Modular Silver-coated Tumour Prostheses for Reconstruction after Resection of Malignant Bone Tumours

Until the end of the last century, malignant bone and soft tissue tumours of the extremities were almost always treated by amputation in order to achieve wide resection margins for disease control. With the invention of chemotherapy, improvements in surgical procedures, including vascular and microsurgery, and the development and evolution of tumour prostheses, limb salvage can be achieved in a high percentage of cases today (see Figure 1), without a significant difference in patient survival when compared with amputation.¹ Furthermore, limb salvage results in a better functional outcome, especially in the lower limb.²

In order to combine maximal functional results and sufficient resection margins, limb salvage and reconstruction with tumour prostheses is the gold standard nowadays and can be performed in over 90 % of cases.³ With modern modular tumour prostheses (see Figure 2), a five-year revision-free interval can be achieved in 80 % of cases.^4,5 However, limb-sparing tumour resection and reconstruction with megaprostheses results in complications such as tumour recurrence in 1–9 % of cases, aseptic loosening of the prosthesis in 5–27 %, and infections or periprosthetic infections in 10–36 % of cases, despite the routine use of systemic, and sometimes local, antibiotic prophylaxis.⁶ There is therefore a need for antimicrobial surfaces, such as silver coatings, in order to prevent bacterial colonisation of the implant.

The Implant
The Modular Universal Tumour and Revision System (MUTARS®, Implantcast, Buxtehude) implants are made of titanium alloy (TiAl6V4) (Implatan®), cast cobalt–chromium alloy (CoCrMo) (Implavit®) and a titanium nitride coating (TiN). The extra-osseous components, that do not form the joint, are available with a silver coating.

Because of the modularity of the system, with variable extension pieces and connecting pieces, MUTARS allows the reconstruction of defects in 1 cm increments, depending on the eventual resection length. The connecting faces of all parts are toothed, which provides great rotational stability and enables the adjustment of rotation in 5° steps. The system allows the reconstruction of defects of the humerus, femur and/or tibia up to the total replacement of the humerus or femur with the corresponding joints. Seldom appearing strictly diaphyseal defects can be reconstructed with a diaphyseal implant.

Intra-osseous fixation can be accomplished by either cementless fixation with hydroxyapatite coated stems or cemented stems made of CoCrMo, which are available in different sizes. In rare cases, extra-short stems can be produced custom-made to preserve the adjacent joint. The stems have a hexagonal shape, which provides excellent fixation and rotational stability. Special hexagonal rasps are used to ensure intramedullary fixation of up to 80 % of the stem. Femoral heads are available in CoCrMo, ceramics (Al2O3) or titanium (TiAl6V4), coated with titanium nitride (TiN). To connect the femoral and tibial components of the knee joint, either the PEEK-OPTIMA® lock or the metal-on-metal (MOM) mechanism can be used. The articulating parts are separated by a polyethylene inlay. Refixation of the soft tissue and reconstruction of the joint capsule can be accomplished using the MUTARS Attachment Tube (made of polyethylene terephthalate), which is sutured to the prosthesis providing effective protection against luxation of the shoulder and hip joint, for example.

Medical History of Silver
The anti-infective effect of silver has been known for thousands of years. The ancient Phoenicians, Greeks, Romans and Egyptians used silver in one form or another to preserve food and water. Silver plates and silver preparations were used by Hippocrates to promote wound healing, for example, in ulcers.⁷ In the following centuries, silver established itself as a very effective modality for the treatment of wounds. Especially in the era prior to the invention of antibiotics, silver was used in nose drops, eyedrops (Crede’s prophylaxis) and for the treatment of syphilis. Today, silver is still important for the treatment of wounds. Furthermore, it is applied to prevent infections of implants. There exist silver-containing wound dressings, silver-coated catheters, endovascular implants and orthopaedic implants.⁸ However, silver is not only used in medical equipment. There is widespread usage of silver in devices such as refrigerators, tableware and toothbrushes, due to its antibacterial effects.

How Does Silver Work?
The anti-infective effects of silver are multifactorial and affect a large spectrum of bacterial and fungal species.⁹ Silver ions bind irreversibly to functional proteins on the cell membrane, transmembrane transport proteins and extra- and intracellular enzymes, inhibiting multiple functions including the respiratory chain and the development of biofilm (oligodynamic effect). These antimicrobial effects can be observed in relatively small concentrations,¹⁰ while toxic effects on human and animal cells require a much higher concentration. Furthermore, the oligodynamic effect can be observed in other metals, such as mercury, copper and lead. Of these, silver exhibits the strongest effects with mostly minor side effects.

Applications
There are various forms of application of silver, ranging from local application through ointments, dressings and solid bodies to colloidal solutions for systemic therapy. The application of silver to different types of medical devices requires different procedures for binding ions to the different surfaces. Some techniques for applying silver to solid bodies are ion beam-assisted deposition (IBAD), plasma or thermal spray and galvanisation. The amount of ionic silver that can be delivered by the coated devices to the surrounding tissue depends on the procedure used to bind the silver and on other factors, such as pH value, temperature, the amount of dissolved ions and the size of the delivering surface.

Side Effects
Due to the occurrence of silver in the natural environment, the human body is exposed to silver during its entire life. The majority of ingested silver is not absorbed but excreted gastrointestinally. Most of the incorporated silver is bound to serum proteins, hepatically metabolised or eliminated by biliary and renal excretion. Small amounts of silver, however, remain bound to proteins and organs in the human body.

The local and systemic side effects or toxic effects of silver are subsumed under the expression ‘argyria’. These include local grey-blue colouration of skin and mucosa, as well as systemic effects such as liver and kidney impairment. In some studies, these effects have been shown for blood concentrations above 300 ppb.^11,12 However, most clinical evaluations of silver-coated medical devices show no evidence for toxic side effects.^13,14 In addition, the study of Hardes et al. could prove ‘the lack of toxic side effects after the implantation of silver-coated megaprostheses’.¹⁵

Clinical Results of Silver-coated Tumour Prostheses
The mid-term clinical results of the MUTARS tumour prostheses are very promising. In the Musculoskeletal Tumor Society (MSTS) score, a commonly used tool for the assessment of subjective and objective functional parameters, patients reach values between 70 % (proximal femur replacement) and 83 % (proximal tibia replacement) for the lower extremity.⁴ Due to the mode of tumour resection (resection of the axillary nerve is necessary in most cases, with partial or total resection of the rotator cuff), the MSTS scores for patients with tumours of the upper extremity, especially the proximal humerus, are slightly worse, with a mean score of 70 %. These figures reflect the common findings in the literature.6 In comparison with the standard titanium alloy tumour prostheses, silver-coated prostheses significantly reduce infection rates, without any severe side effects. For the lower extremity, the infection rate was substantially reduced, from 17.6 % in the titanium group to 5.9 % in the silver group. Within the follow-up period of five years no secondary amputation had been necessary in the silver group. In contrast, amputation was ultimately inevitable in 38.5 % of cases in the titanium group when periprosthetic infection developed.¹⁶

Conclusions
Limb-sparing tumour resection of malignant bone tumours of the upper and lower extremities is the standard procedure today. Modular tumour prostheses allow individual reconstruction,depending on the defects after resection. Because of its effects on a broad spectrum of bacterial and fungal species, the MUTARS silver-coated prostheses significantly reduce the rate of periprosthetic infection and promote the avoidance of secondary amputation of the lower extremity, while no severe or toxic side effects have been observed so far.