Preventing orthopaedic implant infections. This literature reviewPreventing orthopaedic implant infections. This literature review

Preventing
medical device associated infection through laser surface modification

 

Abstract

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With the world population growing and life expectancy
increasing, there is an increasing demand for orthopaedic implants, which is a
medical device inserted into a patient that is designed to replace a missing
joint or bone. Unfortunately, as with any surgery, there is the potential for
infection. Bacteria may colonise the orthopaedic implant by forming a highly
antibiotic-resistant biofilm, which may ultimately lead to the implant having
to be removed and replaced. Infections not only puts the patient at risk, but
are time-consuming and costly to the health service. Staphylococcus aureus and Staphylococcus
epidermidis are the two most commonly implicated pathogens involved,
although it has been shown that infections are very much polymicrobial. Oral
antibiotics have proven to be of limited use in treating these infections due
to the poor blood supply to bone. With all this being said, it is obvious as to
why there is a huge research effort into preventing orthopaedic implant
infections. This literature review will focus mainly on laser surface
modification as a method to prevent infection, covering the methods that have
been used to date, and the likely direction that research is headed.

 

Infectious
complications of orthopaedic implants

 

Types of
organisms implicated

 

Orthopaedic
implant infection is polymicrobial, meaning that there are several
microorganisms implicated in infection 1,2. In the 1970’s,
coagulase-negative Staphylococci,
Propionibacterium, and Streptococci were
uncommon pathogens implicated, but nowadays these organisms are known to cause
several orthopaedic infections 2,3.

The bacteria
isolated from orthopaedic infections are most frequently S. epidermidis and S. aureus.
Staphylococcus aureus and Staphylococcus epidermidis, account
together for two out of three infection isolates. In addition to this, S. aureus is mostly involved in
infection of metallic-based implants 4. Aerobic Gram-negative
bacteria cause 10–20% of all deep infections, and anaerobic Gram-positive bacteria
such as Propionibacterium acnes are
responsible for another 10% 5. Whilst accounting for less than 1% of
PJI cases, it is also possible to have a fungal orthopaedic infection, and it
is thought that their role in orthopaedic infections has to date, been
underestimated. Candida species account for around 80% of fungal orthopaedic
infections 6.

 

Biofilm
formation

 

Bacteria can be classified as either planktonic or biofilm
forming. Planktonic bacteria are metabolically active and replicate rapidly,
whereas biofilm-forming bacteria colonise together on a surface surrounded by
an extracellular matrix composed of extracellular polymeric substances. Biofilms
have been recently defined as a “microbial-derived sessile community
characterized by cells that are irreversibly attached to a substratum or
interface or to each other, are embedded in a matrix of extracellular polymeric
substances that they have produced, and exhibit an altered phenotype with
respect to growth rate and gene transcription” 7. They usually
colonise non-biological substances such as orthopaedic implants. Biofilm
forming bacteria are resistant to antimicrobials for a number of reasons.

Firstly, any antimicrobials administered must diffuse through
the biofilm matrix in order to reach the inactivate cells. The extracellular
polymeric substances act as a diffusion barrier for by reducing the rate of transport
the antimicrobials to the biofilm interior. Studies have demonstrated that the
penetration of ciprofloxacin into a P.
aeruginosa biofilm takes 21 minutes, whereas on a sterile surface, this
would only take 40 seconds 8.

Biofilms have a reduced metabolic rate, and also grow
significantly more slowly than planktonic cells and, as a result, take up
antimicrobial agents more slowly, and so the antimicrobial agent is less
effective. This has been demonstrated in Escherichia
coli biofilms, as the slowest growing biofilm was noted to have had the
most resistant to the antiseptic cetrimide 9.

Many of the microorganisms have a quorum-sensing system that
regulates the production and release of various virulence factors that protect the
biofilm from elimination. Quorum sensing allows for cell-to-cell communication,
allowing upregulation of efflux pumps to expel the antimicrobial 10.
However, further research is required to determine the exact role of quorum
sensing in antimicrobial resistance, as some research has shown that some
bacterial biofilms which have a mutation to prevent quorum sensing, are
actually unaffected in their resistance to antimicrobials 11.

A subpopulation
within the biofilm community differentiate into a unique, dormant phenotypic
state of cells referred to as persister cells. Most bacteria in the biofilm are
killed by antimicrobials. Survivors which only account for approximately 1% or
less of the original population, persist despite continued exposure to the
antimicrobial. Once antimicrobial levels fall, the persister cells can then
give rise to a normal colony once more 10.

To summarise,
there is no simple explanation as to why biofilms exhibit antimicrobial
resistance, but what is clear is that when biofilms form on the implant, they
almost certainly need to be removed. Therefore, antimicrobial prophylaxis of
the implant is more desirable in order to prevent the formation of the biofilm in
the first place.

 

 

Orthopaedic-associated
diseases

 

Orthopaedic
implants are primarily used for joint fixation and for joint replacement 12.
After a joint replacement, it is estimated that prosthetic joint infections
(PJIs) occur in 0.3–1.7%, in 0.5–2% and in 2–9% of patients after total
replacement of the hip, knee and ankle, respectively 13,14. One of
the most important risk factors for this is the relatively low number of
microorganisms needed to cause infection. It has been shown that only 102
colony forming units (CFU) of S. aureus
is needed to cause an infection in a rabbit that has undergone a hip
hemiarthroplasty, compared with 104 CFU when no implant is placed 15.

The number of
complications involved in implants is expected to rise due to the improved
diagnostic criteria for microbial biofilms involved in prosthetic joint
infections, as well as the growing population, and in particular the growing
aging population which will require more orthopaedic implants 16.

Osteomyelitis involves
colonisation of bone with microorganisms, with associated inflammation and bone
destruction. Following an implant, osteomyelitis is a potential complication as
biomaterials elicit an immune response following bacterial adhesion, allowing them
to proliferate and colonise. The patient may complain of fever or pain in the
area 17.

Septic
arthritis is the inflammation of a joint as a result of colonisation of a joint
by a microorganism, most commonly, Staphylococcus
aureus followed by Streptococci.
Septic arthritis can be quite serious, with an 11% mortality rate and can cause
irreversible damage to the bone cartilage, and so following diagnosis, patients
should be admitted to hospital intravenous antibiotic treatment, with the
antibiotic used determined by the pathogen isolated, and aspiration of any pus
from the joint 18.

Prosthetic
joint infections (PJI) is an umbrella term for the infection of the implanted
device and the surrounding tissue, and usually require removal of the affected
implant. PJI’s are a serious economic burden to the healthcare system costing
an estimated $50,000-$60,000 and are estimated to cost the US healthcare system
is expected to reach $1.62 billion by 2020. Staphylococcus aureus and
Staphylococcus epidermidis account for over half of PJIs alone 19,20.

 

Table 1. Microorganisms implicated in 618
patients with periprosthetic joint infections 21
 

Bacteria

Staphylococcus
aureus                                                 
32.8%

Coagulase-negative
staphylococci                          
      26.5%

Streptococcus
spp.                                                         
8.7%

Enterococcus
spp.                                                          
6.6%

Propionibacterium
spp.                                                
  1.9%

Gram-negative
bacilli                                                     
6.5%

Other                                               
                               1.8%

Polymicrobial                                                                  
6.1%

No growth                                                                       
8.9%

 

 

Approaches
used to prevent orthopaedic infection

 

The surface
properties of orthopaedic implants such as surface roughness and chemistry,
hydrophilicity, surface energy, surface potential and conductivity play crucial
roles in initial bacterial adhesion to implants and their subsequent biofilm
formation. Modification of the physiochemical surface properties of the implant
is a relatively simple and economic way to counteract bacterial colonization. Studies
have shown that UV irradiation of wavelengths of 257.7 nm leads to a
”spontaneous” wettability increase of the Ti6Al4V surface, which reduces the
bacterial adhesion on to the implant surface, and therefore prevents biofilm formation.
It also was shown to preserve mechanical properties of the implant that are
crucial for its performance as an orthopaedic 22.

 

Antibiotics

 

One of the
earliest techniques used to prevent orthopaedic implant infection was the use
of titanium implants with covalently attached antibiotics. These are released
slowly at a defined rate in order to prevent pathogen colonisation. S. epidermidis colonization was
significantly inhibited on Vancomycin titanium implants. However, it still
allowed Escherichia coli to grow,
allowing for the potential of antibiotic specificity. It also retains its
antimicrobial properties when challenged again multiple times making it a
potential long-term solution to orthopaedic infections 23.

Indeed, prophylactic
systematic antibiotics are administered routinely to patients who receive an
orthopaedic device in order to prevent peri-operative infection. However,
systemic administration of antibiotics is unlikely to achieve therapeutically
adequate levels of antibiotic at the bone due to the poor vasculature
surrounding bone. Thus, local administration of antibiotics directly at the
implant site is an area of active research. Work has been done into
incorporating antibiotics into polymethylmethacrylate (PMMA) bone cement for
local antibiotic prophylaxis in cemented total joint arthroplasty 24.
The incorporation of tobramycin into a hydroxyapatite coating on titanium
highlighted that could successfully inhibit growth of Staphylococcus aureus and indicates that hydroxyapatite containing
antibiotics could be used to locally prevent post-surgical infections in
orthopaedic implants 25. However, clinical practice is now moving
towards the use of “cementless” implants which exhibit improved osseointegration,
as breakdown of the cement can cause loosening of the implant, resulting in the
need for further surgery, the body can also recognise the cement as a foreign
body, and will elicit and inflammatory response at the hip causing pain.
Another obvious problem is the use of antibiotics in today’s age
prophylactically could propagate the resistance of bacteria to antibiotics,
which would ultimately lead to even more hip implant infections than there
currently is now. Another rare but serious side effect is bone cement
implantation syndrome (BCIS), which is characterized by hypoxia, hypotension or
both and/or unexpected loss of consciousness. Finally, whilst it is rare, the
cement can enter the bloodstream and end up in the lungs causing a pulmonary
embolism, a condition that can be life-threatening to the patient. 26.

Osseointegration is very important to the success of
orthopaedic devices implanted within bone. It refers to a direct connection
being developed between the body’s tissue and the implant. However, allowing
for osseointegration, also may allow for bacterial adhesion. The pathogens may
share many of the same adhesive mechanisms as host tissue cells, such as
fibronectin (Fn). This molecule has been used to coat implants allowing for
control of the rate of antimicrobial release at the site but unfortunately, can
also be recognized by Staphylococci
by its Fn-binding proteins 27,28. Additionally, techniques that
have been used to prevent bacterial colonisation do not usually facilitate
osseointegration.

 

Silver coatings

 

Titanium
nanotubes coated with silver have
been shown to possess broad spectrum antibacterial activity against methicillin-resistant
Staphylococcus aureus (MRSA:
ATCC43300) in vitro and in vivo over a 30-day period. However,
as with many of the experimental techniques described, this still needs to be tested on larger animals, such as
mice, rabbits or dogs in order to determine if there is any clinical
application. Silver has limited systemic toxicity in vivo, however, the
increase in use of small silver particles and silver nanoparticles in cosmetic
products warrants a new evaluation of silver toxicity 29,30.

 

Chitosan
coatings

 

Chitosan is a cationic biopolymer that is derived from
chitin. When combined with osteogenesis-promoting agents like RGD ligands, it
reduces S. aureus and S. epidermidis adhesion by 67% and 85%
respectively, as well as allowing for improved osseointegration 31.
Chitosan has also been used as a drug-carrier coating, with two different
studies using it to deliver vancomycin and ciprofloxacin to the site, however,
it is only capable of delivering a burst release of antibiotic, and so is not
viable for long-term use due to it’s poor pharmacological properties 32,33.

 

Antimicrobial
peptides

 

These molecules are amphiphilic, cationic peptides that
breakdown cell membranes and intracellular organelles, thereby inhibiting
biofilm formation. One application of this involved two antimicrobial peptides,
Tet213 and HHC36, which were bound to a calcium phosphate coat. It exhibited
significant antibacterial activity against S.
aureus and P. aeruginosa 34.
These peptides were combined with titania nanotube-calcium phosphate coating with
a phospholipid capping agent in another study. This allowed for improved drug
kinetics, by allowing the peptides to be released over an extended period of
time 35.

Another way to integrate antimicrobial peptides is to have
them coated to the surface of hydrophilic polymer brushes, allowing
antibacterial and anti-adherent properties 36. Antimicrobial
peptides are advantageous in that they have not only a wide spectrum of
activity, but there are still a huge number of clinically relevant peptides
left to discover. However, there is some concern as to their susceptibility to
chemical and physical degradation in vivo
37.   

 

 

Laser surface
modification

 

Laser surface modification has successfully been used
previously in vivo with Kawano et al. implanting 12-week-old
rats with titanium discs that had been modified with two blue-violet light
sources (365nm and 405nm), this allowed for increased bone formation around the
titanium implant. The same paper also demonstrated that the two light sources
reduced the adherence of P. gingivalis
by 49% and 35% respectively 38.

Cunha et
al modified titanium discs with femtosecond laser texturing,
and demonstrated that the laser treatment significantly reduces the bacterial
adhesion and biofilm formation of s. aureus
compared to an unmodified reference surfaces. This suggests that laser
engineering of titanium surfaces is a simple, repeatable, scalable and exciting
method of improving the antimicrobial properties of orthopaedic implants. The
exact mechanism by which the antimicrobial effect has not yet been elucidated,
but this paper suggests that it may be as a result of the modification of the nanotopography.
The surface increases the distance between bacterial cells, reducing the
penetration of bacteria as well as the area of the contact between bacteria and
titanium 39.

Work carried out by Chan
and Carson et al. involved performing fibre laser surface engineering on
three of the most commonly used metals used in orthopaedic implants for the
very first time (commercially pure CP Ti Grade 2, Ti6Al4V Grade 5 and
CoCrMo alloy implants) to determine if fibre laser surface engineering can be
used to improve the antibacterial properties of various metals, or if it is
only limited to certain alloys. The bacterium used was the most commonly
implicated pathogen in orthopaedic implant infection, S. aureus. Analysis of surface wettability was performed using the
sessile drop method, and it was found that the modified surfaces possessed
reduced hydrophobicity. The results obtained highlighted that fibre laser
engineering produced an antibacterial effect and reduced the bacterial adhesion
with CP Ti and Ti6Al4V, but not with CoCrMo. This paper suggests that the
reason for this antibacterial effect is attributable to a combination of
reduced hydrophobicity, oxide films, and modified nanotopography 40.
Laser surface engineering is a relatively new advancement in the area of
orthopaedics, work is still at an early stage and as such, is an exciting area
of research.

Work published in the Journal of Materials Science and
Engineering modified various titanium alloys of varying copper contents via
selective laser melting. It was shown through antibacterial tests that the
titanium alloys with that 4% and 6% copper had antibacterial properties against
Escherichia coli and Staphylococcus aureus compared to the titanium
with no copper and the titanium with 2% copper. The copper also exerted good
cytocompatibility to the Bone Marrow Stromal Cells (BMSCs) from Sprague Dawley
rats. These studies hold promise to the idea that it is indeed feasible to fabricate
antibacterial alloys direct by SLM processing mixed commercial Ti6Al4V and Cu
powder that can be safely used in vivo 41.

Krypton fluoride 248?nm Excimer laser was utilized to modify
the surface of polyethylene terephthalate (PET). Escherichia coli growth was measured
at high shear flow using a CDC Biofilm reactor over a period of 48 hours. Following
this, characterisation of the surface topography and roughness was determined
with the use of a Micromeasure 2 and a 3D profiler. Through this work, it was
shown that the surface modification significantly influenced the distribution
and morphology of the attached E. coli cells. What is more, it has been
evidenced that the laser-modified PET has been shown to prevent E. coli cells
from attaching themselves within the laser-induced micro-surface-features 42.

Despite the fact that multiple papers have proven the
antibacterial and anti-adherent properties of laser surface modification, there
was been no single technique as of yet has revolutionised the field of
research. Further research needs to be carried out into the area to find a
technique that allows for osseointegration and inhibits bacterial colonization.
Several of the technologies mentioned have shown antibacterial properties with
a good safety profile. Time is required before manufacturing of the techniques
becomes industrialised, and tested in a clinical setting.

 

Conclusion

 

Once formed on an orthopaedic implant, biofilms are hugely
problematic with respect to not only the patient’s health, but the financial
cost to the health service as they are difficult to treat with conventional
antibiotics due to a lack of distribution to the area. As preventing
orthopaedic implant infections via the use of laser surface modification is
still at a relatively early stage, there is little meaningful data available on
the practicality of using this technique in
vivo in humans. However, there has been an abundant amount of research
demonstrating that laser surface modification indeed possesses antibacterial
effects and prevents initial adherence.