibiotic diffusion from antibiotic-impregnated polymethylmethacrylate beads. Clin Orthop Relat Res. 1992 May;(278):24452. Bayston R, Milner RD. The sustained release of antimicrobial drugs from bone cement. An appraisal of laboratory investigations and their significance. J Bone Joint Surg Br. 1982;64(4):460-4. Bowyer GW, Cumberland N. Antibiotic release from impregnated pellets and beads. J Trauma. 1994 Mar;36(3):331-5. Calhoun JH, Henry SL, Anger DM, Cobos JA, Mader JT. The treatment of infected nonunions with gentamicin-polymethylmethacrylate antibiotic beads. Clin Orthop Relat Res. 1993 Oct;(295):23-7. Eckman JB Jr, Henry SL, Mangino PD, Seligson D. Wound and serum levels of tobramycin with the prophylactic use of tobramycin-impregnated polymethylmethacrylate beads in compound fractures. Clin Orthop Relat Res. 1988 Dec;(237):213-5. Evans RP, Nelson CL. Gentamicin-impregnated polymethylmethacrylate beads compared with systemic antibiotic therapy in the treatment of chronic osteomyelitis. Clin Orthop Relat Res. 1993 Oct;(295):37-42.

Ostermann PA, Seligson D, Henry SL. Local antibiotic therapy for severe open fractures. A review of 1085 consecutive cases. J Bone Joint Surg Br. 1995 Jan;77(1):93-7. Scott DM, Rotschafer JC, Behrens F. Use of vancomycin and tobramycin polymethylmethacrylate impregnated beads in the management of chronic osteomyelitis. Drug Intell Clin Pharm. 1988 Jun;22(6):4803. McGraw-JM; Lim-EV. Treatment of open tibial-shaft fractures. External fixation and secondary intramedullary nailing. J Bone Joint Surg Am. 1988 Jul; 70(6): 900-11 Maurer-DJ; Merkow-RL; Gustilo-RB. Infection after intramedullary nailing of severe open tibial fractures initially treated with external fixation. J Bone Joint Surg Am. 1989 Jul; 71(6): 835-8 William R. Taylor, Markus O. Heller, Georg Bergmann, Georg N. Duda. Tibio-femoral loading during human gait and stair climbing. Journal of Orthopaedic Research 22/3 - 2006 Klemm K. Gentamicin-PMMA-beads in treating bone and soft tissue infections. Zentralbl Chir. 1979; 104:934-942. Ohtsuka H, Yokoyama K, Higashi K, et al., Use of antibiotic impregnated bone cement nail to treat septic nonunion after open tibia fractures, J Trauma. 2002; 52:364-366.