Fighting infection

Materials World magazine
,
1 Feb 2015

Professor Robert Akid from the School of Materials at the University of Manchester, UK, explains how manipulating engineering surfaces can help reduce infection from prosthetic implants. 

Arthroplasty surgery is a common day-to-day procedure involving the replacement of human joints, primarily hips and knees. Historically, hip arthroplasty required the removal of bone from the femur, sufficient to accommodate the artificial hip joint and bone cement, which functioned to fix the prosthetic joint and act as a local source of antibiotic to fight potential infection.
A recent survey carried out by the National Joint Registry showed that 76,274 primary hip replacements were carried out in England and Wales in 2013. Of these, 32,416 were cementless, representing 42.5% of all primary interventions. The use of cementless implants has steadily increased over the last 10 years, from 16.8% in 2003 to 42.5% in 2013. The advantages of cementless femoral components include a reduced risk of cement-related cardiovascular and thromboembolic complications, the possibility of biological fixation, the minimisation of stress shielding of the proximal femur and potential for extended implant survival. Furthermore, osseointegration (regrowth of the bone to form a robust physical connection with the implant) is the key element supporting the rationale for using cementless components in certain patients.


Risk management

In the case of cementless reconstruction, prophylaxis is limited to systemic antibiotic and good surgical practice. However, infection by antibiotic-resistant microorganisms poses a major risk for systemic delivery strategies. 

To address the need for local antibiotic delivery during cementless procedures, increasing research into anti-infective coatings for orthopaedic implants is taking place and a number of coating systems are now being investigated.

Several candidate systems are now emerging from orthopaedic manufacturers.

A popular approach is to exploit the antibacterial properties of ionic silver. Silver ions inhibit bacterial replication of DNA and interfere with key metabolic pathways. The incorporation of silver nitrate into hydroxyapatite (HA) has resulted in antimicrobial coatings that retain the osteogenic properties of HA. These provide an anti-infective surface reducing, in vitro, adhesion of staphylococci. An alternative method of delivery of silver ions may be achieved by adopting a biodegradable poly(dL-lactic-co-glycolic acid)/silver nanoparticle release coating. Other in vitro studies have been carried out combining silver nanoparticles with TiO2 in a multi-layered film. Again, antibacterial activities are reported. Incorporation of Cu2+ ions into TiO2 has also been shown to kill methicillin-resistant Staphylococcus aureus (MRSA), and a TiCu alloy showed antimicrobial activity and low cytotoxicity in vitro and in vivo in rabbit models.

Given the unknowns of long-term build up and the potential toxicity effect of silver, an alternative approach based upon the concept of a combination of therapeutic molecules and a sol gel coating was proposed.


Time-honoured methods

Sol gel technology is not new – it has been exploited for more than 100 years. Originally, sol gel coatings were limited to a thickness of 200–300nm, due to the ceramic inorganic composition that caused films to be extremely brittle. Current developments in the field of those coatings are focused on hybrid, organic/inorganic formulations, to gain the benefits of flexibility of the organic polymer component with the mechanical and physical properties of the inorganic component. Additionally, variations in formulation allow modification of the hydrophobic/hydrophilic properties of the coating, which permit tailoring of the elution properties (release kinetics of the antibiotic agent) from the coating.

 The sol gel system offers a higher, sustained level of antibiotic release over that of antibiotic-loaded bone cement, as can be seen in Figure 2. The limited release rate of the antibiotic is due to the nature of bone cement, which has been shown to sequester up to 70% of the antibiotic.

Recent in vivo trials have shown that the proposed sol gel system does not adversely affect the immune system, has a high kill efficacy against major pathogenic bacterial strains – being effective within 24 hours – and that osseointegration takes place between existing bone and the coated implant. The technology is now moving towards trials to assess the effects of up-scaling coating volumes and the ability of the coating to fight infection, in vivo.


The primary requirements of an ideal anti-infective coating system:
 

  • Facilitates immobilisation of single/multiple therapeutic agents
  • Allows tailoring of antibiotics to specific pathogens
  • Provides controlled, finite antibiotic release
    Prevents infection without promoting antibiotic resistance (system equivalent to current antibiotic-containing bone cement)
  • Does not impair the bone healing process
  • Has a total kill efficacy for clinically relevant bacterial strains within 24 hours, and biofilms in less than 72 hours
  • Generates a minimum inhibitory concentration (1μg/ml) for clinically relevant bacterial strains by less than 30-fold within one hour
  • Equivalent mechanical (implant/bone fixation) properties to an uncoated system
  • Low-temperature cure, eliminating risk of heat-induced damage to the immobilised anti-infective component(s)
  • The antimicrobial activity is not affected by sterilisation with gamma radiation
  • Can be applied to existing implant products on the market